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Review

The Role of the MiR-181 Family in Hepatocellular Carcinoma

by
Jinbiao Chen
1,*,
Ken Liu
1,2,
Mathew A. Vadas
3,
Jennifer R. Gamble
3 and
Geoffrey W. McCaughan
1,2,*
1
Liver Injury and Cancer Program, Cancer Innovations Centre, Centenary Institute, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia
2
Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia
3
Vascular Biology Program, Healthy Ageing Centre, Centenary Institute, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia
*
Authors to whom correspondence should be addressed.
Cells 2024, 13(15), 1289; https://doi.org/10.3390/cells13151289 (registering DOI)
Submission received: 28 June 2024 / Revised: 28 July 2024 / Accepted: 30 July 2024 / Published: 31 July 2024
(This article belongs to the Collection MicroRNAs in Cancer: From Molecular Mechanisms to Applications in Diagnostic and Therapeutic Opportunities)
Browse Figures
Versions Notes

Abstract

:
Hepatocellular carcinoma (HCC) is the fourth-leading cause of cancer-related death worldwide. Due to the high mortality rate in HCC patients, discovering and developing novel systemic treatment options for HCC is a vital unmet medical need. Among the numerous molecular alterations in HCCs, microRNAs (miRNAs) have been increasingly recognised to play critical roles in hepatocarcinogenesis. We and others have recently revealed that members of the microRNA-181 (miR-181) family were up-regulated in some, though not all, human cirrhotic and HCC tissues—this up-regulation induced epithelial–mesenchymal transition (EMT) in hepatocytes and tumour cells, promoting HCC progression. MiR-181s play crucial roles in governing the fate and function of various cells, such as endothelial cells, immune cells, and tumour cells. Previous reviews have extensively covered these aspects in detail. This review aims to give some insights into miR-181s, their targets and roles in modulating signal transduction pathways, factors regulating miR-181 expression and function, and their roles in HCC.

1. Introduction

Hepatocellular carcinoma (HCC) is the fourth-leading cause of cancer-related death worldwide [1,2,3]. More than 50% of patients are diagnosed with advanced HCC. Unfortunately, only a few first-line drugs are available for patients with advanced HCC, such as sorafenib, lenvatinib, and the combination of atezolizumab and bevacizumab. Due to the high mortality rate and unmet treatment options in HCC patients, discovering and developing novel systemic treatment options for HCC is a vital unmet medical need [4,5,6,7,8,9].
Among the numerous molecular alterations in HCCs, microRNAs (miRNAs) have been increasingly recognised for their crucial roles in hepatocarcinogenesis. After being extensively studied over the past two decades, the precise significance and function of the miRNAs in HCC formation and progression remain elusive [10,11,12,13]. We and others have recently revealed that members of the microRNA-181 (miR-181) family were up-regulated in some, if not all, human cirrhotic and HCC tissues. Up-regulated miR-181 induced hepatocyte epithelial–mesenchymal transition (EMT), promoting HCC progression [10,14,15,16,17,18,19]. MiR-181 has been widely reported to play vital roles in governing the fate and function of endothelial cells, fibroblasts, and immune cells [10,12,20,21,22,23,24], which are all involved in cancer initiation and progression to a certain extent. Previous reviews have extensively covered these aspects in detail. Herein is a concise review of miR-181, its targets and regulations, and especially its overlooked significance in HCC.

2. MiRNAs and the miR-181 Family

MiRNAs are short non-coding RNA (ncRNA) transcripts that are not translated into proteins [25,26,27,28,29,30]. They are typically 20–24 nucleotides in length and play crucial roles in gene expression regulation by targeting mRNA transcripts. The microRNA database, i.e., miRBase (http://www.mirbase.org), currently records 1917 human miRNA precursors, encompassing over 2600 mature miRNAs. Bioinformatics analysis reveals more than 60% of human protein-coding genes contain conserved miRNA-binding sites, indicating their potential regulatory interactions [31,32,33,34]. Remarkably, a single miRNA can regulate multiple mRNA targets, and reciprocally, multiple miRNAs can target a single mRNA, significantly expanding their functional impact [32,33].
The miR-181 family consists of six highly conserved members: miR-181A1 (Figure 1I), miR-181A2 (Figure 1II), miR-181B1 (Figure 1I), miR-181B2 (Figure 1II), miR-181C (Figure 1III), and miR-181D (Figure 1III). All mature miR-181s share the same “seed” sequence, “ACAUUCA” [20], but their mature sequences are different. MiR-181A1 and miR-181A2 are identical in their mature sequences, but they are located on different chromosomes, and the situation is similar for miR-181B1 and miR-181B2 (Figure 1I,II). Indeed, they are independently derived from three clusters located on three chromosomes. MiR-181A/B1 is found in an intron of a non-coding RNA host gene (MIR181A1HG) on chromosome 1 in mice and humans [13,35,36]. MiR-181A/B2 is found in an intron of the NR6A1 gene on chromosome 2 in mice and chromosome 9 in humans [37]. MiR-181C and miR-181D are found in an uncharacterized sequence on chromosome 8 in mice and chromosome 19 in humans and are transcribed independently [20].
The targets of each miR-181 member are largely overlapping, as all mature miR-181s share the same “seed” sequence [10,20,33,39,40]. On the other hand, the 3p and 5p strands of each miR-181 member are different, albeit by only a few nucleotides [10,20,39]. Different pre-miRNA loop nucleotides also regulate the distinct activities of miR-181 members [39]. Thus, each miR-181 member also targets many genes, leading to multiple potential functions [39,40].
Mice lacking each of the three miR-181 clusters have been successfully generated [41,42,43,44,45]. Notably, the greater the deletion of the three miR-181 clusters, the more significant the reduction in mouse size, weight, and vitality [10,20,41,43]. The generation of triple-knockout mice that lack all three miR-181 clusters has proven unattainable due to embryonic lethality. These findings from mouse genetic studies underscore the crucial role of miR-181 family members in regulating cell growth and development [10,20,41,42,43].

3. Targets of miR-181

3.1. Database of miRNA Targets

MiRNAs primarily regulate gene expression by targeting gene transcripts. Understanding the potential function of a specific miRNA often begins with exploring its targets. Several miRNA target prediction tools have been developed, but due to the complex mechanism underlying miRNA action, the predicted targets often vary [46,47]. Some examples of widely used miRNA target prediction tools are (i) TargetScan (v8.0): TargetScan is a popular miRNA target prediction tool that incorporates information about miRNA seed regions and evolutionary conservation to predict potential target sites [40,48]; (ii) miRanda (v3.3a): miRanda utilizes a scoring algorithm that considers sequence complementarity and conservation to predict miRNA targets [49]; (iii) PicTar: PicTar predicts miRNA targets by integrating sequence complementarity, conservation, and the presence of miRNA target site clusters [50]; (iv) RNAhybrid (v2.2.1): RNAhybrid employs a thermodynamic model to predict the energetically most favourable interaction between an miRNA and its target site [51]; (v) PITA: PITA (miRNA target prediction by base pairing probability) predicts miRNA targets by calculating the base pairing probability between miRNAs and potential target sites [52]; (vi) DIANA-microT (v2023): DIANA-microT employs a machine learning approach to predict miRNA targets by integrating multiple features, such as site accessibility and seed region conservation [53]; and (vii) miRDB (v6.0): miRDB is an online database that provides miRNA target predictions based on a machine learning algorithm trained on experimental data [54]. While TargetScan, miRanda, and DIANA-microT are popular and perform well, their false positive and false negative rates are still very high.
Thus, experimental evidence is required to validate miRNA–target interactions [55]. MiRNA research has yielded a growing number of experimentally validated miRNA–target interactions since 1993. These valuable findings have been compiled and summarized in several databases, including miRWalk (v3) and miRTarBase (v9.0 beta) [56,57]. The miRTarBase is a fully manually curated online database that stores validated miRNA targets. The more validated experimental data that accumulate, the more miRNA targets will be verified.
It should also be noted that phenotypic changes of disrupting single miRNA–target interaction are often subtle for the following reasons: (i) most (>90%) of gene transcripts are targeted by more than one miRNA, so most miRNA targets would be down-regulated by less than 50%; (ii) the protein expression of most miRNA targeted genes can vary by two-fold without causing detectable consequences; and (iii) miRNA targets are regulated by many regulatory elements, i.e., buffering effects of the regulatory network [32].

3.2. MiR-181 Targets and Their Roles in Modulating Signal Transduction Pathways

According to TargetScan analysis, it has been predicted that 1371 human transcripts harbour conserved miR-181-5p binding sites. These transcripts collectively contain 1694 conserved binding sites and 960 poorly conserved binding sites. On average, each transcript possesses approximately two binding sites. In the miRTarBase database, there are 2556 documented instances of miR-181, including 1350 validated miR-181 (both miR-181-5p and miR-181-3p) targets. After comparing the predicted miR-181 targets with the validated miR-181 targets, only 435 of the targets overlapped. This discrepancy suggests the limitations of miRNA target predictors due to the intricate mechanisms governing the actions of miRNAs. Interestingly, a new study found an alternative seed match and identified a distinct set of miR-181 targets within the coding sequence of genes, revealing that miR-181 acts primarily through RNA destabilization and translational inhibition [58], but more studies are needed to determine whether the results of this study can eliminate the discrepancy mentioned above.
The miR-181 family has been extensively studied. There are more than 2600 original papers in PubMed that discuss miR-181 to some extent. MiRNA overexpression, knockdown, or BlockmiR are often used to investigate the function of a specific miRNA [20,59]. It is complex to dissect the miR-181 family because it consists of six members, and each member exhibits different expression levels in different types of cells [39,41,42,44,60,61,62]. Furthermore, each member of the miR-181 family shows variable expression levels within a single cell [60]. Thus, miR-181 overexpression experiments should be carefully designed and interpreted, as any of the miR-181 family members could also affect targets of other miR-181 family members [20]. The deletion of miR-181s is more likely to accurately reveal the functions of an miR-181 member. Results obtained with selective inhibition of one miR-181 member by anti-miRs or similar techniques are also difficult to interpret because the effects of these anti-miRs could not be ruled out from silencing other miR-181 family members [20]. Nonetheless, hundreds of genes have been reported as targets of miR-181 [13], for example, Smad7 [63,64,65,66], TGFBR3 [67], TGFBR1 [68,69], Sema3A [70], Bim, ATM, Cbx7 [60,71,72,73], TIMP3 [17,19,74,75], CDH1, CDNK1B, and BCL2 [13]. Interestingly, many of these are important components of signalling pathways, such as TGF-β, PI3K/AKT, MAPK/ERK, Notch, and NFκB, as summarized in several reviews [10,11,13,20]. The role of miR-181 in regulating TGF-β, PI3K/AKT, and MAPK/ERK signalling is briefly discussed below.
A biological process known as epithelial–mesenchymal transition (EMT) involves the loss of polarity and cell–cell adhesion in epithelial cells, leading to the acquisition of migratory and invasive characteristics, ultimately transforming epithelial cells into mesenchymal stem cells [14,76,77,78,79,80]. The EMT plays a significant role in tissue fibrosis, cell migration (tumour metastasis), and the development of chemoresistance in cancer [14,77,79,81,82]. TGF-β has been well documented to induce EMT in many cells, including hepatocytes and tumour cells [14,77,79,82]. Interestingly, miR-181 targets many components of the TGF-beta signalling pathway, e.g., Smad7 [63,64,65,66], TGFBR1 [64,65,68,69,83], and TGFBR3 [67,84]. It has been widely reported that either TGF-β or miR-181 can induce EMT, but the detailed underlying molecular mechanisms responsible for the interaction between TGF-β and miR-181 and their roles in EMT are yet to be fully elucidated. TGF-β suppresses the early stages of tumour development by inducing cell-cycle arrest and apoptosis, but it later promotes tumour progression by increasing proliferative and anti-apoptotic signals via transactivating PI3K/AKT, MAPK/ERK, or other mitogenic pathways [60,85,86]. Our studies and others indicate that miR-181 may similarly play a dual role in the control of proliferation and apoptosis [13,60].
The PI3K/AKT signalling is a ubiquitously growth factor–regulated network. Its aberrant activation often impairs the proper control of cell growth, survival, and metabolism [87]. This pathway has been well documented to be regulated by miR-181 [42,62,72,88,89,90,91,92,93,94,95,96,97,98,99]. MiR-181 targets many components in the PI3K/AKT signalling pathway, such as PTEN, in vitro and in vivo [42,62,72,88,100]. The miR-181-PI3K/AKT axis conceivably plays a vital role in development, regeneration, immune homeostasis, and cardiac remodelling [42,62,100,101]. However, the precise role of miR-181 in regulating the PI3K/AKT signalling network in cancer cells has not been conclusively established, particularly considering the significant influence of various potent exogenous growth stimuli.
The highly conserved MAPK/ERK signalling pathway plays crucial roles in various biological events, including cell proliferation, differentiation, and death [102,103,104]. Gene mutations in the MAPK/ERK signalling network are common in many human tumours [102,103,104]. Approximately one-third of all human cancers, including pancreatic, lung, colorectal, and ovarian cancers, are driven by mutations in the RAS oncogenes (KRAS, HRAS, and NRAS), which are upstream molecules in the MAPK/ERK signalling pathway [102,103,104]. MiR-181 could be a tumour suppressor by reducing Ras signalling [102]. However, more reports show that miR-181 enhances the MAPK/ERK signalling, for example, by targeting DUSP6 [105,106,107,108,109]. Deletion of miR-181a/b1 suppressed the initiation and progression of KRAS mutant–induced primary lung and pancreatic cancer in mice, convincingly demonstrating that miR-181a/b1 mediates Ras signalling. It is unclear whether miR-181s and members of the Ras pathway form a feedback loop.

