Cancers

2023

Jump to: 2022, 2021

14 pages, 2735 KiB

Open AccessArticle

Dual Function of CCAT2 in Regulating Luminal Subtype of Breast Cancer Depending on the Subcellular Distribution

by Heying Xie, Yuefan Guo, Zhen Xu, Qiong Wang, Tao Wang, Yi Gu, Danni Li, Yu Liu, Wenjing Ma, Pengfei Liu, Qian Zhao, Jinhui Lü, Junjun Liu and Zuoren Yu

Cancers 2023, 15(2), 538; https://doi.org/10.3390/cancers15020538 - 16 Jan 2023

Cited by 2 | Viewed by 2219

Abstract

Breast cancer is the most common cancer in women around the world. Emerging evidence has indicated the important roles that non-coding RNAs play in regulating tumor development and progression in breast cancer. Herein, we found a dual function of long non-coding RNA (LncRNA) [...] Read more.

Breast cancer is the most common cancer in women around the world. Emerging evidence has indicated the important roles that non-coding RNAs play in regulating tumor development and progression in breast cancer. Herein, we found a dual function of long non-coding RNA (LncRNA) CCAT2 in the luminal subtype of breast cancer, depending on its subcellular distribution. CCAT2 showed an overall downregulation in the tumor tissues from luminal breast cancer patients. Transient overexpression of CCAT2 in the luminal subtype of breast cancer cell MCF-7 or T47D significantly suppressed cell proliferation in vitro and inhibited tumor growth in vivo. Gene expression analysis of cancer stem cell markers including OCT4, NANOG, h-TERT, SOX2 and KLF4; flow cytometry analysis of breast cancer stem cell population, and mammosphere formation assay demonstrated inhibition of cancer cell stemness with transient transfection of CCAT2 in which exogenous CCAT2 mainly distributed in the cytoplasm and regulated miR-221-p27 signaling via RNA sequence interaction. However, overexpression of CCAT2 in MCF-7 cells through pMX retroviral nuclear expression vector accumulated CCAT2 in the nucleus, leading to upregulation of OCT4-PG1, a pseudogene of stem gene OCT4, thereby promoting the cancer cell stemness. In conclusion, the current study, for the first time, revealed a dual function of lncRNA CCAT2 as a tumor suppressor or oncogene depending upon its subcellular distribution. It also demonstrated the regulatory mechanism of cytoplasmic CCAT2 in suppressing tumorigenesis in the luminal subtype of breast cancer. Full article

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2022

Jump to: 2023, 2021

23 pages, 1843 KiB

Open AccessReview

MiRNAs and snoRNAs in Bone Metastasis: Functional Roles and Clinical Potential

by Margherita Puppo, Mariam Jaafar, Jean-Jacques Diaz, Virginie Marcel and Philippe Clézardin

Cancers 2023, 15(1), 242; https://doi.org/10.3390/cancers15010242 - 30 Dec 2022

Cited by 5 | Viewed by 2233

Abstract

Bone is a frequent site of metastasis. Bone metastasis is associated with a short-term prognosis in cancer patients, and current treatments aim to slow its growth, but are rarely curative. Thus, revealing molecular mechanisms that explain why metastatic cells are attracted to the [...] Read more.

Bone is a frequent site of metastasis. Bone metastasis is associated with a short-term prognosis in cancer patients, and current treatments aim to slow its growth, but are rarely curative. Thus, revealing molecular mechanisms that explain why metastatic cells are attracted to the bone micro-environment, and how they successfully settle in the bone marrow—taking advantage over bone resident cells—and grow into macro-metastasis, is essential to propose new therapeutic approaches. MicroRNAs and snoRNAs are two classes of small non-coding RNAs that post-transcriptionally regulate gene expression. Recently, microRNAs and snoRNAs have been pointed out as important players in bone metastasis by (i) preparing the pre-metastatic niche, directly and indirectly affecting the activities of osteoclasts and osteoblasts, (ii) promoting metastatic properties within cancer cells, and (iii) acting as mediators within cells to support cancer cell growth in bone. This review aims to highlight the importance of microRNAs and snoRNAs in metastasis, specifically in bone, and how their roles can be linked together. We then discuss how microRNAs and snoRNAs are secreted by cancer cells and be found as extracellular vesicle cargo. Finally, we provide evidence of how microRNAs and snoRNAs can be potential therapeutic targets, at least in pre-clinical settings, and how their detection in liquid biopsies can be a useful diagnostic and/or prognostic biomarker to predict the risk of relapse in cancer patients. Full article

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24 pages, 2342 KiB

Open AccessReview

The Intricate Interplay between the ZNF217 Oncogene and Epigenetic Processes Shapes Tumor Progression

by Pia Fahmé, Farah Ramadan, Diep Tien Le, Kieu-Oanh Nguyen Thi, Sandra E. Ghayad, Nader Hussein, Chantal Diaz, Martine Croset, Philippe Clézardin and Pascale A. Cohen

Cancers 2022, 14(24), 6043; https://doi.org/10.3390/cancers14246043 - 8 Dec 2022

Cited by 4 | Viewed by 2979

Abstract

The oncogenic transcription factor ZNF217 orchestrates several molecular signaling networks to reprogram integrated circuits governing hallmark capabilities within cancer cells. High levels of ZNF217 expression provide advantages to a specific subset of cancer cells to reprogram tumor progression, drug resistance and cancer cell [...] Read more.

