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Review

The Roles of miRNAs in Predicting Bladder Cancer Recurrence and Resistance to Treatment

by
Sanjna Das
1,
Joshua Hayden
2,
Travis Sullivan
1 and
Kimberly Rieger-Christ
1,*
1
Department of Translational Research, Lahey Hospital & Medical Center, Burlington, MA 01805, USA
2
Department of Urology, Lahey Hospital & Medical Center, Burlington, MA 01805, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(2), 964; https://doi.org/10.3390/ijms24020964
Submission received: 30 November 2022 / Revised: 22 December 2022 / Accepted: 28 December 2022 / Published: 4 January 2023
(This article belongs to the Special Issue Non-coding RNAs and Human Diseases: Current Status and Future Perspectives)
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Abstract

:
Bladder cancer (BCa) is associated with significant morbidity, with development linked to environmental, lifestyle, and genetic causes. Recurrence presents a significant issue and is managed in the clinical setting with intravesical chemotherapy or immunotherapy. In order to address challenges such as a limited supply of BCG and identifying cases likely to recur, it would be advantageous to use molecular biomarkers to determine likelihood of recurrence and treatment response. Here, we review microRNAs (miRNAs) that have shown promise as predictors of BCa recurrence. MiRNAs are also discussed in the context of predicting resistance or susceptibility to BCa treatment.

1. Introduction

Bladder cancer (BCa) is among the most common human malignancies, resulting in over 17,000 deaths annually in the United States [1]. Prognosis of BCa is largely dependent on whether there is muscle invasion present or not. Approximately 75% of bladder tumors are non-muscle invasive at the time of diagnosis, and even with treatment approximately 40% will recur and 10% will progress. [2]. Muscle-invasive bladder cancer (MIBC) is associated with greater morbidity and mortality, and is typically managed more aggressively than non-muscle invasive bladder cancer (NMIBC), often requiring neoadjuvant chemotherapy, radical cystectomy, and pelvic lymph node dissection.
Progression to muscle-invasive disease is a critical element to address in reducing the morbidity and mortality associated with BCa and may be dependent on several factors. First, BCas have historically been described as arising from two distinct pathways: a non-invasive pathway characterized by mutations in oncogenes, and an invasive pathway characterized by mutations in tumor suppressor genes [3]. Specific genetic alterations may indeed influence risk of developing muscle invasive disease. Recent work has evaluated differential RNA expression in BCa in order to characterize the disease into distinct molecular subtypes, which links genetic alterations with clinical characteristics such as recurrence and progression of disease [4,5,6,7,8]. Mutations in genes that impact chromosomal stability, such as DDR, P53 and APOBEC genes are associated with high risk of recurrence and progression, while alterations in genes involved in early cell-cycle processes such as RAS, FGFR3, and uroplakin genes are associated with low risk of recurrence and progression [9,10].
Several studies have identified microRNAs (miRNAs) as potential biomarkers for diagnosing and predicting survival among patients with BCa [11,12,13]. MiRNAs are short, noncoding molecules that negatively regulate gene expression by binding to the untranslated regions of gene transcripts. In addition to miRNAs, there are long non-coding RNAs (lncRNAs) and circular RNAs (cirRNAs); these are both classes of non-coding RNAs that work within axes involving miRNAs to regulate gene expression and that will be discussed briefly. MiRNAs are readily isolated from cell-free matrices such as urine [14] and serum [15] of patients with BCa with minimal risk to the patient. In BCa, they have been studied in conjunction with the epithelial to mesenchymal transition (EMT) phenotype [16,17], as well as chemoresistance and recurrence. The focus of this manuscript are those miRNAs that have been specifically linked to BCa resistance and recurrence. Several recent studies that have examined miRNA-based biomarkers and identified the roles of these miRNAs in BCa recurrence and resistance; this has the potential to inform the management of BCa patients.

2. Methods

In this review, PubMed (https://www.ncbi.nlm.nih.gov/pmc/) and Google searches from 19 September through 24 October 2022 were used to identify miRNAs associated with either BCa recurrence or chemoresistance. Search terms used to identify relevant papers include microRNA, bladder cancer, chemoresistance, recurrence, and selection focused on primary research papers that also included gene targets. A selection of papers looking at other non-coding RNAs were also included to highlight that (i) they also play a role in bladder cancer outcomes and that (ii) axes involving miRNAs frequently also include non-coding RNAs. These miRNAs and details pertaining to their potential gene targets are listed in Table 1 and Table 2 below. MiRNAs identified in the search were then analyzed in KEGG pathway analysis using DIANA-mirPath v. 3.0 [18]. Predicted gene targets are based on the experimentally validated miRNA interactions derived from TarBase v. 7.0 [19] (University of Thessaly, Volos, Greece).
The resulting heat maps depict significant pathways resulting from pathways union analysis using FDR correction and conservative statistics with a modified Fisher’s Exact Test, p < 0.0001. The results of the KEGG analyses are included below in Figure 1 and Figure 2. Notable pathways for recurrence include cell cycle, transcriptional regulation in cancer, the Hippo signaling pathway, and fatty acid metabolism/biosynthesis. For chemoresistance, these pathways include TGF-beta, fatty acid metabolism/biosynthesis, cell cycle, and the Hippo signaling pathway. These pathways and their aberrant expression are linked to cancer-associated phenotypes such as EMT.