4. Factors Regulating miR-181 Expression and Function

The vital steps in miRNA biogenesis, such as the processing of miRNA precursors by Dicer, Drosha, and RISC loading, have been largely elucidated [110,111,112,113]. The expression levels and functions of individual miRNAs are regulated by chromosomal alterations (e.g., genetic changes in cancers), transcriptional regulation, epigenetic regulation, post-transcriptional regulation, and competing endogenous RNAs (e.g., miRNA sponging) [110,111,112,113,114,115,116]. The expression of miR-181s is regulated by BMP/TGF-β [13,14,19,63,64,65,67,69,70,83,117], WNT/β-catenin [13,16,118], VEGF signalling, and JAK/STAT3 [88], as well as being sponged by lncRNA SNHG7 and ITGA1 mRNA [73,96,119]. They are explained further below.
Many studies have consistently demonstrated that TGF-β increased the expression levels of miR-181s in multiple cells, including liver cancer cells [13,14,19,63,64,65,67,69,70,83,117]. However, only a few studies examined the transcriptional regulation of miR-181s [120,121]. Lutz CT and his team have successfully mapped human MIR181A1B1 and MIR181A2B2 transcription start sites (TSS) to 78.3 kb and 34.0 kb upstream of the mature miRNAs, respectively. They also identified transcription factor–binding sites of miR-181a/b1 and miR-181a/b2 in 51–201 nucleotides (nt) and 150–301 nt upstream of their TSS, respectively [120]. It has been shown that SMAD3 and SMAD4 could transactivate miR-181a/b2 promoter [120]. GATA3 has also been proposed to transactivate miR-181a/b1 promoter in mutant KRAS–induced cancers, in which TGF-β signalling was involved [121].
It has been reported that the expression level of miR-181 is up-regulated by Wnt/β-catenin signalling, which plays a vital role in the pathogenesis of multiple cancers, including HCC [13,16,118]. It has been reported that the promoter of miR-181a/b2 contains several TCF/LEF binding sites [118]. Interestingly, miR-181s target NLK, TIMP3, and GSK3β, all of which are negative regulators of Wnt/β-catenin signalling [16,74,122], indicating miR-181s and the Wnt/β-catenin signalling may form a positive feedback loop.
In addition to miRNAs, other ncRNAs, such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), have recently emerged as important regulators of miRNA function [25,26,27,28,29,30]. The function of miR-181s could be blocked by lncRNAs and circRNAs such as ANRIL, AFAP1-AS, ZEB1-AS1, ITGA1, Lnc-Nr6a1, CRNDE, circ-ANAPC7, cSMARCA5, and circHMGB2, which act as competing endogenous RNAs (ceRNAs) or miRNA sponges [37,73,75,119,123,124,125,126,127,128,129,130,131,132,133,134]. For example, lncRNA-ANRIL has been proposed to block the inhibitory effects of miR-181s on HMGB1, Sirt1, Prox1, and NFκB, especially in cardiovascular diseases [123,128,130,131,132,133,134].

5. Roles of miR-181 Family in Hepatocellular Carcinoma

5.1. Insights into the Role of miR-181 Family in HCC: Current Discoveries

MiRNAs are extensively recognised for their significant roles in liver diseases, as evidenced by numerous studies [11,14,15,16,17,18,19,60,78,92,96,101,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151]. Their dysregulated expression has been identified in hepatocellular carcinoma (HCC) and is directly associated with tumour initiation and progression [136,147,148,149,150,151,152].
Since Ji J. et al. first reported the role of miR-181a in liver cancer stem cells in 2009 [16], many studies have further confirmed the impact of the miR-181 family in liver disease and liver cancer, albeit via various miR-181 target genes (Table 1) [14,15,16,17,18,19,60,75,96,118,137,153,154,155,156,157,158,159,160,161,162,163,164,165,166]. The importance of miR-181s in liver cancer has been much obscured by a large body of literature reporting the role of other miRs in hepatocarcinogenesis [136,147,148,149,150,151,152]. As such, the role of miR-181s in HCC has been largely unrecognized [18,147,148,152,167,168,169,170]. This can be attributed to many reasons, such as the inconsistent expression profiles of miR-181s in HCC [13,60,136,153], the heterogeneity of HCC [2,3,9], the dual regulatory effects of miR-181 on cancer formation [13], the different role of miR-181s in multiple cells [10,12,20,21,22,23,24], and the complexity of the miR-181 family, as described in Section 3.2 [20].
In 2009, it was reported for the first time that the expression of the miR-181 family was notably elevated in HCC, typically in liver cancer stem cells [16]. Its elevation played a pivotal role in sustaining the population of liver cancer stem cells by inhibiting CDX2, GATA6, and NLK [16]. Interestingly, TGF-β was shown to induce the upregulation of miR-181b, which in turn promoted HCC formation by down-regulating TIMP3 [19]. We found that miR-181a is one of the most amplified miRNAs during TGF-β-induced hepatocyte epithelial–mesenchymal transition (EMT) and is upregulated in fibrotic liver tissues and HCC samples from humans and mice [14].
The importance of miR-181a in human HCC was further enhanced by a seminal study using TCGA-LIHC human samples, where miR-181a was expressed at much higher levels than any other member of the miR-181 family. This paper grouped HCC cases based on multiple molecular parameters, including genomic mutations, DNA methylation, DNA copy number, and mRNA and miR expression. HCC cases were divided into three clusters, i.e., iClusters 1, 2, and 3. Patients in iCluster 1 had the worst prognosis. Strikingly, miR-181a was highly expressed in iCluster 1 compared with iClusters 2 and 3 [60,171].
Global or conditional miR-181 knockout (KO) mice have been generated and made available to the public. They have been widely used to study the roles of miR-181 in immune cells [20,39,41,44,60,62,93,100,101,108,121,146,172,173,174,175]. These valuable genetically engineered mouse models (GEMMs) are just beginning to be used to study miR-181s in cancer [60,121]. Our subsequent experiments using these GEMMS firmly corroborated the vital role of miR-181a/b1 in promoting chemically induced hepatocarcinogenesis [60]. In our experiments, liver tumour size was significantly reduced by 90% in global KO (GKO) or liver-specific KO (LKO) mice of miR-181a/b1 but not in hematopoietic and endothelial lineage-specific KO mice. However, we also showed that tumour induction requires both hepatic and non-hepatic miR-181 overexpression [60]. We showed that EMT was partially reversed in GKO tumours, linking to earlier studies that showed that miR-181a induced hepatocyte EMT [14]. The results obtained from these GEMMs indicate that miR-181a/b1 in tumour cells, but not in tumour-associated cells, plays the dominant role in the formation of DEN-induced liver cancer [60].
We identified CBX7, a known target of miR-181a/b1, as upregulated in miR-181a/b1 KO tumours. Furthermore, key CBX7-regulated genes were also upregulated. Stable upregulated CBX7 expression in vivo (using AAV) inhibited liver tumour progression, whilst hepatic CBX7 deletion restored the progression of LKO liver tumours. Thus, miR-181a/b1 upregulation via CBX7 inhibition in the tumour cells—rather than non-tumour cells within the tumour microenvironment (TME)—led to liver tumour progression [60].
CBX7 protein is a component of the Polycomb repressive complex 1 (PRC1) [60,73,176,177]. CBX7 plays a dual role in oncogenesis [176,177,178,179,180,181,182,183]. It may contribute to cancer progression by inhibiting tumour suppressor genes such as INK4a/ARF [176,177,179,180,181,182,183,184]. However, it has been shown more often to suppress cancer progression by transcriptionally or epigenetically regulating the expression of related proteins, therefore regulating tumour cell proliferation, migration, and invasion [60,71,178,179,185,186,187]. In addition, CBX7 protein may interact with different non-coding RNAs (microRNAs, long non-coding RNAs, circular RNAs) [72,73,187,188]. Post-translational modifications and distinct functions of CBX7 isoforms may add additional functional layers of CBX7 complexity [189,190]. Importantly, the miR-181/CBX7 axis has been widely verified in cancer and stem cells [60,71,72,73,178,191].
According to the results of our animal experiments and analysis of human HCC datasets, CBX7 was clearly shown to inhibit (rather than enhance) liver cancer progression via targeting multiple genes, such as WNT10a, DUSP4, FGFR2, and CCNE1 [60].
In the analysis of these data, we also showed that low miR-181 combined with high CBX7 expression in HCC was associated with the best prognosis and vice versa, with high miR-181 and low CBX7 HCC having the worst prognosis [60]. Furthermore, gene expression profiles of miR-181a/b1 KO HCCs in mice overlapped with low-proliferative periportal-type human HCCs with a good prognosis [60,192]. Thus, miRT-181a/b1-deficient liver tumours may be an ideal model for low-proliferative periportal-type human HCC.

5.2. The miR-181 Family in HCC: Summary and Future Perspectives

In summary, the biological functions of miRNAs and their diagnostic, therapeutic, and prognostic value in liver cancer have been extensively studied to a certain extent [16,18,59,60,135,136,147,149,171]. MiR-181a/b1, especially miR-181a, plays a crucial role in the formation of liver cancer by directly controlling the fate and function of tumour cells [12,20,21,60,71,72,73]. MiR-181s play a crucial pathogenic role in the formation and maintenance of stem cells, including liver cancer stem cells, deserving more studies to explore this aspect [16,17,45,72,99,144,157]. It will be very helpful to further thoroughly examine the expression levels of miR-181 members in different subtypes of HCC and different components of TME in humans. To do that, novel technologies are desired to effectively dissect the heterogeneity of HCC, the complexity of the miR-181 family, and their interactions. The emerging technologies, such as single-cell and spatial multi-omics technologies, including miRNA or miRNA-mRNA co-sequencing, may bring more clarity to miR-181s in human HCC [193,194,195].
Among the signalling pathways modified by the miR-181 family [10,11,13,20], TGF-β-induced EMT signalling has been extensively explored and confirmed to be regulated by the miR-181 family. However, the detailed molecular mechanisms responsible for miR-181-induced EMT are largely unknown. CBX7 also plays a vital role in the regulation of EMT [60,76,185,186,196,197,198]. It is unclear how EMT is regulated by the TGF-β-miR-181-CBX7 axis if validated, and the interaction and regulation between TGF-β, miR-181, CBX7, and EMT is likewise unclear (Figure 2). Answering these questions will deepen our understanding of this axis and may provide new targets for intervention.
Once a significant miRNA and its critical targets are identified to play critical roles in the progression of HCC, several approaches can block miRNA activity, such as anti-miRs and blockmiRs [59,135,199,200,201]. Anti-miRs are antisense oligonucleotides with complementary bases that pair with the miRNA target, leading to miRNA silencing, mainly by sterically blocking the target miRNA [201]. One miRNA can target many, even hundreds, of mRNAs. Thus, it is very challenging for the anti-miR to prevent one specific mRNA only from miR-induced inhibition, as it will target many other mRNAs. BlockmiRs use antisense technology to reduce miRNA activity by specifically binding to the target mRNA rather than miRNA [59,201]. Whether it can be used for miR-181 and its specific targets is yet to be determined.