The oncogenic transcription factor ZNF217 orchestrates several molecular signaling networks to reprogram integrated circuits governing hallmark capabilities within cancer cells. High levels of ZNF217 expression provide advantages to a specific subset of cancer cells to reprogram tumor progression, drug resistance and cancer cell plasticity. ZNF217 expression level, thus, provides a powerful biomarker of poor prognosis and a predictive biomarker for anticancer therapies. Cancer epigenetic mechanisms are well known to support the acquisition of hallmark characteristics during oncogenesis. However, the complex interactions between ZNF217 and epigenetic processes have been poorly appreciated. Deregulated DNA methylation status at ZNF217 locus or an intricate cross-talk between ZNF217 and noncoding RNA networks could explain aberrant ZNF217 expression levels in a cancer cell context. On the other hand, the ZNF217 protein controls gene expression signatures and molecular signaling for tumor progression by tuning DNA methylation status at key promoters by interfering with noncoding RNAs or by refining the epitranscriptome. Altogether, this review focuses on the recent advances in the understanding of ZNF217 collaboration with epigenetics processes to orchestrate oncogenesis. We also discuss the exciting burgeoning translational medicine and candidate therapeutic strategies emerging from those recent findings connecting ZNF217 to epigenetic deregulation in cancer. Full article

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18 pages, 853 KiB

Open AccessReview

Long Non-Coding RNAs: Tools for Understanding and Targeting Cancer Pathways

by Gaurav Kumar Pandey and Chandrasekhar Kanduri

Cancers 2022, 14(19), 4760; https://doi.org/10.3390/cancers14194760 - 29 Sep 2022

Cited by 14 | Viewed by 3143

Abstract

The regulatory nature of long non-coding RNAs (lncRNAs) has been well established in various processes of cellular growth, development, and differentiation. Therefore, it is vital to examine their contribution to cancer development. There are ample examples of lncRNAs whose cellular levels are significantly [...] Read more.

The regulatory nature of long non-coding RNAs (lncRNAs) has been well established in various processes of cellular growth, development, and differentiation. Therefore, it is vital to examine their contribution to cancer development. There are ample examples of lncRNAs whose cellular levels are significantly associated with clinical outcomes. However, whether these non-coding molecules can work as either key drivers or barriers to cancer development remains unknown. The current review aims to discuss some well-characterised lncRNAs in the process of oncogenesis and extrapolate the extent of their decisive contribution to tumour development. We ask if these lncRNAs can independently initiate neoplastic lesions or they always need the modulation of well characterized oncogenes or tumour suppressors to exert their functional properties. Finally, we discuss the emerging genetic approaches and appropriate animal and humanised models that can significantly contribute to the functional dissection of lncRNAs in cancer development and progression. Full article

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13 pages, 7476 KiB

Open AccessReview

Insight into LncRNA- and CircRNA-Mediated CeRNAs: Regulatory Network and Implications in Nasopharyngeal Carcinoma—A Narrative Literature Review

by Senmiao Zhang, Yanling Li, Shuyu Xin, Li Yang, Mingjuan Jiang, Yujie Xin, Yiwei Wang, Jing Yang and Jianhong Lu

Cancers 2022, 14(19), 4564; https://doi.org/10.3390/cancers14194564 - 20 Sep 2022

Cited by 15 | Viewed by 2232

Abstract

Nasopharyngeal carcinoma (NPC) is a kind of head-and-neck malignant tumor, and distant metastasis treatment resistance is the leading cause of patient death. In-depth understanding of NPC progression and treatment failure remains to be explored. Long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) are [...] Read more.

Nasopharyngeal carcinoma (NPC) is a kind of head-and-neck malignant tumor, and distant metastasis treatment resistance is the leading cause of patient death. In-depth understanding of NPC progression and treatment failure remains to be explored. Long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) are noncoding RNAs that play key regulatory role in shaping tumor cell activities. Recent studies have revealed that lncRNA and circRNA function as competitive endogenous RNAs (ceRNAs) by regulating the posttranscriptional expression of genes as miRNA baits. The imbalanced ceRNA networks derived from lncRNA/circRNA-miRNA-mRNA interaction are widely found to contribute to NPC development. Herein, we summarize typical examples of lncRNA/circRNA-associated ceRNAs in recent years, which involved the potential molecular mechanisms in the regulation of proliferation, apoptosis, treatment resistance and metastasis of NPC, and discuss their potential clinical significance in the prognosis and treatment of NPC. Interpreting the involvement of ceRNAs networks will provide new insight into the pathogenesis and treatment strategies of NPC. However, ceRNA regulatory mechanism has some limitations currently. Screening the most effective ceRNA targets and the clinical application of ceRNA still has many challenges. Full article

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14 pages, 9385 KiB

Open AccessArticle

A Novel tiRNA-Gly-GCC-1 Promotes Progression of Urothelial Bladder Carcinoma and Directly Targets TLR4

by Chuan Qin, Zheng-Hao Chen, Rui Cao, Ming-Jun Shi and Ye Tian

Cancers 2022, 14(19), 4555; https://doi.org/10.3390/cancers14194555 - 20 Sep 2022

Cited by 12 | Viewed by 1624

Abstract

Background: Patients with urothelial bladder carcinoma (UBC) have a poor prognosis and a high risk of progression. Recently, tRNA-derived small RNAs (tsRNAs), a novel type of noncoding RNA, have been identified. In our previous study, we found tiRNA-Gly-GCC-1 was significantly upregulated in UBC [...] Read more.