3. EMT

An important mechanism linked to both recurrence and chemoresistance is EMT. This process involves the conversion of epithelial to mesenchymal cells resulting from changes in polarity and adhesion [67], and is characterized at the molecular level by changes including E-cadherin downregulation and N-cadherin upregulation [67]. Notably, EMT is a mechanism of metastasis, since the aforementioned molecular, and consequently cellular, changes allow cancer cells to move to other areas of the body using means such as migration and invasion [68]. There is a significant body of work investigating the role of EMT in BCa, especially with respect to recurrence and chemoresistance, the central themes of this review. Specifically, studies have looked at EMT-related genes to predict prognostic outcomes in patients with BCa [50,69] and at the role of non-coding RNAs that regulate the EMT pathway through axes involving miRNAs [70,71]. One important group of miRNAs involved in BCa EMT is the miR-200 family: work has shown that miR-200c and miR-200b inhibit EMT [72,73], and miR-200 expression is broadly linked to improved bladder cancer survival [74]. Other miRNAs involved in the EMT phenotype and included in Table 1 include miR-302b, which inhibits proliferation, migration, and invasion [34] and let-7f-5p, which is also characterized by tumor suppressor activity and inhibits cell viability and migration [35]. In addition to recurrence, EMT is also involved in mediating chemoresistance; in fact, EMT, recurrence, and chemoresistance work in concert with one another. Studies have found that EMT markers are upregulated in chemoresistant cells, with restoration of sensitivity via TGF-beta downregulation [75] and that oncogenic proteins modulate EMT to induce resistance to chemotherapeutic agents [76,77]. Two key pathways that have been linked to the EMT phenotype are Wnt signaling [78,79] and TGF-beta [80,81]. While the TGF-beta pathway is not focused on in detail here, there are several manuscripts looking at non-coding RNAs, including miRNAs, that are involved in BCa carcinogenesis (and specifically EMT): This includes miR-758-3p which is regulated by the lncRNA CASC9 [82], miR-663, which represses invasion and migration [83], miR-143-3p, which acts as a tumor suppressor and whose downregulation via LINC02470 promotes EMT [84], and miR-200b, which inhibits the metastatic phenotype [85]. TGF-beta signaling has also been linked to chemoresistance in a pathway that involves miR-145 downregulation [86]. The Wnt pathway, on the other hand, will be explored in greater detail in connection to PTEN, a protein target regulated by miR-21 (Table 2) and whose downregulation has been linked to poor prognosis and chemoresistance in BCa.

4. Cell Cycle

The cell cycle, or the process through which cells grow, undergo DNA replication, and ultimately divide is carefully regulated, and disruptions can result in adverse consequences. The cycle is separated into five phases: G1, and G2, which precede DNA replication (S) and the mitotic (M) phases, respectively, and G0, a dormant phase [87]. One key family of proteins that regulates the cycle is cyclin-dependent kinases (CDKs), which work in concert with cyclin protein substrates [87]. Cyclins and their associated kinases have been implicated in BCa, where they show biomarker and treatment potential [88,89]. While there does not appear to be any work showing that miRNAs directly bind to and regulate the expression of cyclins in connection to BCa recurrence, work by Wu et al. 2022 described an axis in which circGLIS3 sponges miR-1273f, effectively inhibiting its expression [90]. This leads to expression of SKP1 and cyclin D1, promoting BCa cell proliferation [90]. This is an excellent example of how different classes of noncoding RNAs such as cirRNAs and miRNAs work together to regulate gene expression and consequently the cellular phenotype. Additionally, miR-138, included in Table 1, is positively correlated with cyclin D3 expression [23].
Cyclin D3, and FGFR3, a well-studied protein explored below, may be used to identify BCa patients who are likely to recur using noninvasive methods [91]. Additional work has explored the utility of cyclins as biomarkers for recurrence including in papillary urothelial bladder cancer [92,93]. There is very limited literature looking at cyclins in BCa chemoresistance, and the potential role of non-coding RNAs; this represents an area requiring further exploration.