Author Contributions

Conceptualization, J.C. and G.W.M.; writing—original draft preparation, J.C. and G.W.M.; writing—review and editing, J.C., K.L., G.W.M., J.R.G. and M.A.V.; funding acquisition, J.C., G.W.M., J.R.G. and M.A.V. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Australian National Health and Medical Research Council (Grant ID: 571408) to M.A.V., J.R.G., and G.W.M. and by Cancer Council NSW (Grant ID: RG 20-3) to G.W.M. and J.C.

Acknowledgments

The miR-181 clusters in Figure 1 are screenshots of the UCSC Genome Browser. Due to limited space, many excellent papers we read are not able to be listed in the references.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Siegel, R.L.; Giaquinto, A.N.; Jemal, A. Cancer statistics, 2024. CA Cancer J. Clin. 2024, 74, 12–49. [Google Scholar] [CrossRef] [PubMed]
  2. Villanueva, A. Hepatocellular Carcinoma. N. Engl. J. Med. 2019, 380, 1450–1462. [Google Scholar] [CrossRef] [PubMed]
  3. Vogel, A.; Meyer, T.; Sapisochin, G.; Salem, R.; Saborowski, A. Hepatocellular carcinoma. Lancet 2022, 400, 1345–1362. [Google Scholar] [CrossRef]
  4. Cappuyns, S.; Corbett, V.; Yarchoan, M.; Finn, R.S.; Llovet, J.M. Critical Appraisal of Guideline Recommendations on Systemic Therapies for Advanced Hepatocellular Carcinoma: A Review. JAMA Oncol. 2023, 10, 395–404. [Google Scholar] [CrossRef]
  5. Cerreto, M.; Cardone, F.; Cerrito, L.; Stella, L.; Santopaolo, F.; Pallozzi, M.; Gasbarrini, A.; Ponziani, F.R. The New Era of Systemic Treatment for Hepatocellular Carcinoma: From the First Line to the Optimal Sequence. Curr. Oncol. 2023, 30, 8774–8792. [Google Scholar] [CrossRef]
  6. Ciliberto, D.; Carida, G.; Staropoli, N.; Romeo, C.; Arillotta, G.M.; Napoli, C.; Gervasi, L.; Luciano, F.; Riillo, C.; Tassone, P.; et al. First-line systemic treatment for hepatocellular carcinoma: A systematic review and network meta-analysis. Heliyon 2023, 9, e18696. [Google Scholar] [CrossRef] [PubMed]
  7. Lee, M.M.P.; Chan, L.L.; Chan, S.L. The role of lenvatinib in the era of immunotherapy of hepatocellular carcinoma. J. Liver Cancer 2023, 23, 262–271. [Google Scholar] [CrossRef]
  8. Vogel, A.; Finn, R.S.; Blanchet Zumofen, M.H.; Heuser, C.; Alvarez, J.S.; Leibfried, M.; Mitchell, C.R.; Batson, S.; Redhead, G.; Gaillard, V.E.; et al. Atezolizumab in Combination with Bevacizumab for the Management of Patients with Hepatocellular Carcinoma in the First-Line Setting: Systematic Literature Review and Meta-Analysis. Liver Cancer 2023, 12, 510–520. [Google Scholar] [CrossRef] [PubMed]
  9. Yang, C.; Zhang, H.; Zhang, L.; Zhu, A.X.; Bernards, R.; Qin, W.; Wang, C. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 2023, 20, 203–222. [Google Scholar] [CrossRef]
  10. Bell-Hensley, A.; Das, S.; McAlinden, A. The miR-181 family: Wide-ranging pathophysiological effects on cell fate and function. J. Cell Physiol. 2023, 238, 698–713. [Google Scholar] [CrossRef]
  11. Doghish, A.S.; Elballal, M.S.; Elazazy, O.; Elesawy, A.E.; Elrebehy, M.A.; Shahin, R.K.; Midan, H.M.; Sallam, A.M. The role of miRNAs in liver diseases: Potential therapeutic and clinical applications. Pathol. Res. Pract. 2023, 243, 154375. [Google Scholar] [CrossRef] [PubMed]
  12. Pop-Bica, C.; Pintea, S.; Cojocneanu-Petric, R.; Del Sal, G.; Piazza, S.; Wu, Z.H.; Alencar, A.J.; Lossos, I.S.; Berindan-Neagoe, I.; Calin, G.A. MiR-181 family-specific behavior in different cancers: A meta-analysis view. Cancer Metastasis Rev. 2018, 37, 17–32. [Google Scholar] [CrossRef] [PubMed]
  13. Rezaei, T.; Amini, M.; Hashemi, Z.S.; Mansoori, B.; Rezaei, S.; Karami, H.; Mosafer, J.; Mokhtarzadeh, A.; Baradaran, B. microRNA-181 serves as a dual-role regulator in the development of human cancers. Free Radic. Biol. Med. 2020, 152, 432–454. [Google Scholar] [CrossRef] [PubMed]
  14. Brockhausen, J.; Tay, S.S.; Grzelak, C.A.; Bertolino, P.; Bowen, D.G.; d’Avigdor, W.M.; Teoh, N.; Pok, S.; Shackel, N.; Gamble, J.R.; et al. miR-181a mediates TGF-beta-induced hepatocyte EMT and is dysregulated in cirrhosis and hepatocellular cancer. Liver Int. 2015, 35, 240–253. [Google Scholar] [CrossRef] [PubMed]
  15. Ji, D.; Chen, Z.; Li, M.; Zhan, T.; Yao, Y.; Zhang, Z.; Xi, J.; Yan, L.; Gu, J. MicroRNA-181a promotes tumor growth and liver metastasis in colorectal cancer by targeting the tumor suppressor WIF-1. Mol. Cancer 2014, 13, 86. [Google Scholar] [CrossRef] [PubMed]
  16. Ji, J.; Yamashita, T.; Budhu, A.; Forgues, M.; Jia, H.L.; Li, C.; Deng, C.; Wauthier, E.; Reid, L.M.; Ye, Q.H.; et al. Identification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells. Hepatology 2009, 50, 472–480. [Google Scholar] [CrossRef] [PubMed]
  17. Meng, F.; Glaser, S.S.; Francis, H.; DeMorrow, S.; Han, Y.; Passarini, J.D.; Stokes, A.; Cleary, J.P.; Liu, X.; Venter, J.; et al. Functional analysis of microRNAs in human hepatocellular cancer stem cells. J. Cell Mol. Med. 2012, 16, 160–173. [Google Scholar] [CrossRef] [PubMed]
  18. Nishida, N.; Arizumi, T.; Hagiwara, S.; Ida, H.; Sakurai, T.; Kudo, M. MicroRNAs for the Prediction of Early Response to Sorafenib Treatment in Human Hepatocellular Carcinoma. Liver Cancer 2017, 6, 113–125. [Google Scholar] [CrossRef] [PubMed]
  19. Wang, B.; Hsu, S.H.; Majumder, S.; Kutay, H.; Huang, W.; Jacob, S.T.; Ghoshal, K. TGFbeta-mediated upregulation of hepatic miR-181b promotes hepatocarcinogenesis by targeting TIMP3. Oncogene 2010, 29, 1787–1797. [Google Scholar] [CrossRef] [PubMed]
  20. Grewers, Z.; Krueger, A. MicroRNA miR-181-A Rheostat for TCR Signaling in Thymic Selection and Peripheral T-Cell Function. Int. J. Mol. Sci. 2020, 21, 6200. [Google Scholar] [CrossRef]
  21. Yang, C.; Passos Gibson, V.; Hardy, P. The Role of MiR-181 Family Members in Endothelial Cell Dysfunction and Tumor Angiogenesis. Cells 2022, 11, 1670. [Google Scholar] [CrossRef] [PubMed]
  22. Gu, Y.; Becker, M.A.; Muller, L.; Reuss, K.; Umlauf, F.; Tang, T.; Menger, M.D.; Laschke, M.W. MicroRNAs in Tumor Endothelial Cells: Regulation, Function and Therapeutic Applications. Cells 2023, 12, 1692. [Google Scholar] [CrossRef] [PubMed]
  23. Sun, X.; Sit, A.; Feinberg, M.W. Role of miR-181 family in regulating vascular inflammation and immunity. Trends Cardiovasc. Med. 2014, 24, 105–112. [Google Scholar] [CrossRef] [PubMed]
  24. Sun, T.; Yin, L.; Kuang, H. miR-181a/b-5p regulates human umbilical vein endothelial cell angiogenesis by targeting PDGFRA. Cell Biochem. Funct. 2020, 38, 222–230. [Google Scholar] [CrossRef] [PubMed]
  25. Zeng, Q.; Liu, C.H.; Wu, D.; Jiang, W.; Zhang, N.; Tang, H. LncRNA and circRNA in Patients with Non-Alcoholic Fatty Liver Disease: A Systematic Review. Biomolecules 2023, 13, 560. [Google Scholar] [CrossRef] [PubMed]
  26. You, J.; Xia, H.; Huang, Z.; He, R.; Zhao, X.; Chen, J.; Liu, S.; Xu, Y.; Cui, Y. Research progress of circulating non-coding RNA in diagnosis and treatment of hepatocellular carcinoma. Front. Oncol. 2023, 13, 1204715. [Google Scholar] [CrossRef]
  27. Nemeth, K.; Bayraktar, R.; Ferracin, M.; Calin, G.A. Non-coding RNAs in disease: From mechanisms to therapeutics. Nat. Rev. Genet. 2024, 25, 211–232. [Google Scholar] [CrossRef]
  28. Mattick, J.S.; Amaral, P.P.; Carninci, P.; Carpenter, S.; Chang, H.Y.; Chen, L.L.; Chen, R.; Dean, C.; Dinger, M.E.; Fitzgerald, K.A.; et al. Long non-coding RNAs: Definitions, functions, challenges and recommendations. Nat. Rev. Mol. Cell Biol. 2023, 24, 430–447. [Google Scholar] [CrossRef]
  29. Statello, L.; Guo, C.J.; Chen, L.L.; Huarte, M. Gene regulation by long non-coding RNAs and its biological functions. Nat. Rev. Mol. Cell Biol. 2021, 22, 96–118. [Google Scholar] [CrossRef]
  30. van Zonneveld, A.J.; Zhao, Q.; Rotmans, J.I.; Bijkerk, R. Circulating non-coding RNAs in chronic kidney disease and its complications. Nat. Rev. Nephrol. 2023, 19, 573–586. [Google Scholar] [CrossRef]
  31. Carthew, R.W.; Sontheimer, E.J. Origins and Mechanisms of miRNAs and siRNAs. Cell 2009, 136, 642–655. [Google Scholar] [CrossRef] [PubMed]
  32. Ebert, M.S.; Sharp, P.A. Roles for microRNAs in conferring robustness to biological processes. Cell 2012, 149, 515–524. [Google Scholar] [CrossRef] [PubMed]
  33. Kozomara, A.; Birgaoanu, M.; Griffiths-Jones, S. miRBase: From microRNA sequences to function. Nucleic Acids Res. 2019, 47, D155–D162. [Google Scholar] [CrossRef] [PubMed]
  34. Slack, F.J.; Chinnaiyan, A.M. The Role of Non-coding RNAs in Oncology. Cell 2019, 179, 1033–1055. [Google Scholar] [CrossRef] [PubMed]
  35. Huang, Y.; Chen, L.; Ye, M.; Lin, S.; Zi, Y.; Wang, S. Protein expression and subcellular localization of familial acute myelogenous leukemia-related factor. Oncol. Rep. 2013, 30, 2672–2676. [Google Scholar] [CrossRef] [PubMed]
  36. Lu, J.; Huang, X.; Wang, L.; Li, Y. MiR-181b Inhibits the Proliferation of Lymphoma Rajixi Cell Line by Regulating the Expression of Target Gene FAMLF. Cell. Mol. Biol. 2022, 67, 11–17. [Google Scholar] [CrossRef] [PubMed]
  37. Polo-Generelo, S.; Torres, B.; Guerrero-Martinez, J.A.; Camafeita, E.; Vazquez, J.; Reyes, J.C.; Pintor-Toro, J.A. TGF-beta-Upregulated Lnc-Nr6a1 Acts as a Reservoir of miR-181 and Mediates Assembly of a Glycolytic Complex. Noncoding RNA 2022, 8, 62. [Google Scholar] [CrossRef]