Background: Patients with urothelial bladder carcinoma (UBC) have a poor prognosis and a high risk of progression. Recently, tRNA-derived small RNAs (tsRNAs), a novel type of noncoding RNA, have been identified. In our previous study, we found tiRNA-Gly-GCC-1 was significantly upregulated in UBC tissue and might target the predicted target gene toll-like receptor 4 (TLR4) to play a regulatory role in UBC. Thus, the aim of this study was to identify the functional roles of tiRNA-Gly-GCC-1 and the relationship between tiRNA-Gly-GCC-1 and TLR4. Methods: After lentiviral transfection in 5637 and T24 cell lines, quantitative reverse transcription-PCR, Cell Counting Kit-8, IncuCyte ZOOM™ live cell imaging, flow cytometry, Transwell assays, scratch assay, and luciferase assay were performed. Results: The results showed down-regulation of tiRNA-Gly-GCC-1 inhibits cell proliferation, migration and invasion, promotes cell apoptosis, and affects the cell cycle. Besides, tiRNA-Gly-GCC-1 was found to inhibit TLR4 expression by directly targeting its 3′UTR. Conclusions: Our study demonstrated that tiRNA-Gly-GCC-1 promotes the progression of UBC and directly targets TLR4. This study provides novel insights for future investigations to explore the mechanisms and therapeutic targets for UBC. Full article

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16 pages, 2159 KiB

Open AccessReview

LincRNAs and snoRNAs in Breast Cancer Cell Metastasis: The Unknown Players

by Maria Louca and Vasiliki Gkretsi

Cancers 2022, 14(18), 4528; https://doi.org/10.3390/cancers14184528 - 19 Sep 2022

Cited by 9 | Viewed by 2380

Abstract

Recent advances in research have led to earlier diagnosis and targeted therapies against breast cancer, which has resulted in reduced breast cancer-related mortality. However, the majority of breast cancer-related deaths are due to metastasis of cancer cells to other organs, a process that [...] Read more.

Recent advances in research have led to earlier diagnosis and targeted therapies against breast cancer, which has resulted in reduced breast cancer-related mortality. However, the majority of breast cancer-related deaths are due to metastasis of cancer cells to other organs, a process that has not been fully elucidated. Among the factors and genes implicated in the metastatic process regulation, non-coding RNAs have emerged as crucial players. This review focuses on the role of long intergenic noncoding RNAs (lincRNAs) and small nucleolar RNAs (snoRNAs) in breast cancer cell metastasis. LincRNAs are transcribed between two protein-coding genes and are longer than 200 nucleotides, they do not code for a specific protein but function as regulatory molecules in processes such as cell proliferation, apoptosis, epithelial-to-mesenchymal transition, migration, and invasion while most of them are highly elevated in breast cancer tissues and seem to function as competing endogenous RNAs (ceRNAs) inhibiting relevant miRNAs that specifically target vital metastasis-related genes. Similarly, snoRNAs are 60–300 nucleotides long and are found in the nucleolus being responsible for the post-transcriptional modification of ribosomal and spliceosomal RNAs. Most snoRNAs are hosted inside intron sequences of protein-coding and non-protein-coding genes, and they also regulate metastasis-related genes affecting related cellular properties. Full article

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38 pages, 2315 KiB

Open AccessReview

MicroRNAs and the Diagnosis of Childhood Acute Lymphoblastic Leukemia: Systematic Review, Meta-Analysis and Re-Analysis with Novel Small RNA-Seq Tools

by Ioannis Kyriakidis, Konstantinos Kyriakidis and Aspasia Tsezou

Cancers 2022, 14(16), 3976; https://doi.org/10.3390/cancers14163976 - 17 Aug 2022

Cited by 9 | Viewed by 4740

Abstract

MicroRNAs (miRNAs) have been implicated in childhood acute lymphoblastic leukemia (ALL) pathogenesis. We performed a systematic review and meta-analysis of miRNA single-nucleotide polymorphisms (SNPs) in childhood ALL compared with healthy children, which revealed (i) that the CC genotype of rs4938723 in pri-miR-34b/c and [...] Read more.

MicroRNAs (miRNAs) have been implicated in childhood acute lymphoblastic leukemia (ALL) pathogenesis. We performed a systematic review and meta-analysis of miRNA single-nucleotide polymorphisms (SNPs) in childhood ALL compared with healthy children, which revealed (i) that the CC genotype of rs4938723 in pri-miR-34b/c and the TT genotype of rs543412 in miR-100 confer protection against ALL occurrence in children; (ii) no significant association between rs2910164 genotypes in miR-146a and childhood ALL; and (iii) SNPs in DROSHA, miR-449b, miR-938, miR-3117 and miR-3689d-2 genes seem to be associated with susceptibility to B-ALL in childhood. A review of published literature on differential expression of miRNAs in children with ALL compared with controls revealed a significant upregulation of the miR-128 family, miR-130b, miR-155, miR-181 family, miR-210, miR-222, miR-363 and miR-708, along with significant downregulation of miR-143 and miR-148a, seem to have a definite role in childhood ALL development. MicroRNA signatures among childhood ALL subtypes, along with differential miRNA expression patterns between B-ALL and T-ALL cases, were scrutinized. With respect to T-ALL pediatric cases, we reanalyzed RNA-seq datasets with a robust and sensitive pipeline and confirmed the significant differential expression of hsa-miR-16-5p, hsa-miR-19b-3p, hsa-miR-92a-2-5p, hsa-miR-128-3p (ranked first), hsa-miR-130b-3p and -5p, hsa-miR-181a-5p, -2-3p and -3p, hsa-miR-181b-5p and -3p, hsa-miR-145-5p and hsa-miR-574-3p, as described in the literature, along with novel identified miRNAs. Full article