  38. Arnold, M.; Stengel, K.R. Emerging insights into enhancer biology and function. Transcription 2023, 14, 68–87. [Google Scholar] [CrossRef] [PubMed]
  39. Liu, G.; Min, H.; Yue, S.; Chen, C.Z. Pre-miRNA loop nucleotides control the distinct activities of mir-181a-1 and mir-181c in early T cell development. PLoS ONE 2008, 3, e3592. [Google Scholar] [CrossRef]
  40. McGeary, S.E.; Lin, K.S.; Shi, C.Y.; Pham, T.M.; Bisaria, N.; Kelley, G.M.; Bartel, D.P. The biochemical basis of microRNA targeting efficacy. Science 2019, 366, eaav1741. [Google Scholar] [CrossRef]
  41. Fragoso, R.; Mao, T.; Wang, S.; Schaffert, S.; Gong, X.; Yue, S.; Luong, R.; Min, H.; Yashiro-Ohtani, Y.; Davis, M.; et al. Modulating the strength and threshold of NOTCH oncogenic signals by mir-181a-1/b-1. PLoS Genet. 2012, 8, e1002855. [Google Scholar] [CrossRef] [PubMed]
  42. Henao-Mejia, J.; Williams, A.; Goff, L.A.; Staron, M.; Licona-Limon, P.; Kaech, S.M.; Nakayama, M.; Rinn, J.L.; Flavell, R.A. The microRNA miR-181 is a critical cellular metabolic rheostat essential for NKT cell ontogenesis and lymphocyte development and homeostasis. Immunity 2013, 38, 984–997. [Google Scholar] [CrossRef] [PubMed]
  43. Williams, A.; Henao-Mejia, J.; Harman, C.C.; Flavell, R.A. miR-181 and metabolic regulation in the immune system. Cold Spring Harb. Symp. Quant. Biol. 2013, 78, 223–230. [Google Scholar] [CrossRef] [PubMed]
  44. Zietara, N.; Lyszkiewicz, M.; Witzlau, K.; Naumann, R.; Hurwitz, R.; Langemeier, J.; Bohne, J.; Sandrock, I.; Ballmaier, M.; Weiss, S.; et al. Critical role for miR-181a/b-1 in agonist selection of invariant natural killer T cells. Proc. Natl. Acad. Sci. USA 2013, 110, 7407–7412. [Google Scholar] [CrossRef] [PubMed]
  45. Chen, C.Z.; Li, L.; Lodish, H.F.; Bartel, D.P. MicroRNAs modulate hematopoietic lineage differentiation. Science 2004, 303, 83–86. [Google Scholar] [CrossRef] [PubMed]
  46. Arif, K.T.; Okolicsanyi, R.K.; Haupt, L.M.; Griffiths, L.R. A combinatorial in silico approach for microRNA-target identification: Order out of chaos. Biochimie 2021, 187, 121–130. [Google Scholar] [CrossRef] [PubMed]
  47. Luna Buitrago, D.; Lovering, R.C.; Caporali, A. Insights into Online microRNA Bioinformatics Tools. Noncoding RNA 2023, 9, 18. [Google Scholar] [CrossRef]
  48. Lewis, B.P.; Burge, C.B.; Bartel, D.P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005, 120, 15–20. [Google Scholar] [CrossRef] [PubMed]
  49. Enright, A.J.; John, B.; Gaul, U.; Tuschl, T.; Sander, C.; Marks, D.S. MicroRNA targets in Drosophila. Genome Biol. 2003, 5, R1. [Google Scholar] [CrossRef] [PubMed]
  50. Krek, A.; Grun, D.; Poy, M.N.; Wolf, R.; Rosenberg, L.; Epstein, E.J.; MacMenamin, P.; da Piedade, I.; Gunsalus, K.C.; Stoffel, M.; et al. Combinatorial microRNA target predictions. Nat. Genet. 2005, 37, 495–500. [Google Scholar] [CrossRef]
  51. Rehmsmeier, M.; Steffen, P.; Hochsmann, M.; Giegerich, R. Fast and effective prediction of microRNA/target duplexes. RNA 2004, 10, 1507–1517. [Google Scholar] [CrossRef] [PubMed]
  52. Kertesz, M.; Iovino, N.; Unnerstall, U.; Gaul, U.; Segal, E. The role of site accessibility in microRNA target recognition. Nat. Genet. 2007, 39, 1278–1284. [Google Scholar] [CrossRef] [PubMed]
  53. Tastsoglou, S.; Alexiou, A.; Karagkouni, D.; Skoufos, G.; Zacharopoulou, E.; Hatzigeorgiou, A.G. DIANA-microT 2023: Including predicted targets of virally encoded miRNAs. Nucleic Acids Res. 2023, 51, W148–W153. [Google Scholar] [CrossRef] [PubMed]
  54. Wang, X. miRDB: A microRNA target prediction and functional annotation database with a wiki interface. RNA 2008, 14, 1012–1017. [Google Scholar] [CrossRef]
  55. Riolo, G.; Cantara, S.; Marzocchi, C.; Ricci, C. miRNA Targets: From Prediction Tools to Experimental Validation. Methods Protoc. 2020, 4, 1. [Google Scholar] [CrossRef] [PubMed]
  56. Dweep, H.; Gretz, N.; Sticht, C. miRWalk database for miRNA-target interactions. Methods Mol. Biol. 2014, 1182, 289–305. [Google Scholar] [CrossRef] [PubMed]
  57. Hsu, S.D.; Lin, F.M.; Wu, W.Y.; Liang, C.; Huang, W.C.; Chan, W.L.; Tsai, W.T.; Chen, G.Z.; Lee, C.J.; Chiu, C.M.; et al. miRTarBase: A database curates experimentally validated microRNA-target interactions. Nucleic Acids Res. 2011, 39, D163–D169. [Google Scholar] [CrossRef]
  58. Verheyden, N.A.; Klostermann, M.; Bruggemann, M.; Steede, H.M.; Scholz, A.; Amr, S.; Lichtenthaeler, C.; Munch, C.; Schmid, T.; Zarnack, K.; et al. A high-resolution map of functional miR-181 response elements in the thymus reveals the role of coding sequence targeting and an alternative seed match. Nucleic Acids Res. 2024. [Google Scholar] [CrossRef]
  59. Liu, K.; Chen, J.; Zhao, Y.; Boland, J.; Ting, K.K.; Lockwood, G.; McKenzie, C.; Kench, J.; Vadas, M.A.; Gamble, J.R.; et al. Novel miRNA-based drug CD5-2 reduces liver tumor growth in diethylnitrosamine-treated mice by normalizing tumor vasculature and altering immune infiltrate. Front. Immunol. 2023, 14, 1245708. [Google Scholar] [CrossRef]
  60. Chen, J.; Zhao, Y.; Zhang, F.; Li, J.; Boland, J.A.; Cheng, N.C.; Liu, K.; Tiffen, J.C.; Bertolino, P.; Bowen, D.G.; et al. Liver-specific deletion of miR-181ab1 reduces liver tumour progression via upregulation of CBX7. Cell. Mol. Life Sci. 2022, 79, 443. [Google Scholar] [CrossRef]
  61. Cambronne, X.A.; Shen, R.; Auer, P.L.; Goodman, R.H. Capturing microRNA targets using an RNA-induced silencing complex (RISC)-trap approach. Proc. Natl. Acad. Sci. USA 2012, 109, 20473–20478. [Google Scholar] [CrossRef]
  62. Das, S.; Kohr, M.; Dunkerly-Eyring, B.; Lee, D.I.; Bedja, D.; Kent, O.A.; Leung, A.K.; Henao-Mejia, J.; Flavell, R.A.; Steenbergen, C. Divergent Effects of miR-181 Family Members on Myocardial Function Through Protective Cytosolic and Detrimental Mitochondrial microRNA Targets. J. Am. Heart Assoc. 2017, 6, e004694. [Google Scholar] [CrossRef] [PubMed]
  63. Parikh, A.; Lee, C.; Joseph, P.; Marchini, S.; Baccarini, A.; Kolev, V.; Romualdi, C.; Fruscio, R.; Shah, H.; Wang, F.; et al. microRNA-181a has a critical role in ovarian cancer progression through the regulation of the epithelial-mesenchymal transition. Nat. Commun. 2014, 5, 2977. [Google Scholar] [CrossRef]
  64. Ouyang, D.; Xu, L.; Zhang, L.; Guo, D.; Tan, X.; Yu, X.; Qi, J.; Ye, Y.; Liu, Q.; Ma, Y.; et al. MiR-181a-5p regulates 3T3-L1 cell adipogenesis by targeting Smad7 and Tcf7l2. Acta Biochim. Biophys. Sin. 2016, 48, 1034–1041. [Google Scholar] [CrossRef]
  65. Yao, W.; Pan, Z.; Du, X.; Zhang, J.; Li, Q. miR-181b-induced SMAD7 downregulation controls granulosa cell apoptosis through TGF-β signaling by interacting with the TGFBR1 promoter. J. Cell. Physiol. 2018, 233, 6807–6821. [Google Scholar] [CrossRef]
  66. Jankauskas, S.S.; Mone, P.; Avvisato, R.; Varzideh, F.; De Gennaro, S.; Salemme, L.; Macina, G.; Kansakar, U.; Cioppa, A.; Frullone, S.; et al. miR-181c targets Parkin and SMAD7 in human cardiac fibroblasts: Validation of differential microRNA expression in patients with diabetes and heart failure with preserved ejection fraction. Mech. Ageing Dev. 2023, 212, 111818. [Google Scholar] [CrossRef] [PubMed]
  67. Chitsazzadeh, V.; Nguyen, T.N.; de Mingo Pulido, A.; Bittencourt, B.B.; Du, L.; Adelmann, C.H.; Ortiz Rivera, I.; Nguyen, K.A.; Guerra, L.D.; Davis, A.; et al. miR-181a Promotes Multiple Protumorigenic Functions by Targeting TGFβR3. J. Investig. Dermatol. 2022, 142, 1956–1965.e2. [Google Scholar] [CrossRef]
  68. Zhao, H.; Wang, Y.; Zhang, X.; Guo, Y.; Wang, X. miR-181b-5p inhibits endothelial-mesenchymal transition in monocrotaline-induced pulmonary arterial hypertension by targeting endocan and TGFBR1. Toxicol. Appl. Pharmacol. 2020, 386, 114827. [Google Scholar] [CrossRef] [PubMed]
  69. Bhushan, R.; Grunhagen, J.; Becker, J.; Robinson, P.N.; Ott, C.E.; Knaus, P. miR-181a promotes osteoblastic differentiation through repression of TGF-beta signaling molecules. Int. J. Biochem. Cell Biol. 2013, 45, 696–705. [Google Scholar] [CrossRef] [PubMed]
  70. Lai, Y.J.; Tsai, F.C.; Chang, G.J.; Chang, S.H.; Huang, C.C.; Chen, W.J.; Yeh, Y.H. miR-181b targets semaphorin 3A to mediate TGF-β-induced endothelial-mesenchymal transition related to atrial fibrillation. J. Clin. Investig. 2022, 132, e142584. [Google Scholar] [CrossRef]
  71. Mansueto, G.; Forzati, F.; Ferraro, A.; Pallante, P.; Bianco, M.; Esposito, F.; Iaccarino, A.; Troncone, G.; Fusco, A. Identification of a New Pathway for Tumor Progression: MicroRNA-181b Up-Regulation and CBX7 Down-Regulation by HMGA1 Protein. Genes. Cancer 2010, 1, 210–224. [Google Scholar] [CrossRef] [PubMed]
  72. O’Loghlen, A.; Munoz-Cabello, A.M.; Gaspar-Maia, A.; Wu, H.A.; Banito, A.; Kunowska, N.; Racek, T.; Pemberton, H.N.; Beolchi, P.; Lavial, F.; et al. MicroRNA regulation of Cbx7 mediates a switch of Polycomb orthologs during ESC differentiation. Cell Stem Cell 2012, 10, 33–46. [Google Scholar] [CrossRef] [PubMed]
  73. Pei, Y.F.; He, Y.; Hu, L.Z.; Zhou, B.; Xu, H.Y.; Liu, X.Q. The Crosstalk between lncRNA-SNHG7/miRNA-181/cbx7 Modulates Malignant Character in Lung Adenocarcinoma. Am. J. Pathol. 2020, 190, 1343–1354. [Google Scholar] [CrossRef] [PubMed]
  74. Hojilla, C.V.; Kim, I.; Kassiri, Z.; Fata, J.E.; Fang, H.; Khokha, R. Metalloproteinase axes increase beta-catenin signaling in primary mouse mammary epithelial cells lacking TIMP3. J. Cell Sci. 2007, 120, 1050–1060. [Google Scholar] [CrossRef] [PubMed]
  75. Yu, J.; Xu, Q.G.; Wang, Z.G.; Yang, Y.; Zhang, L.; Ma, J.Z.; Sun, S.H.; Yang, F.; Zhou, W.P. Circular RNA cSMARCA5 inhibits growth and metastasis in hepatocellular carcinoma. J. Hepatol. 2018, 68, 1214–1227. [Google Scholar] [CrossRef] [PubMed]
  76. Musavi Shenas, M.H.; Eghbal-Fard, S.; Mehrisofiani, V.; Abd Yazdani, N.; Rahbar Farzam, O.; Marofi, F.; Yousefi, M. MicroRNAs and signaling networks involved in epithelial-mesenchymal transition. J. Cell. Physiol. 2019, 234, 5775–5785. [Google Scholar] [CrossRef] [PubMed]
  77. Bracken, C.P.; Goodall, G.J. The many regulators of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 2022, 23, 89–90. [Google Scholar] [CrossRef] [PubMed]
  78. Yang, X.; Jiang, Z.; Li, Y.; Zhang, Y.; Han, Y.; Gao, L. Non-coding RNAs regulating epithelial-mesenchymal transition: Research progress in liver disease. Biomed. Pharmacother. 2022, 150, 112972. [Google Scholar] [CrossRef] [PubMed]
  79. Akhurst, R.J. From shape-shifting embryonic cells to oncology: The fascinating history of epithelial mesenchymal transition. Semin. Cancer Biol. 2023, 96, 100–114. [Google Scholar] [CrossRef]
  80. Dongre, A.; Weinberg, R.A. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat. Rev. Mol. Cell Biol. 2019, 20, 69–84. [Google Scholar] [CrossRef]
  81. Giannelli, G.; Koudelkova, P.; Dituri, F.; Mikulits, W. Role of epithelial to mesenchymal transition in hepatocellular carcinoma. J. Hepatol. 2016, 65, 798–808. [Google Scholar] [CrossRef]
  82. Fabregat, I.; Caballero-Diaz, D. Transforming Growth Factor-beta-Induced Cell Plasticity in Liver Fibrosis and Hepatocarcinogenesis. Front. Oncol. 2018, 8, 357. [Google Scholar] [CrossRef] [PubMed]
  83. Zhang, Z.; Gao, Y.; Xu, M.Q.; Wang, C.J.; Fu, X.H.; Liu, J.B.; Han, D.X.; Jiang, H.; Yuan, B.; Zhang, J.B. miR-181a regulate porcine preadipocyte differentiation by targeting TGFBR1. Gene 2019, 681, 45–51. [Google Scholar] [CrossRef] [PubMed]
  84. Chen, P.; Pan, J.; Zhang, X.; Shi, Z.; Yang, X. The Role of MicroRNA-181a in Myocardial Fibrosis Following Myocardial Infarction in a Rat Model. Med. Sci. Monit. 2018, 24, 4121–4127. [Google Scholar] [CrossRef] [PubMed]
  85. Fabregat, I.; Moreno-Caceres, J.; Sanchez, A.; Dooley, S.; Dewidar, B.; Giannelli, G.; Ten Dijke, P.; Consortium, I.-L. TGF-beta signalling and liver disease. FEBS J. 2016, 283, 2219–2232. [Google Scholar] [CrossRef] [PubMed]
  86. Richardson, L.; Wilcockson, S.G.; Guglielmi, L.; Hill, C.S. Context-dependent TGFbeta family signalling in cell fate regulation. Nat. Rev. Mol. Cell Biol. 2023, 24, 876–894. [Google Scholar] [CrossRef] [PubMed]
  87. Hoxhaj, G.; Manning, B.D. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat. Rev. Cancer 2020, 20, 74–88. [Google Scholar] [CrossRef] [PubMed]
  88. Iliopoulos, D.; Jaeger, S.A.; Hirsch, H.A.; Bulyk, M.L.; Struhl, K. STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol. Cell 2010, 39, 493–506. [Google Scholar] [CrossRef]
  89. Liu, J.; Xu, D.; Wang, Q.; Zheng, D.; Jiang, X.; Xu, L. LPS induced miR-181a promotes pancreatic cancer cell migration via targeting PTEN and MAP2K4. Dig. Dis. Sci. 2014, 59, 1452–1460. [Google Scholar] [CrossRef]
  90. Wei, Z.; Cui, L.; Mei, Z.; Liu, M.; Zhang, D. miR-181a mediates metabolic shift in colon cancer cells via the PTEN/AKT pathway. FEBS Lett. 2014, 588, 1773–1779. [Google Scholar] [CrossRef]
  91. Zhang, W.L.; Zhang, J.H. miR-181c promotes proliferation via suppressing PTEN expression in inflammatory breast cancer. Int. J. Oncol. 2015, 46, 2011–2020. [Google Scholar] [CrossRef]
  92. Zheng, J.; Wu, C.; Xu, Z.; Xia, P.; Dong, P.; Chen, B.; Yu, F. Hepatic stellate cell is activated by microRNA-181b via PTEN/Akt pathway. Mol. Cell. Biochem. 2015, 398, 1–9. [Google Scholar] [CrossRef] [PubMed]
  93. Blume, J.; Zur Lage, S.; Witzlau, K.; Georgiev, H.; Weiss, S.; Łyszkiewicz, M.; Ziȩtara, N.; Krueger, A. Overexpression of Vα14Jα18 TCR promotes development of iNKT cells in the absence of miR-181a/b-1. Immunol. Cell Biol. 2016, 94, 741–746. [Google Scholar] [CrossRef]
  94. Zhao, L.; Li, Y.; Song, X.; Zhou, H.; Li, N.; Miao, Y.; Jia, L. Upregulation of miR-181c inhibits chemoresistance by targeting ST8SIA4 in chronic myelocytic leukemia. Oncotarget 2016, 7, 60074–60086. [Google Scholar] [CrossRef] [PubMed]
  95. Strotbek, M.; Schmid, S.; Sánchez-González, I.; Boerries, M.; Busch, H.; Olayioye, M.A. miR-181 elevates Akt signaling by co-targeting PHLPP2 and INPP4B phosphatases in luminal breast cancer. Int. J. Cancer 2017, 140, 2310–2320. [Google Scholar] [CrossRef] [PubMed]
  96. Jin, H.; Li, C.; Dong, P.; Huang, J.; Yu, J.; Zheng, J. Circular RNA cMTO1 Promotes PTEN Expression Through Sponging miR-181b-5p in Liver Fibrosis. Front. Cell Dev. Biol. 2020, 8, 714. [Google Scholar] [CrossRef] [PubMed]
  97. Wang, Y.; Lu, J.; Chen, L.; Bian, H.; Hu, J.; Li, D.; Xia, C.; Xu, H. Tumor-Derived EV-Encapsulated miR-181b-5p Induces Angiogenesis to Foster Tumorigenesis and Metastasis of ESCC. Mol. Ther. Nucleic Acids 2020, 20, 421–437. [Google Scholar] [CrossRef] [PubMed]
  98. Pakravan, K.; Mossahebi-Mohammadi, M.; Ghazimoradi, M.H.; Cho, W.C.; Sadeghizadeh, M.; Babashah, S. Monocytes educated by cancer-associated fibroblasts secrete exosomal miR-181a to activate AKT signaling in breast cancer cells. J. Transl. Med. 2022, 20, 559. [Google Scholar] [CrossRef] [PubMed]
  99. Sun, Q.; Ma, L.; Qiao, J.; Wang, X.; Li, J.; Wang, Y.; Tan, A.; Ye, Z.; Wu, Y.; Xi, J.; et al. MiR-181a-5p promotes neural stem cell proliferation and enhances the learning and memory of aged mice. Aging Cell 2023, 22, e13794. [Google Scholar] [CrossRef]
  100. Witkowski, M.; Witkowski, M.; Saffarzadeh, M.; Friebel, J.; Tabaraie, T.; Ta Bao, L.; Chakraborty, A.; Dörner, A.; Stratmann, B.; Tschoepe, D.; et al. Vascular miR-181b controls tissue factor-dependent thrombogenicity and inflammation in type 2 diabetes. Cardiovasc. Diabetol. 2020, 19, 20. [Google Scholar] [CrossRef]
  101. Sandrock, I.; Ziętara, N.; Łyszkiewicz, M.; Oberdörfer, L.; Witzlau, K.; Krueger, A.; Prinz, I. MicroRNA-181a/b-1 Is Not Required for Innate γδ NKT Effector Cell Development. PLoS ONE 2015, 10, e0145010. [Google Scholar] [CrossRef]
  102. Asl, E.R.; Amini, M.; Najafi, S.; Mansoori, B.; Mokhtarzadeh, A.; Mohammadi, A.; Lotfinejad, P.; Bagheri, M.; Shirjang, S.; Lotfi, Z.; et al. Interplay between MAPK/ERK signaling pathway and MicroRNAs: A crucial mechanism regulating cancer cell metabolism and tumor progression. Life Sci. 2021, 278, 119499. [Google Scholar] [CrossRef]
  103. Arthur, J.S.; Ley, S.C. Mitogen-activated protein kinases in innate immunity. Nat. Rev. Immunol. 2013, 13, 679–692. [Google Scholar] [CrossRef] [PubMed]
  104. Lavoie, H.; Gagnon, J.; Therrien, M. ERK signalling: A master regulator of cell behaviour, life and fate. Nat. Rev. Mol. Cell Biol. 2020, 21, 607–632. [Google Scholar] [CrossRef] [PubMed]
  105. Li, G.; Yu, M.; Lee, W.W.; Tsang, M.; Krishnan, E.; Weyand, C.M.; Goronzy, J.J. Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat. Med. 2012, 18, 1518–1524. [Google Scholar] [CrossRef]
  106. Carrella, S.; Barbato, S.; D’Agostino, Y.; Salierno, F.G.; Manfredi, A.; Banfi, S.; Conte, I. TGF-β Controls miR-181/ERK Regulatory Network during Retinal Axon Specification and Growth. PLoS ONE 2015, 10, e0144129. [Google Scholar] [CrossRef] [PubMed]
  107. Mele, F.; Basso, C.; Leoni, C.; Aschenbrenner, D.; Becattini, S.; Latorre, D.; Lanzavecchia, A.; Sallusto, F.; Monticelli, S. ERK phosphorylation and miR-181a expression modulate activation of human memory TH17 cells. Nat. Commun. 2015, 6, 6431. [Google Scholar] [CrossRef]
  108. Schaffert, S.A.; Loh, C.; Wang, S.; Arnold, C.P.; Axtell, R.C.; Newell, E.W.; Nolan, G.; Ansel, K.M.; Davis, M.M.; Steinman, L.; et al. mir-181a-1/b-1 Modulates Tolerance through Opposing Activities in Selection and Peripheral T Cell Function. J. Immunol. 2015, 195, 1470–1479. [Google Scholar] [CrossRef]
  109. Lim, C.X.; Lee, B.; Geiger, O.; Passegger, C.; Beitzinger, M.; Romberger, J.; Stracke, A.; Högenauer, C.; Stift, A.; Stoiber, H.; et al. miR-181a Modulation of ERK-MAPK Signaling Sustains DC-SIGN Expression and Limits Activation of Monocyte-Derived Dendritic Cells. Cell Rep. 2020, 30, 3793–3805.e5. [Google Scholar] [CrossRef]
  110. Lin, S.; Gregory, R.I. MicroRNA biogenesis pathways in cancer. Nat. Rev. Cancer 2015, 15, 321–333. [Google Scholar] [CrossRef]
  111. Shang, R.; Lee, S.; Senavirathne, G.; Lai, E.C. microRNAs in action: Biogenesis, function and regulation. Nat. Rev. Genet. 2023, 24, 816–833. [Google Scholar] [CrossRef]
  112. Treiber, T.; Treiber, N.; Meister, G. Regulation of microRNA biogenesis and its crosstalk with other cellular pathways. Nat. Rev. Mol. Cell Biol. 2019, 20, 5–20. [Google Scholar] [CrossRef] [PubMed]