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18 pages, 1596 KiB

Open AccessArticle

LncRNA-Associated Genetic Etiologies Are Shared between Type 2 Diabetes and Cancers in the UAE Population

by Roberta Giordo, Rida Gulsha, Sarah Kalla, George A. Calin and Leonard Lipovich

Cancers 2022, 14(14), 3313; https://doi.org/10.3390/cancers14143313 - 7 Jul 2022

Cited by 4 | Viewed by 2147

Abstract

Numerous epidemiological studies place patients with T2D at a higher risk for cancer. Many risk factors, such as obesity, ageing, poor diet and low physical activity, are shared between T2D and cancer; however, the biological mechanisms linking the two diseases remain largely unknown. [...] Read more.

Numerous epidemiological studies place patients with T2D at a higher risk for cancer. Many risk factors, such as obesity, ageing, poor diet and low physical activity, are shared between T2D and cancer; however, the biological mechanisms linking the two diseases remain largely unknown. The advent of genome wide association studies (GWAS) revealed large numbers of genetic variants associated with both T2D and cancer. Most significant disease-associated variants reside in non-coding regions of the genome. Several studies show that single nucleotide polymorphisms (SNPs) at or near long non-coding RNA (lncRNA) genes may impact the susceptibility to T2D and cancer. Therefore, the identification of genetic variants predisposing individuals to both T2D and cancer may help explain the increased risk of cancer in T2D patients. We aim to investigate whether lncRNA genetic variants with significant diabetes and cancer associations overlap in the UAE population. We first performed an annotation-based analysis of UAE T2D GWAS, confirming the high prevalence of variants at or near non-coding RNA genes. We then explored whether these T2D SNPs in lncRNAs were relevant to cancer. We highlighted six non-coding genetic variants, jointly reaching statistical significance in T2D and cancer, implicating a shared genetic architecture between the two diseases in the UAE population. Full article

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Graphical abstract

17 pages, 2884 KiB

Open AccessArticle

MALINC1 an Immune-Related Long Non-Coding RNA Associated with Early-Stage Breast Cancer Progression

by María Laura Fabre, Romina Canzoneri, Agustina Gurruchaga, Jaeho Lee, Pradeep Tatineni, Hyunsuk Kil, Ezequiel Lacunza, C. Marcelo Aldaz and Martín Carlos Abba

Cancers 2022, 14(12), 2819; https://doi.org/10.3390/cancers14122819 - 7 Jun 2022

Cited by 2 | Viewed by 2374

Abstract

Long non-coding RNAs are increasingly being recognized as cancer biomarkers in various malignancies, acting as either tumor suppressors or oncogenes. The long non-coding MALINC1 intergenic RNA was identified as significantly upregulated in breast ductal carcinoma in situ. The aim of this study was [...] Read more.

Long non-coding RNAs are increasingly being recognized as cancer biomarkers in various malignancies, acting as either tumor suppressors or oncogenes. The long non-coding MALINC1 intergenic RNA was identified as significantly upregulated in breast ductal carcinoma in situ. The aim of this study was to characterize MALINC1 expression, localization, and phenotypic and molecular effects in non-invasive and invasive breast cancer cells. We determined that MALINC1 is an estrogen–estrogen receptor-modulated lncRNA enriched in the cytoplasmic fraction of luminal A/B breast cancer cells that is associated with worse overall survival in patients with primary invasive breast carcinomas. Transcriptomic studies in normal and DCIS cells identified the main signaling pathways modulated by MALINC1, which mainly involve bioprocesses related to innate and adaptive immune responses, extracellular matrix remodeling, cell adhesion, and activation of AP-1 signaling pathway. We determined that MALINC1 induces premalignant phenotypic changes by increasing cell migration in normal breast cells. Moreover, high MALINC1 expression in invasive carcinomas was associated with a pro-tumorigenic immune environment and a favorable predicted response to immunotherapy both in luminal and basal-like subtypes compared with low-MALINC1-expression tumors. We conclude that MALINC1 behaves as an oncogenic and immune-related lncRNA involved with early-stage breast cancer progression. Full article

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16 pages, 3110 KiB

Open AccessArticle

Tracking miR-17-5p Levels following Expression of Seven Reported Target mRNAs

by Kevin Y. Du, Javeria Qadir, Burton B. Yang, Albert J. Yee and Weining Yang

Cancers 2022, 14(11), 2585; https://doi.org/10.3390/cancers14112585 - 24 May 2022

Cited by 2 | Viewed by 2145

Abstract

As the most prominent member of the miR-17-92 cluster, miR-17-5p is well associated with tumorigenesis and cancer progression. It can exert both oncogenic and tumor-suppressive functions by inducing translational repression and/or mRNA decay. The complexity of the tissue-specific expression of the targeted transcripts [...] Read more.