  113. Shenoy, A.; Blelloch, R.H. Regulation of microRNA function in somatic stem cell proliferation and differentiation. Nat. Rev. Mol. Cell Biol. 2014, 15, 565–576. [Google Scholar] [CrossRef]
  114. Wang, P.; Guo, Q.; Qi, Y.; Hao, Y.; Gao, Y.; Zhi, H.; Zhang, Y.; Sun, Y.; Zhang, Y.; Xin, M.; et al. LncACTdb 3.0: An updated database of experimentally supported ceRNA interactions and personalized networks contributing to precision medicine. Nucleic Acids Res. 2022, 50, D183–D189. [Google Scholar] [CrossRef] [PubMed]
  115. Misiewicz-Krzeminska, I.; Krzeminski, P.; Corchete, L.A.; Quwaider, D.; Rojas, E.A.; Herrero, A.B.; Gutierrez, N.C. Factors Regulating microRNA Expression and Function in Multiple Myeloma. Noncoding RNA 2019, 5, 9. [Google Scholar] [CrossRef] [PubMed]
  116. Dai, E.; Yu, X.; Zhang, Y.; Meng, F.; Wang, S.; Liu, X.; Liu, D.; Wang, J.; Li, X.; Jiang, W. EpimiR: A database of curated mutual regulation between miRNAs and epigenetic modifications. Database 2014, 2014, bau023. [Google Scholar] [CrossRef]
  117. Taylor, M.A.; Sossey-Alaoui, K.; Thompson, C.L.; Danielpour, D.; Schiemann, W.P. TGF-β upregulates miR-181a expression to promote breast cancer metastasis. J. Clin. Investig. 2013, 123, 150–163. [Google Scholar] [CrossRef]
  118. Ji, J.; Yamashita, T.; Wang, X.W. Wnt/beta-catenin signaling activates microRNA-181 expression in hepatocellular carcinoma. Cell Biosci. 2011, 1, 4. [Google Scholar] [CrossRef]
  119. Tan, X.; Banerjee, P.; Liu, X.; Yu, J.; Gibbons, D.L.; Wu, P.; Scott, K.L.; Diao, L.; Zheng, X.; Wang, J.; et al. The epithelial-to-mesenchymal transition activator ZEB1 initiates a prometastatic competing endogenous RNA network. J. Clin. Investig. 2018, 128, 1267–1282. [Google Scholar] [CrossRef]
  120. Presnell, S.R.; Al-Attar, A.; Cichocki, F.; Miller, J.S.; Lutz, C.T. Human natural killer cell microRNA: Differential expression of MIR181A1B1 and MIR181A2B2 genes encoding identical mature microRNAs. Genes. Immun. 2015, 16, 89–98. [Google Scholar] [CrossRef]
  121. Valencia, K.; Erice, O.; Kostyrko, K.; Hausmann, S.; Guruceaga, E.; Tathireddy, A.; Flores, N.M.; Sayles, L.C.; Lee, A.G.; Fragoso, R.; et al. The Mir181ab1 cluster promotes KRAS-driven oncogenesis and progression in lung and pancreas. J. Clin. Investig. 2020, 130, 1879–1895. [Google Scholar] [CrossRef] [PubMed]
  122. Ishitani, T.; Kishida, S.; Hyodo-Miura, J.; Ueno, N.; Yasuda, J.; Waterman, M.; Shibuya, H.; Moon, R.T.; Ninomiya-Tsuji, J.; Matsumoto, K. The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca(2+) pathway to antagonize Wnt/beta-catenin signaling. Mol. Cell Biol. 2003, 23, 131–139. [Google Scholar] [CrossRef] [PubMed]
  123. Sun, C.; Shen, C.; Zhang, Y.; Hu, C. LncRNA ANRIL negatively regulated chitooligosaccharide-induced radiosensitivity in colon cancer cells by sponging miR-181a-5p. Adv. Clin. Exp. Med. 2021, 30, 55–65. [Google Scholar] [CrossRef] [PubMed]
  124. Lv, S.Y.; Shan, T.D.; Pan, X.T.; Tian, Z.B.; Liu, X.S.; Liu, F.G.; Sun, X.G.; Xue, H.G.; Li, X.H.; Han, Y.; et al. The lncRNA ZEB1-AS1 sponges miR-181a-5p to promote colorectal cancer cell proliferation by regulating Wnt/β-catenin signaling. Cell Cycle 2018, 17, 1245–1254. [Google Scholar] [CrossRef] [PubMed]
  125. Chen, H.; Liu, T.; Liu, J.; Feng, Y.; Wang, B.; Wang, J.; Bai, J.; Zhao, W.; Shen, Y.; Wang, X.; et al. Circ-ANAPC7 is Upregulated in Acute Myeloid Leukemia and Appears to Target the MiR-181 Family. Cell. Physiol. Biochem. 2018, 47, 1998–2007. [Google Scholar] [CrossRef] [PubMed]
  126. Wang, Y.; Xu, Z.; Yue, D.; Zeng, Z.; Yuan, W.; Xu, K. Linkage of lncRNA CRNDE sponging miR-181a-5p with aggravated inflammation underlying sepsis. Innate Immun. 2020, 26, 152–161. [Google Scholar] [CrossRef] [PubMed]
  127. Chen, G.; Peng, L.; Zhu, Z.; Du, C.; Shen, Z.; Zang, R.; Su, Y.; Xia, Y.; Tang, W. LncRNA AFAP1-AS Functions as a Competing Endogenous RNA to Regulate RAP1B Expression by sponging miR-181a in the HSCR. Int. J. Med. Sci. 2017, 14, 1022–1030. [Google Scholar] [CrossRef] [PubMed]
  128. He, Z.Y.; Wei, T.H.; Zhang, P.H.; Zhou, J.; Huang, X.Y. Long noncoding RNA-antisense noncoding RNA in the INK4 locus accelerates wound healing in diabetes by promoting lymphangiogenesis via regulating miR-181a/Prox1 axis. J. Cell. Physiol. 2019, 234, 4627–4640. [Google Scholar] [CrossRef] [PubMed]
  129. Zhang, L.X.; Gao, J.; Long, X.; Zhang, P.F.; Yang, X.; Zhu, S.Q.; Pei, X.; Qiu, B.Q.; Chen, S.W.; Lu, F.; et al. The circular RNA circHMGB2 drives immunosuppression and anti-PD-1 resistance in lung adenocarcinomas and squamous cell carcinomas via the miR-181a-5p/CARM1 axis. Mol. Cancer 2022, 21, 110. [Google Scholar] [CrossRef]
  130. Wang, L.; Bi, R.; Li, L.; Zhou, K.; Yin, H. lncRNA ANRIL aggravates the chemoresistance of pancreatic cancer cells to gemcitabine by targeting inhibition of miR-181a and targeting HMGB1-induced autophagy. Aging (Albany NY) 2021, 13, 19272–19281. [Google Scholar] [CrossRef]
  131. Tan, P.; Guo, Y.H.; Zhan, J.K.; Long, L.M.; Xu, M.L.; Ye, L.; Ma, X.Y.; Cui, X.J.; Wang, H.Q. LncRNA-ANRIL inhibits cell senescence of vascular smooth muscle cells by regulating miR-181a/Sirt1. Biochem. Cell Biol. 2019, 97, 571–580. [Google Scholar] [CrossRef] [PubMed]
  132. Guo, F.; Tang, C.; Li, Y.; Liu, Y.; Lv, P.; Wang, W.; Mu, Y. The interplay of LncRNA ANRIL and miR-181b on the inflammation-relevant coronary artery disease through mediating NF-κB signalling pathway. J. Cell. Mol. Med. 2018, 22, 5062–5075. [Google Scholar] [CrossRef] [PubMed]
  133. Song, B.; Wei, D.; Yin, G.; Song, X.; Wang, S.; Jia, S.; Zhang, J.; Li, L.; Wu, X. Critical role of SIRT1 upregulation on the protective effect of lncRNA ANRIL against hypoxia/reoxygenation injury in H9c2 cardiomyocytes. Mol. Med. Rep. 2021, 24, 547. [Google Scholar] [CrossRef]
  134. Xu, Y.; Chen, J.; Wang, M.; Yu, R.; Zou, W.; Shen, W. Mechanism of lncRNA-ANRIL/miR-181b in autophagy of cardiomyocytes in mice with uremia by targeting ATG5. PLoS ONE 2021, 16, e0256734. [Google Scholar] [CrossRef] [PubMed]
  135. Rupaimoole, R.; Slack, F.J. MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases. Nat. Rev. Drug Discov. 2017, 16, 203–222. [Google Scholar] [CrossRef]
  136. Abu-Shahba, N.; Hegazy, E.; Khan, F.M.; Elhefnawi, M. In Silico Analysis of MicroRNA Expression Data in Liver Cancer. Cancer Inform. 2023, 22, 11769351231171743. [Google Scholar] [CrossRef] [PubMed]
  137. Xiao, H.; Du, X.; Tao, Z.; Jing, N.; Bao, S.; Gao, W.Q.; Dong, B.; Fang, Y.X. Taurine Inhibits Ferroptosis Mediated by the Crosstalk between Tumor Cells and Tumor-Associated Macrophages in Prostate Cancer. Adv. Sci. 2024, 11, e2303894. [Google Scholar] [CrossRef] [PubMed]
  138. Wang, B.; Li, W.; Guo, K.; Xiao, Y.; Wang, Y.; Fan, J. miR-181b promotes hepatic stellate cells proliferation by targeting p27 and is elevated in the serum of cirrhosis patients. Biochem. Biophys. Res. Commun. 2012, 421, 4–8. [Google Scholar] [CrossRef]
  139. Wang, Y.; Zhu, K.; Yu, W.; Wang, H.; Liu, L.; Wu, Q.; Li, S.; Guo, J. MiR-181b regulates steatosis in nonalcoholic fatty liver disease via targeting SIRT1. Biochem. Biophys. Res. Commun. 2017, 493, 227–232. [Google Scholar] [CrossRef]
  140. Kim, C.; Jadhav, R.R.; Gustafson, C.E.; Smithey, M.J.; Hirsch, A.J.; Uhrlaub, J.L.; Hildebrand, W.H.; Nikolich-Žugich, J.; Weyand, C.M.; Goronzy, J.J. Defects in Antiviral T Cell Responses Inflicted by Aging-Associated miR-181a Deficiency. Cell Rep. 2019, 29, 2202–2216.e5. [Google Scholar] [CrossRef]
  141. Zhou, B.; Li, C.; Qi, W.; Zhang, Y.; Zhang, F.; Wu, J.X.; Hu, Y.N.; Wu, D.M.; Liu, Y.; Yan, T.T.; et al. Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity. Diabetologia 2012, 55, 2032–2043. [Google Scholar] [CrossRef] [PubMed]
  142. Yang, J.; He, Y.; Zhai, N.; Ding, S.; Li, J.; Peng, Z. MicroRNA-181a inhibits autophagy by targeting Atg5 in hepatocellular carcinoma. Front. Biosci. 2018, 23, 388–396. [Google Scholar] [CrossRef]
  143. Patra, T.; Meyer, K.; Ray, R.B.; Ray, R. Hepatitis C Virus Mediated Inhibition of miR-181c Activates ATM Signaling and Promotes Hepatocyte Growth. Hepatology 2020, 71, 780–793. [Google Scholar] [CrossRef]
  144. Oishi, N.; Wang, X.W. Novel therapeutic strategies for targeting liver cancer stem cells. Int. J. Biol. Sci. 2011, 7, 517–535. [Google Scholar] [CrossRef]
  145. Zhao, J.; Gong, A.Y.; Zhou, R.; Liu, J.; Eischeid, A.N.; Chen, X.M. Downregulation of PCAF by miR-181a/b provides feedback regulation to TNF-α-induced transcription of proinflammatory genes in liver epithelial cells. J. Immunol. 2012, 188, 1266–1274. [Google Scholar] [CrossRef] [PubMed]
  146. Akiyoshi, K.; Boersma, G.J.; Johnson, M.D.; Velasquez, F.C.; Dunkerly-Eyring, B.; O’Brien, S.; Yamaguchi, A.; Steenbergen, C.; Tamashiro, K.L.K.; Das, S. Role of miR-181c in Diet-induced obesity through regulation of lipid synthesis in liver. PLoS ONE 2021, 16, e0256973. [Google Scholar] [CrossRef] [PubMed]