As the most prominent member of the miR-17-92 cluster, miR-17-5p is well associated with tumorigenesis and cancer progression. It can exert both oncogenic and tumor-suppressive functions by inducing translational repression and/or mRNA decay. The complexity of the tissue-specific expression of the targeted transcripts seems to contribute to the differential functions of miR-17-5p in different types of cancers. In this study, we selected 12 reported miR-17-5p targeting genes with mRNA levels unaffected by miR-17-5p expression and analyzed their expression in 31 organ tissues in transgenic mice by real-time PCR. Surprisingly, miR-17-5p expressing transgenic mice showed a positive correlation in these tissues between miR-17-5p expression levels and the selected miR-17-5p targeted transcripts; with high expression of the miRNA in organs with high selected miRNA-targeted mRNA levels. In cancer cell lines, overexpression of 7 reported miR-17-5p targeted genes’ 3′-UTRs promoted miR-17-5p expression; meanwhile, transfection of 3′-UTRs with mutations had no significant effect. Moreover, an increase in AGO2 mRNA was associated with 3′-UTR expression as confirmed by real-time PCR. Hence, miR-17-5p regulation by these target genes might be an alternative mechanism to maintain miR-17-5p expression at tissue-specific levels. Full article

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31 pages, 1311 KiB

Open AccessReview

Long Non-Coding RNAs in Pancreatic Cancer: Biologic Functions, Mechanisms, and Clinical Significance

by Jiajia Li, Sicong Hou, Ziping Ye, Wujun Wang, Xiaolin Hu and Qinglei Hang

Cancers 2022, 14(9), 2115; https://doi.org/10.3390/cancers14092115 - 24 Apr 2022

Cited by 17 | Viewed by 3344

Abstract

Despite tremendous efforts devoted to research in pancreatic cancer (PC), the mechanism underlying the tumorigenesis and progression of PC is still not completely clear. Additionally, ideal biomarkers and satisfactory therapeutic strategies for clinical application in PC are still lacking. Accumulating evidence suggests that [...] Read more.

Despite tremendous efforts devoted to research in pancreatic cancer (PC), the mechanism underlying the tumorigenesis and progression of PC is still not completely clear. Additionally, ideal biomarkers and satisfactory therapeutic strategies for clinical application in PC are still lacking. Accumulating evidence suggests that long non-coding RNAs (lncRNAs) might participate in the pathogenesis of diverse cancers, including PC. The abnormal expression of lncRNAs in PC is considered a vital factor during tumorigenesis that affects tumor cell proliferation, migration, invasion, apoptosis, angiogenesis, and drug resistance. With this review of relevant articles published in recent years, we aimed to summarize the biogenesis mechanism, classifications, and modes of action of lncRNAs and to review the functions and mechanisms of lncRNAs in PC. Additionally, the clinical significance of lncRNAs in PC was discussed. Finally, we pointed out the questions remaining from recent studies and anticipated that further investigations would address these gaps in knowledge in this field. Full article

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15 pages, 2262 KiB

Open AccessArticle

Deciphering the Non-Coding RNA Landscape of Pediatric Acute Myeloid Leukemia

by Jolien Vanhooren, Laurens Van Camp, Barbara Depreter, Martijn de Jong, Anne Uyttebroeck, An Van Damme, Laurence Dedeken, Marie-Françoise Dresse, Jutte van der Werff ten Bosch, Mattias Hofmans, Jan Philippé, Barbara De Moerloose and Tim Lammens

Cancers 2022, 14(9), 2098; https://doi.org/10.3390/cancers14092098 - 22 Apr 2022

Cited by 4 | Viewed by 2460

Abstract

Pediatric acute myeloid leukemia (pedAML) is a heterogeneous blood cancer that affects children. Although survival rates have significantly improved over the past few decades, 20–30% of children will succumb due to treatment-related toxicity or relapse. The molecular characterization of the leukemic stem cell, [...] Read more.

Pediatric acute myeloid leukemia (pedAML) is a heterogeneous blood cancer that affects children. Although survival rates have significantly improved over the past few decades, 20–30% of children will succumb due to treatment-related toxicity or relapse. The molecular characterization of the leukemic stem cell, shown to be responsible for relapse, is needed to improve treatment options and survival. Recently, it has become clear that non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), play a role in the development of human diseases, including pediatric cancer. Nevertheless, non-coding RNA expression data in pedAML are scarce. Here, we explored lncRNA (n = 30,168) and miRNA (n = 627) expression in pedAML subpopulations (leukemic stem cells (LSCs) and leukemic blasts (L-blasts)) and their normal counterparts (hematopoietic stem cells and control myeloblasts). The potential regulatory activity of differentially expressed lncRNAs in LSCs (unique or shared with the L-blast comparison) on miRNAs was assessed. Moreover, pre-ranked gene set enrichment analyses of (anti-) correlated protein-coding genes were performed to predict the functional relevance of the differentially upregulated lncRNAs in LSCs (unique or shared with the L-blast comparison). In conclusion, this study provides a catalog of non-coding RNAs with a potential role in the pathogenesis of pedAML, paving the way for further translational research studies. Full article

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20 pages, 1328 KiB

Open AccessReview

Enhancer RNAs (eRNAs) in Cancer: The Jacks of All Trades

by Sara Napoli, Nicolas Munz, Francesca Guidetti and Francesco Bertoni

Cancers 2022, 14(8), 1978; https://doi.org/10.3390/cancers14081978 - 14 Apr 2022

Cited by 8 | Viewed by 3400

Abstract

Enhancer RNAs (eRNAs) are non-coding RNAs (ncRNAs) transcribed in enhancer regions. They play an important role in transcriptional regulation, mainly during cellular differentiation. eRNAs are tightly tissue- and cell-type specific and are induced by specific stimuli, activating promoters of target genes in turn. [...] Read more.