  147. Mallela, V.R.; Rajtmajerová, M.; Trailin, A.; Liška, V.; Hemminki, K.; Ambrozkiewicz, F. miRNA and lncRNA as potential tissue biomarkers in hepatocellular carcinoma. Noncoding RNA Res. 2024, 9, 24–32. [Google Scholar] [CrossRef] [PubMed]
  148. Lv, Y.; Sun, X. Role of miRNA in pathogenesis, diagnosis, and prognosis in hepatocellular carcinoma. Chem. Biol. Drug Des. 2024, 103, e14352. [Google Scholar] [CrossRef] [PubMed]
  149. Moldogazieva, N.T.; Zavadskiy, S.P.; Astakhov, D.V.; Sologova, S.S.; Margaryan, A.G.; Safrygina, A.A.; Smolyarchuk, E.A. Differentially expressed non-coding RNAs and their regulatory networks in liver cancer. Heliyon 2023, 9, e19223. [Google Scholar] [CrossRef]
  150. Jouve, M.; Carpentier, R.; Kraiem, S.; Legrand, N.; Sobolewski, C. MiRNAs in Alcohol-Related Liver Diseases and Hepatocellular Carcinoma: A Step toward New Therapeutic Approaches? Cancers 2023, 15, 5557. [Google Scholar] [CrossRef]
  151. El-Aziz, M.K.A.; Dawoud, A.; Kiriacos, C.J.; Fahmy, S.A.; Hamdy, N.M.; Youness, R.A. Decoding hepatocarcinogenesis from a noncoding RNAs perspective. J. Cell. Physiol. 2023, 238, 1982–2009. [Google Scholar] [CrossRef]
  152. Hajizadeh, M.; Hajizadeh, F.; Ghaffarei, S.; Amin Doustvandi, M.; Hajizadeh, K.; Yaghoubi, S.M.; Mohammadnejad, F.; Khiabani, N.A.; Mousavi, P.; Baradaran, B. MicroRNAs and their vital role in apoptosis in hepatocellular carcinoma: miRNA-based diagnostic and treatment methods. Gene 2023, 888, 147803. [Google Scholar] [CrossRef] [PubMed]
  153. Song, M.K.; Park, Y.K.; Ryu, J.C. Polycyclic aromatic hydrocarbon (PAH)-mediated upregulation of hepatic microRNA-181 family promotes cancer cell migration by targeting MAPK phosphatase-5, regulating the activation of p38 MAPK. Toxicol. Appl. Pharmacol. 2013, 273, 130–139. [Google Scholar] [CrossRef]
  154. Zou, C.; Li, Y.; Cao, Y.; Zhang, J.; Jiang, J.; Sheng, Y.; Wang, S.; Huang, A.; Tang, H. Up-regulated MicroRNA-181a induces carcinogenesis in hepatitis B virus-related hepatocellular carcinoma by targeting E2F5. BMC Cancer 2014, 14, 97. [Google Scholar] [CrossRef] [PubMed]
  155. Chang, S.; Chen, B.; Wang, X.; Wu, K.; Sun, Y. Long non-coding RNA XIST regulates PTEN expression by sponging miR-181a and promotes hepatocellular carcinoma progression. BMC Cancer 2017, 17, 248. [Google Scholar] [CrossRef]
  156. Zhuang, X.; Chen, Y.; Wu, Z.; Xu, Q.; Chen, M.; Shao, M.; Cao, X.; Zhou, Y.; Xie, M.; Shi, Y.; et al. Mitochondrial miR-181a-5p promotes glucose metabolism reprogramming in liver cancer by regulating the electron transport chain. Carcinogenesis 2020, 41, 972–983. [Google Scholar] [CrossRef]
  157. Arzumanyan, A.; Friedman, T.; Ng, I.O.; Clayton, M.M.; Lian, Z.; Feitelson, M.A. Does the hepatitis B antigen HBx promote the appearance of liver cancer stem cells? Cancer Res. 2011, 71, 3701–3708. [Google Scholar] [CrossRef]
  158. Li, J.P.; Zheng, J.Y.; Du, J.J.; Zhang, R.; Yang, A.G. What is the relationship among microRNA-181, epithelial cell-adhesion molecule (EpCAM) and beta-catenin in hepatic cancer stem cells. Hepatology 2009, 50, 2047–2048, author reply 2448. [Google Scholar] [CrossRef]
  159. Abd ElAziz, O.N.; Elfiky, A.M.; Yassin, M.A.; Abd El-Hakam, F.E.; Saleh, E.M.; El-Hefnawi, M.; Mohamed, R.H. In Silico and In Vivo Evaluation of microRNA-181c-5p’s Role in Hepatocellular Carcinoma. Genes. 2022, 13, 2343. [Google Scholar] [CrossRef] [PubMed]
  160. Liu, J.; Liu, R.; Liu, Y.; Li, L.; Cao, H.; Liu, J.; Cao, G. ZSCAN16-AS1 expedites hepatocellular carcinoma progression via modulating the miR-181c-5p/SPAG9 axis to activate the JNK pathway. Cell Cycle 2021, 20, 1134–1146. [Google Scholar] [CrossRef]
  161. Korhan, P.; Erdal, E.; Atabey, N. MiR-181a-5p is downregulated in hepatocellular carcinoma and suppresses motility, invasion and branching-morphogenesis by directly targeting c-Met. Biochem. Biophys. Res. Commun. 2014, 450, 1304–1312. [Google Scholar] [CrossRef]
  162. Cui, X.W.; Qian, Z.L.; Li, C.; Cui, S.C. Identification of miRNA and mRNA expression profiles by PCR microarray in hepatitis B virus-associated hepatocellular carcinoma. Mol. Med. Rep. 2018, 18, 5123–5132. [Google Scholar] [CrossRef]
  163. Bi, J.G.; Zheng, J.F.; Li, Q.; Bao, S.Y.; Yu, X.F.; Xu, P.; Liao, C.X. MicroRNA-181a-5p suppresses cell proliferation by targeting Egr1 and inhibiting Egr1/TGF-β/Smad pathway in hepatocellular carcinoma. Int. J. Biochem. Cell Biol. 2019, 106, 107–116. [Google Scholar] [CrossRef]
  164. Azumi, J.; Tsubota, T.; Sakabe, T.; Shiota, G. miR-181a induces sorafenib resistance of hepatocellular carcinoma cells through downregulation of RASSF1 expression. Cancer Sci. 2016, 107, 1256–1262. [Google Scholar] [CrossRef] [PubMed]
  165. Zhuo, L.; Liu, J.; Wang, B.; Gao, M.; Huang, A. Differential miRNA expression profiles in hepatocellular carcinoma cells and drug-resistant sublines. Oncol. Rep. 2013, 29, 555–562. [Google Scholar] [CrossRef]
  166. Azar, F.; Courtet, K.; Dekky, B.; Bonnier, D.; Dameron, O.; Colige, A.; Legagneux, V.; Théret, N. Integration of miRNA-regulatory networks in hepatic stellate cells identifies TIMP3 as a key factor in chronic liver disease. Liver Int. 2020, 40, 2021–2033. [Google Scholar] [CrossRef] [PubMed]
  167. Tavakoli Pirzaman, A.; Alishah, A.; Babajani, B.; Ebrahimi, P.; Sheikhi, S.A.; Moosaei, F.; Salarfar, A.; Doostmohamadian, S.; Kazemi, S. The Role of microRNAs in Hepatocellular Cancer: A Narrative Review Focused on Tumor Microenvironment and Drug Resistance. Technol. Cancer Res. Treat. 2024, 23, 15330338241239188. [Google Scholar] [CrossRef] [PubMed]
  168. Farsi, N.R.; Naghipour, B.; Shahabi, P.; Safaralizadeh, R.; Hajiasgharzadeh, K.; Dastmalchi, N.; Alipour, M.R. The role of microRNAs in hepatocellular carcinoma: Therapeutic targeting of tumor suppressor and oncogenic genes. Clin. Exp. Hepatol. 2023, 9, 307–319. [Google Scholar] [CrossRef]
  169. Zhou, Y.; Liu, F.; Ma, C.; Cheng, Q. Involvement of microRNAs and their potential diagnostic, therapeutic, and prognostic role in hepatocellular carcinoma. J. Clin. Lab. Anal. 2022, 36, e24673. [Google Scholar] [CrossRef]
  170. Khan, S.; Zhang, D.Y.; Zhang, J.Y.; Hayat, M.K.; Ren, J.; Nasir, S.; Fawad, M.; Bai, Q. The Key Role of microRNAs in Initiation and Progression of Hepatocellular Carcinoma. Front. Oncol. 2022, 12, 950374. [Google Scholar] [CrossRef]
  171. Wheeler, D.A.; Roberts, L.R.; Cancer Genome Atlas Research Network. Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. Cell 2017, 169, 1327–1341. [Google Scholar] [CrossRef]
  172. Lee, C.W.; Wohlan, K.; Dallmann, I.; Förster, R.; Ganser, A.; Krueger, A.; Scherr, M.; Eder, M.; Koenecke, C. miR-181a Expression in Donor T Cells Modulates Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation. J. Immunol. 2016, 196, 3927–3934. [Google Scholar] [CrossRef] [PubMed]
  173. Roman, B.; Kaur, P.; Ashok, D.; Kohr, M.; Biswas, R.; O’Rourke, B.; Steenbergen, C.; Das, S. Nuclear-mitochondrial communication involving miR-181c plays an important role in cardiac dysfunction during obesity. J. Mol. Cell. Cardiol. 2020, 144, 87–96. [Google Scholar] [CrossRef] [PubMed]
  174. Łyszkiewicz, M.; Winter, S.J.; Witzlau, K.; Föhse, L.; Brownlie, R.; Puchałka, J.; Verheyden, N.A.; Kunze-Schumacher, H.; Imelmann, E.; Blume, J.; et al. miR-181a/b-1 controls thymic selection of Treg cells and tunes their suppressive capacity. PLoS Biol. 2019, 17, e2006716. [Google Scholar] [CrossRef] [PubMed]
  175. Belkaya, S.; van Oers, N.S. Transgenic expression of microRNA-181d augments the stress-sensitivity of CD4(+)CD8(+) thymocytes. PLoS ONE 2014, 9, e85274. [Google Scholar] [CrossRef] [PubMed]
  176. Parreno, V.; Martinez, A.M.; Cavalli, G. Mechanisms of Polycomb group protein function in cancer. Cell Res. 2022, 32, 231–253. [Google Scholar] [CrossRef] [PubMed]
  177. Aloia, L.; Di Stefano, B.; Di Croce, L. Polycomb complexes in stem cells and embryonic development. Development 2013, 140, 2525–2534. [Google Scholar] [CrossRef] [PubMed]
  178. Czerwinska, P.; Mackiewicz, A.A. Mining Transcriptomic Data to Uncover the Association between CBX Family Members and Cancer Stemness. Int. J. Mol. Sci. 2022, 23, 13083. [Google Scholar] [CrossRef] [PubMed]
  179. Li, J.; Ouyang, T.; Li, M.; Hong, T.; Alriashy, M.; Meng, W.; Zhang, N. CBX7 is Dualistic in Cancer Progression Based on its Function and Molecular Interactions. Front. Genet. 2021, 12, 740794. [Google Scholar] [CrossRef]
  180. Blackledge, N.P.; Klose, R.J. The molecular principles of gene regulation by Polycomb repressive complexes. Nat. Rev. Mol. Cell Biol. 2021, 22, 815–833. [Google Scholar] [CrossRef]
  181. Jung, J.; Buisman, S.C.; Weersing, E.; Dethmers-Ausema, A.; Zwart, E.; Schepers, H.; Dekker, M.R.; Lazare, S.S.; Hammerl, F.; Skokova, Y.; et al. CBX7 Induces Self-Renewal of Human Normal and Malignant Hematopoietic Stem and Progenitor Cells by Canonical and Non-canonical Interactions. Cell Rep. 2019, 26, 1906–1918. [Google Scholar] [CrossRef]
  182. Klauke, K.; Radulović, V.; Broekhuis, M.; Weersing, E.; Zwart, E.; Olthof, S.; Ritsema, M.; Bruggeman, S.; Wu, X.; Helin, K.; et al. Polycomb Cbx family members mediate the balance between haematopoietic stem cell self-renewal and differentiation. Nat. Cell Biol. 2013, 15, 353–362. [Google Scholar] [CrossRef] [PubMed]