Enhancer RNAs (eRNAs) are non-coding RNAs (ncRNAs) transcribed in enhancer regions. They play an important role in transcriptional regulation, mainly during cellular differentiation. eRNAs are tightly tissue- and cell-type specific and are induced by specific stimuli, activating promoters of target genes in turn. eRNAs usually have a very short half-life but in some cases, once activated, they can be stably expressed and acquire additional functions. Due to their critical role, eRNAs are often dysregulated in cancer and growing number of interactions with chromatin modifiers, transcription factors, and splicing machinery have been described. Enhancer activation and eRNA transcription have particular relevance also in inflammatory response, placing the eRNAs at the interplay between cancer and immune cells. Here, we summarize all the possible molecular mechanisms recently reported in association with eRNAs activity. Full article

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19 pages, 8270 KiB

Open AccessReview

The Landscape of lncRNAs in Multiple Myeloma: Implications in the “Hallmarks of Cancer”, Clinical Perspectives and Therapeutic Opportunities

by Ilaria Saltarella, Benedetta Apollonio, Aurelia Lamanuzzi, Vanessa Desantis, Maria Addolorata Mariggiò, Jean-François Desaphy, Angelo Vacca and Maria Antonia Frassanito

Cancers 2022, 14(8), 1963; https://doi.org/10.3390/cancers14081963 - 13 Apr 2022

Cited by 12 | Viewed by 2726

Abstract

Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides that are not translated into proteins. Nowadays, lncRNAs are gaining importance as key regulators of gene expression and, consequently, of several biological functions in physiological and pathological conditions, including cancer. Here, we point [...] Read more.

Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides that are not translated into proteins. Nowadays, lncRNAs are gaining importance as key regulators of gene expression and, consequently, of several biological functions in physiological and pathological conditions, including cancer. Here, we point out the role of lncRNAs in the pathogenesis of multiple myeloma (MM). We focus on their ability to regulate the biological processes identified as “hallmarks of cancer” that enable malignant cell transformation, early tumor onset and progression. The aberrant expression of lncRNAs in MM suggests their potential use as clinical biomarkers for diagnosis, patient stratification, and clinical management. Moreover, they represent ideal candidates for therapeutic targeting. Full article

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24 pages, 1677 KiB

Open AccessEditor’s ChoiceReview

Clinical Applications of Short Non-Coding RNA-Based Therapies in the Era of Precision Medicine

by Ellen S. Smith, Eric Whitty, Byunghee Yoo, Anna Moore, Lorenzo F. Sempere and Zdravka Medarova

Cancers 2022, 14(6), 1588; https://doi.org/10.3390/cancers14061588 - 21 Mar 2022

Cited by 39 | Viewed by 5340

Abstract

Traditional targeted therapeutic agents have relied on small synthetic molecules or large proteins, such as monoclonal antibodies. These agents leave a lot of therapeutic targets undruggable because of the lack or inaccessibility of active sites and/or pockets in their three-dimensional structure that can [...] Read more.

Traditional targeted therapeutic agents have relied on small synthetic molecules or large proteins, such as monoclonal antibodies. These agents leave a lot of therapeutic targets undruggable because of the lack or inaccessibility of active sites and/or pockets in their three-dimensional structure that can be chemically engaged. RNA presents an attractive, transformative opportunity to reach any genetic target with therapeutic intent. RNA therapeutic design is amenable to modularity and tunability and is based on a computational blueprint presented by the genetic code. Here, we will focus on short non-coding RNAs (sncRNAs) as a promising therapeutic modality because of their potency and versatility. We review recent progress towards clinical application of small interfering RNAs (siRNAs) for single-target therapy and microRNA (miRNA) activity modulators for multi-target therapy. siRNAs derive their potency from the fact that the underlying RNA interference (RNAi) mechanism is catalytic and reliant on post-transcriptional mRNA degradation. Therapeutic siRNAs can be designed against virtually any mRNA sequence in the transcriptome and specifically target a disease-causing mRNA variant. Two main classes of microRNA activity modulators exist to increase (miRNA mimics) or decrease (anti-miRNA inhibitors) the function of a specific microRNA. Since a single microRNA regulates the expression of multiple target genes, a miRNA activity modulator can have a more profound effect on global gene expression and protein output than siRNAs do. Both types of sncRNA-based drugs have been investigated in clinical trials and some siRNAs have already been granted FDA approval for the treatment of genetic, cardiometabolic, and infectious diseases. Here, we detail clinical results using siRNA and miRNA therapeutics and present an outlook for the potential of these sncRNAs in medicine. Full article

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18 pages, 6494 KiB

Open AccessArticle

Downregulation of LOC441461 Promotes Cell Growth and Motility in Human Gastric Cancer

by Sang-soo Lee, JeongMan Park, Sooyeon Oh and KyuBum Kwack

Cancers 2022, 14(5), 1149; https://doi.org/10.3390/cancers14051149 - 23 Feb 2022

Cited by 2 | Viewed by 2573

Abstract

Gastric cancer is a common tumor, with a high mortality rate. The severity of gastric cancer is assessed by TNM staging. Long noncoding RNAs (lncRNAs) play a role in cancer treatment; investigating the clinical significance of novel biomarkers associated with TNM staging, such [...] Read more.

Gastric cancer is a common tumor, with a high mortality rate. The severity of gastric cancer is assessed by TNM staging. Long noncoding RNAs (lncRNAs) play a role in cancer treatment; investigating the clinical significance of novel biomarkers associated with TNM staging, such as lncRNAs, is important. In this study, we investigated the association between the expression of the lncRNA LOC441461 and gastric cancer stage. LOC441461 expression was lower in stage IV than in stages I, II, and III. The depletion of LOC441461 promoted cell proliferation, cell cycle progression, apoptosis, cell motility, and invasiveness. LOC441461 downregulation increased the epithelial-to-mesenchymal transition, as indicated by increased TRAIL signaling and decreased RUNX1 interactions. The interaction of the transcription factors RELA, IRF1, ESR1, AR, POU5F1, TRIM28, and GATA1 with LOC441461 affected the degree of the malignancy of gastric cancer by modulating gene transcription. The present study identified LOC441461 and seven transcription factors as potential biomarkers and therapeutic targets for the treatment of gastric cancer. Full article

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14 pages, 3618 KiB

Open AccessArticle

Validation in an Independent Cohort of MiR-122, MiR-1271, and MiR-15b as Urinary Biomarkers for the Potential Early Diagnosis of Clear Cell Renal Cell Carcinoma

by Giovanni Cochetti, Luigi Cari, Vincenza Maulà, Rosy Cagnani, Alessio Paladini, Michele Del Zingaro, Giuseppe Nocentini and Ettore Mearini

Cancers 2022, 14(5), 1112; https://doi.org/10.3390/cancers14051112 - 22 Feb 2022

Cited by 24 | Viewed by 2376

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma, and the absence of symptoms in the early stages makes metastasis more likely and reduces survival. To aid in the early diagnosis of ccRCC, we recently developed a [...] Read more.

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma, and the absence of symptoms in the early stages makes metastasis more likely and reduces survival. To aid in the early diagnosis of ccRCC, we recently developed a method based on urinary miR-122-5p, miR-1271-5p, and miR-15b-5p levels and three controls. The study here presented aimed to validate the previously published method through its application on an independent cohort. The expression of miRNAs in urine specimens from 28 ccRCC patients and 28 healthy subjects (HSs) of the same sex and age was evaluated by RT-qPCR. Statistical analyses were performed, including the preparation of receiver operating characteristic (ROC) curves. The mean ccRCC diameter in ccRCC patients was 4.2 ± 2.4 mm. Urinary miRNA levels were higher in patients than in HSs. The data were processed using the previously developed algorithm (7p-urinary score), and the area under the curve (AUC) of the algorithm’s ROC curve was 0.81 (p-value = 0.0003), with a sensitivity of 96% and specificity of 65%. Therefore, the 7p-urinary score is a potential tool for the early diagnosis of ccRCC. Full article

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2021

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16 pages, 2609 KiB

Open AccessArticle

tRNA^GlyGCC-Derived Internal Fragment (i-tRF-GlyGCC) in Ovarian Cancer Treatment Outcome and Progression

by Konstantina Panoutsopoulou, Tobias Dreyer, Julia Dorn, Eva Obermayr, Sven Mahner, Toon van Gorp, Ioana Braicu, Robert Zeillinger, Viktor Magdolen, Margaritis Avgeris and Andreas Scorilas

Cancers 2022, 14(1), 24; https://doi.org/10.3390/cancers14010024 - 22 Dec 2021

Cited by 29 | Viewed by 4135

Abstract

Epithelial ovarian cancer (EOC) remains a highly-lethal gynecological malignancy, characterized by frequent recurrence, chemotherapy resistance and poor 5-year survival. Identifying novel predictive molecular markers remains an overdue challenge in the disease’s clinical management. Herein, in silico analysis of TCGA-OV highlighted the tRNA-derived internal [...] Read more.

Epithelial ovarian cancer (EOC) remains a highly-lethal gynecological malignancy, characterized by frequent recurrence, chemotherapy resistance and poor 5-year survival. Identifying novel predictive molecular markers remains an overdue challenge in the disease’s clinical management. Herein, in silico analysis of TCGA-OV highlighted the tRNA-derived internal fragment (i-tRF-GlyGCC) among the most abundant tRFs in ovarian tumors, while target prediction and gene ontology (GO) enrichment analysis predicted its implication in key biological processes. Thereafter, i-tRF-GlyGCC levels were quantified in a screening EOC (n = 98) and an institutionally-independent serous ovarian cancer (SOC) validation cohort (n = 100, OVCAD multicenter study). Disease progression and patient death were used as clinical endpoints for the survival analysis. Internal validation was performed by bootstrap analysis and the clinical net benefit was estimated by decision curve analysis. The analysis highlighted the significant association of i-tRF-GlyGCC with advanced FIGO stages, suboptimal debulking and most importantly, with early progression and poor overall survival of EOC patients. The OVCAD validation cohort corroborated the unfavorable predictive value of i-tRF-GlyGCC in EOC. Ultimately, evaluation of i-tRF-GlyGCC with the established/clinically used prognostic markers offered superior patient risk-stratification and enhanced clinical benefit in EOC prognosis. In conclusion, i-tRF-GlyGCC assessment could aid towards personalized prognosis and support precision medicine decisions in EOC. Full article