  183. Zhang, X.W.; Zhang, L.; Qin, W.; Yao, X.H.; Zheng, L.Z.; Liu, X.; Li, J.; Guo, W.J. Oncogenic role of the chromobox protein CBX7 in gastric cancer. J. Exp. Clin. Cancer Res. 2010, 29, 114. [Google Scholar] [CrossRef]
  184. Scott, C.L.; Gil, J.; Hernando, E.; Teruya-Feldstein, J.; Narita, M.; Martínez, D.; Visakorpi, T.; Mu, D.; Cordon-Cardo, C.; Peters, G.; et al. Role of the chromobox protein CBX7 in lymphomagenesis. Proc. Natl. Acad. Sci. USA 2007, 104, 5389–5394. [Google Scholar] [CrossRef]
  185. Li, J.; Alvero, A.B.; Nuti, S.; Tedja, R.; Roberts, C.M.; Pitruzzello, M.; Li, Y.; Xiao, Q.; Zhang, S.; Gan, Y.; et al. CBX7 binds the E-box to inhibit TWIST-1 function and inhibit tumorigenicity and metastatic potential. Oncogene 2020, 39, 3965–3979. [Google Scholar] [CrossRef] [PubMed]
  186. Federico, A.; Sepe, R.; Cozzolino, F.; Piccolo, C.; Iannone, C.; Iacobucci, I.; Pucci, P.; Monti, M.; Fusco, A. The complex CBX7-PRMT1 has a critical role in regulating E-cadherin gene expression and cell migration. Biochim. Biophys. Acta Gene Regul. Mech. 2019, 1862, 509–521. [Google Scholar] [CrossRef] [PubMed]
  187. Yap, K.L.; Li, S.; Muñoz-Cabello, A.M.; Raguz, S.; Zeng, L.; Mujtaba, S.; Gil, J.; Walsh, M.J.; Zhou, M.M. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol. Cell 2010, 38, 662–674. [Google Scholar] [CrossRef]
  188. Rapisarda, V.; Borghesan, M.; Miguela, V.; Encheva, V.; Snijders, A.P.; Lujambio, A.; O’Loghlen, A. Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway. Cell Rep. 2017, 18, 2480–2493. [Google Scholar] [CrossRef]
  189. Cho, K.W.; Andrade, M.; Zhang, Y.; Yoon, Y.S. Mammalian CBX7 isoforms p36 and p22 exhibit differential responses to serum, varying functions for proliferation, and distinct subcellular localization. Sci. Rep. 2020, 10, 8061. [Google Scholar] [CrossRef]
  190. Wu, H.A.; Balsbaugh, J.L.; Chandler, H.; Georgilis, A.; Zullow, H.; Shabanowitz, J.; Hunt, D.F.; Gil, J.; Peters, G.; Bernstein, E. Mitogen-activated protein kinase signaling mediates phosphorylation of polycomb ortholog Cbx7. J. Biol. Chem. 2013, 288, 36398–36408. [Google Scholar] [CrossRef]
  191. Ortega-Ribera, M.; Gibert-Ramos, A.; Abad-Jordà, L.; Magaz, M.; Téllez, L.; Paule, L.; Castillo, E.; Pastó, R.; de Souza Basso, B.; Olivas, P.; et al. Increased sinusoidal pressure impairs liver endothelial mechanosensing, uncovering novel biomarkers of portal hypertension. JHEP Rep. 2023, 5, 100722. [Google Scholar] [CrossRef] [PubMed]
  192. Desert, R.; Rohart, F.; Canal, F.; Sicard, M.; Desille, M.; Renaud, S.; Turlin, B.; Bellaud, P.; Perret, C.; Clement, B.; et al. Human hepatocellular carcinomas with a periportal phenotype have the lowest potential for early recurrence after curative resection. Hepatology 2017, 66, 1502–1518. [Google Scholar] [CrossRef] [PubMed]
  193. Wang, N.; Zheng, J.; Chen, Z.; Liu, Y.; Dura, B.; Kwak, M.; Xavier-Ferrucio, J.; Lu, Y.C.; Zhang, M.; Roden, C.; et al. Single-cell microRNA-mRNA co-sequencing reveals non-genetic heterogeneity and mechanisms of microRNA regulation. Nat. Commun. 2019, 10, 95. [Google Scholar] [CrossRef] [PubMed]
  194. Nagarajan, M.B.; Tentori, A.M.; Zhang, W.C.; Slack, F.J.; Doyle, P.S. Spatially resolved and multiplexed MicroRNA quantification from tissue using nanoliter well arrays. Microsyst. Nanoeng. 2020, 6, 51. [Google Scholar] [CrossRef] [PubMed]
  195. Vandereyken, K.; Sifrim, A.; Thienpont, B.; Voet, T. Methods and applications for single-cell and spatial multi-omics. Nat. Rev. Genet. 2023, 24, 494–515. [Google Scholar] [CrossRef] [PubMed]
  196. Tian, P.; Zhang, C.; Ma, C.; Ding, L.; Tao, N.; Ning, L.; Wang, Y.; Yong, X.; Yan, Q.; Lin, X.; et al. Decreased chromobox homologue 7 expression is associated with epithelial-mesenchymal transition and poor prognosis in cervical cancer. Open Med. 2021, 16, 410–418. [Google Scholar] [CrossRef] [PubMed]
  197. Federico, A.; Pallante, P.; Bianco, M.; Ferraro, A.; Esposito, F.; Monti, M.; Cozzolino, M.; Keller, S.; Fedele, M.; Leone, V.; et al. Chromobox protein homologue 7 protein, with decreased expression in human carcinomas, positively regulates E-cadherin expression by interacting with the histone deacetylase 2 protein. Cancer Res. 2009, 69, 7079–7087. [Google Scholar] [CrossRef]
  198. Huang, Z.; Liu, J.; Yang, J.; Yan, Y.; Yang, C.; He, X.; Huang, R.; Tan, M.; Wu, D.; Yan, J.; et al. PDE4B Induces Epithelial-to-Mesenchymal Transition in Bladder Cancer Cells and Is Transcriptionally Suppressed by CBX7. Front. Cell Dev. Biol. 2021, 9, 783050. [Google Scholar] [CrossRef]
  199. Bayraktar, E.; Bayraktar, R.; Oztatlici, H.; Lopez-Berestein, G.; Amero, P.; Rodriguez-Aguayo, C. Targeting miRNAs and Other Non-Coding RNAs as a Therapeutic Approach: An Update. Noncoding RNA 2023, 9, 27. [Google Scholar] [CrossRef]
  200. Overby, S.J.; Cerro-Herreros, E.; Gonzalez-Martinez, I.; Varela, M.A.; Seoane-Miraz, D.; Jad, Y.; Raz, R.; Moller, T.; Perez-Alonso, M.; Wood, M.J.; et al. Proof of concept of peptide-linked blockmiR-induced MBNL functional rescue in myotonic dystrophy type 1 mouse model. Mol. Ther. Nucleic Acids 2022, 27, 1146–1155. [Google Scholar] [CrossRef]
  201. Lima, J.F.; Cerqueira, L.; Figueiredo, C.; Oliveira, C.; Azevedo, N.F. Anti-miRNA oligonucleotides: A comprehensive guide for design. RNA Biol. 2018, 15, 338–352. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. Chromosomal position of the three miR-181 clusters. (I) Mir181A/B1 and (II) mir181A/B2 transcription start sites (TSS) have been mapped to 78.3 kb and 34.0 kb upstream of the mature miRNAs, respectively, consistent with the position of H3K27Ac (in blue/pink), which is associated with the higher activation of transcription [38]. (III) The putative TSS of miR181C/D might be 9 kb upstream of the miR-181C/D precursor. Please note that the clusters are not drawn to scale.
Figure 1. Chromosomal position of the three miR-181 clusters. (I) Mir181A/B1 and (II) mir181A/B2 transcription start sites (TSS) have been mapped to 78.3 kb and 34.0 kb upstream of the mature miRNAs, respectively, consistent with the position of H3K27Ac (in blue/pink), which is associated with the higher activation of transcription [38]. (III) The putative TSS of miR181C/D might be 9 kb upstream of the miR-181C/D precursor. Please note that the clusters are not drawn to scale.
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Figure 2. The TGF-β-miR-181-CBX7 axis. Arrow end lines mean activating, inducing, promoting; blunt end lines mean inhibiting, blocking, or reducing. EMT: epithelial–mesenchymal transition. Pathways such as Wnt-TCF/LEF-miR-181-CDX2/GATA6/NLK and KRAS-GATA3-miR-181a/b1 are partially shown. Several miR-181 targets other than CBX7 are also shown (in grey).
Figure 2. The TGF-β-miR-181-CBX7 axis. Arrow end lines mean activating, inducing, promoting; blunt end lines mean inhibiting, blocking, or reducing. EMT: epithelial–mesenchymal transition. Pathways such as Wnt-TCF/LEF-miR-181-CDX2/GATA6/NLK and KRAS-GATA3-miR-181a/b1 are partially shown. Several miR-181 targets other than CBX7 are also shown (in grey).
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Table 1. The miR-181 family in HCC 1,2.
Table 1. The miR-181 family in HCC 1,2.
MemberExpressionTargetEffectReference
miR-181aUpCBX7pro-tumoral[14,60] *
miR-181aUpPTENpro-tumoral[155]
miR-181aUpE2F5pro-tumoral[154]
miR-181a-5pUpmt-CYB, mt-CO2pro-tumoral[156]
miR-181b/dUpTIMP3pro-tumoral[19]
miR-181b-5pUpTIMP3pro-tumoral[75]
miR-181a/bUpTIMP3, RASSF1A, NLKpro-tumoral[17]
miR-181a/bUpunknownpro-tumoral[157]
miR-181a/b/cUpCDX2, GATA6, NLKpro-tumoral[16,118,158]
miR-181a/b/dUpMKP-5pro-tumoral[153]
miR-181c-5pUpFbxl3, SPAG9pro-tumoral[159,160]
miR-181a-5pDownc-Metanti-tumoral[161]
miR-181a-5pDownIGF2, CCNE1anti-tumoral[162]
miR-181a-5pDownEgr1anti-tumoral[163]
miR-181aUpRASSF1drug resistance [164]
miR-181a/dUpunknowndrug resistance[165]
miR-181a-5pUpunknowndrug response[18]
miR-181a Sirt1hepatic insulin sensitivity[141]
miR-181b Sirt1hepatic steatosis[139]
miR-181b-5pUpPTENactivating HSC[96]
miR-181b-5pUpTIMP3activating HSC[166]
1 This table does not list all studies. 2 It also includes a few of non-HCC papers, which may be helpful for understanding roles of miR-181s in HCC. * Tissue-specific miR-181ab1 knockout mice were used.
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Chen, J.; Liu, K.; Vadas, M.A.; Gamble, J.R.; McCaughan, G.W. The Role of the MiR-181 Family in Hepatocellular Carcinoma. Cells 2024, 13, 1289. https://doi.org/10.3390/cells13151289

AMA Style

Chen J, Liu K, Vadas MA, Gamble JR, McCaughan GW. The Role of the MiR-181 Family in Hepatocellular Carcinoma. Cells. 2024; 13(15):1289. https://doi.org/10.3390/cells13151289

Chicago/Turabian Style

Chen, Jinbiao, Ken Liu, Mathew A. Vadas, Jennifer R. Gamble, and Geoffrey W. McCaughan. 2024. "The Role of the MiR-181 Family in Hepatocellular Carcinoma" Cells 13, no. 15: 1289. https://doi.org/10.3390/cells13151289

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