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16 pages, 3537 KiB

Open AccessArticle

Overexpression of the GR Riborepressor LncRNA GAS5 Results in Poor Treatment Response and Early Relapse in Childhood B-ALL

by Marieta Xagorari, Antonios Marmarinos, Lydia Kossiva, Margarita Baka, Dimitrios Doganis, Marina Servitzoglou, Maria Tsolia, Andreas Scorilas, Margaritis Avgeris and Dimitrios Gourgiotis

Cancers 2021, 13(23), 6064; https://doi.org/10.3390/cancers13236064 - 1 Dec 2021

Cited by 7 | Viewed by 2276

Abstract

Glucocorticoids (GCs) remain the cornerstone of childhood acute lymphoblastic leukemia (chALL) therapy, exerting their cytotoxic effects through binding and activating of the glucocorticoid receptor (GR). GAS5 lncRNA acts as a potent riborepressor of GR transcriptional activity, and thus targeting GAS5 in GC-treated chALL [...] Read more.

Glucocorticoids (GCs) remain the cornerstone of childhood acute lymphoblastic leukemia (chALL) therapy, exerting their cytotoxic effects through binding and activating of the glucocorticoid receptor (GR). GAS5 lncRNA acts as a potent riborepressor of GR transcriptional activity, and thus targeting GAS5 in GC-treated chALL could provide further insights into GC resistance and support personalized treatment decisions. Herein, to study the clinical utility of GAS5 in chALL prognosis and chemotherapy response, GAS5 expression was quantified by RT-qPCR in bone marrow samples of chB-ALL patients at diagnosis (n = 164) and at end-of-induction (n = 109), treated with ALL-BFM protocol. Patients’ relapse and death were used as clinical end-points for survival analysis. Bootstrap analysis was performed for internal validation, and decision curve analysis assessed the clinical net benefit for chALL prognosis. Our findings demonstrated the elevated GAS5 levels in blasts of chALL patients compared to controls and the significantly higher risk for short-term relapse and poor treatment outcome of patients overexpressing GAS5, independently of their clinicopathological data. The unfavorable prognostic value of GAS5 overexpression was strongly validated in the high-risk/stem-cell transplantation subgroup. Finally, multivariate models incorporating GAS5 levels resulted in superior risk stratification and clinical benefit for chALL prognostication, supporting personalized prognosis and precision medicine decisions in chALL. Full article

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13 pages, 5404 KiB

Open AccessFeature PaperArticle

MiRNA-424-5p Suppresses Proliferation, Migration, and Invasion of Clear Cell Renal Cell Carcinoma and Attenuates Expression of O-GlcNAc-Transferase

by Thomas J. Kalantzakos, Travis B. Sullivan, Thales Gloria, David Canes, Alireza Moinzadeh and Kimberly M. Rieger-Christ

Cancers 2021, 13(20), 5160; https://doi.org/10.3390/cancers13205160 - 14 Oct 2021

Cited by 11 | Viewed by 2469

Abstract

MicroRNAs (miRNAs) are non-coding post-transcriptional regulators of gene expression that are dysregulated in clear cell renal cell carcinoma (ccRCC) and play an important role in tumor progression. Our prior work identified a subset of miRNAs in pT1 ccRCC tumors, including miR-424-5p, that are [...] Read more.

MicroRNAs (miRNAs) are non-coding post-transcriptional regulators of gene expression that are dysregulated in clear cell renal cell carcinoma (ccRCC) and play an important role in tumor progression. Our prior work identified a subset of miRNAs in pT1 ccRCC tumors, including miR-424-5p, that are associated with an aggressive phenotype. We investigate the impact of this dysregulated miRNA and its protein target O-GlcNAc-transferase (OGT) to better understand the mechanisms behind aggressive stage I ccRCC. The ccRCC cell lines 786-O and Caki-1 were used to assess the impact of miR-424-5p and OGT. Cells were transfected with pre-miR-424-5p, a lentiviral anti-OGT shRNA, or were treated with the demethylating agent 5-Aza-2′-deoxycytidine. Cell proliferation was measured via MT cell viability assay. Cell migration and invasion were analyzed using Transwell assays. The expression of miR-424-5p was determined through qRT-PCR, while OGT protein expression was evaluated through Western blotting. The interaction between miR-424-5p and OGT was confirmed via luciferase reporter assay. The transfection of ccRCC cells with pre-miR-424-5p or anti-OGT shRNA significantly inhibited cell proliferation, migration, and OGT expression, while miR-424-5p also attenuated cell invasion. Addition of the demethylating agent significantly reduced cell proliferation, migration, invasion, and OGT expression, while significantly increasing the expression of miR-424-5p. Altogether, these findings suggest that epigenetic downregulation of miR-424-5p, which in turn augments OGT expression, contributes to the creation of aggressive forms of stage I ccRCC. Full article

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Molecular Function and Clinical Value of Non-coding RNAs (ncRNAs) in Cancer Regulation (Closed)

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