5. FGFR3

The Fibroblast growth factor receptor 3 (FGFR3) gene is often mutated in BCa, and these mutations may be associated with less aggressive cancers and better patient outcomes [94,95,96]. FGFR3 is included here because of its importance in BCa development, the progress that has been made so far in developing FGFR3-focused treatments, and due to its potential regulation by several miRNAs in BCa [97], including miR-99/100, which may be connected to recurrence. Measuring miR-100 levels in either blood or urine may offer insight into FGFR3 expression and aid in identifying patients who may benefit from targeted therapies [96]. More broadly, there is a plethora of information around FGFR3 in recurrence. Recent work by Sikic et al. 2021 found that FGFR3 expression was correlated with a higher likelihood of recurrence [98], and an earlier study looked at FGFR3 as one of three urine biomarkers for BCa recurrence [99]. Studies of FGFR3 in BCa are fairly well developed; in fact, there are clinical trials examining FGFR3 inhibitors in cancer treatment. Two such trials are PROOF 302 (phase III), which is investigating the utility of infigratinib, an inhibitor, in a specific subset of BCa patients [100] and FIGHT-101 (phase I/II), which is evaluating the treatment potential of pemigatinib, another FGFR inhibitor, in patients across different cancers including bladder [101]. Interestingly, while the PROOF 302 patient population includes only patients with FGFR3 mutations, FIGHT-101 is nonspecific [100,101].
There is more limited information around FGFR3 in chemoresistance although FGFR3 mutations have been linked to chemoresistance via Akt pathway activation [102,103]. On the flip side, FGFR3 mutations in conjunction with ERCC1 expression has also been reported to confer chemosensitivity [104]. This suggests that response to chemotherapy in patients with FGFR3 mutations varies according to the specific genetic alteration. Interestingly, di Martino et al. 2019 describe overlap between FGFR3 and the Hippo pathway, discussed further below. They found that FGFR3 acts through ETV5 and ultimately TAZ upregulation to initiate morphological changes promoting BCa progression [105]. Convergence between FGFR3 and the Hippo pathway is an important finding, because TAZ may represent an important target to halt BCa progression.

6. Hippo Signaling

One pathway implicated in the KEGG analyses for both BCa recurrence and chemoresistance is Hippo. This pathway is involved in regulating organ size and is characterized as a tumor suppressor, with its dysregulation linked extensively to cancer [106,107,108]. One of the key molecules within the pathway is the oncogenic Yes-associated protein (YAP) [106], which works in concert with TAZ and TEAD to control proliferation and apoptosis at the transcriptional level [109]. Proliferation and apoptosis are characteristics whose regulation (or lack thereof) is linked to invasive potential and consequently recurrence. While there is limited work examining the role of YAP in BCa recurrence, a study by Ghasemi et al. reported higher YAP expression in recurrent BCa [110]. There is additional work looking more broadly at agents that modulate BCa progression through YAP [111,112] and at molecules, including miRNAs, that affect BCa development through YAP [113,114]. YAP is also involved in BCa chemoresistance, with studies examining the naturally-derived ailanthone as an inhibitor of proliferation and migration in cisplatin-resistant BCa cells through YAP and Nrf2 repression [115,116]. Nrf2 is another transcription factor regulating phenotypic characteristics including chemoresistance, and it appears to communicate with YAP in modulating response to chemotherapy, with work showing that repression of the two increases chemosensitivity [117]. YAP, described in Table 1, along with Nrf2, are targets that merit further exploration in BCa treatment and have been explored by Cheng et al. where they discuss YAP-targeting agents as a way to address chemoresistance [118].

7. Wnt Signaling

Another important mechanism is the Wnt signaling pathway, which plays a role in organismal development [119]. Aberrant Wnt signaling is observed in BCa, especially in relation to invasive characteristics and EMT [120]. Specifically, studies have identified molecules such as EFEMP2, PYCR1, and TMEM88 which work through Wnt signaling to promote BCa invasiveness [78,121,122]. There is significantly less information around the connection between the Wnt pathway and BCa recurrence. A study by Cai et al. 2022 identified several lncRNAs associated with BCa prognosis in which KEGG analyses implicated Wnt among the associated signaling pathways [123]. There is limited work on miRNAs and Wnt signaling in recurrence, an area that warrants further investigation, as it could yield additional targets for BCa therapy. Non-coding RNAs, including miR-148b-3p, noted in Table 2, also regulate Wnt signaling, affecting the response of BCa cells to chemotherapy [124]. PTEN, a binding target of miR-148b-3p, exerts an anticancer effect in BCa cells via Wnt downregulation [124]. In addition to PTEN, another molecule in the Wnt pathway that is often modulated is beta-catenin, a transcription factor [119] whose downregulation results in greater chemosensitivity of BCa cells [125].

8. Fatty Acid Metabolism and Synthesis

In the DIANA miRPATH KEGG analyses for BCa recurrence and chemoresistance, both fatty acid biosynthesis and metabolism were implicated. Fatty acids represent an energy source for cancer cells, which obtain these acids through processes including lipogenesis and fatty acid intake [126]. Jeong et al. 2021 found that upregulation of proteins that mediate fatty acid intake is associated with poorer pathological and clinical outcomes [126]. In addition to these proteins, Abdelrahman et al. 2019 reported that upregulation of fatty acid synthase (FASN), as well as E2F1 and Her2/neu expression, is associated with BCa recurrence [127,128]. FASN has been reported to act through AKT and CCND1 to promote survival and growth in BCa [128]. In addition to the proteins implicated in fatty acid metabolism in BCa, downstream molecules like AKT and CCND1 may hold treatment and/or biomarker potential. More limited work addresses the role of fatty acids in chemoresistance. Okamura et al. 2021 found that miR-486-5p, downregulated in cisplatin-resistant BCa cell lines, binds to EHHADH, which has been implicated in fatty acid metabolism [129]. Additionally EHHADH is involved in metastatic characteristics including migration and invasion [129], and therefore may also mediate resistance.

9. Conclusions

Analysis of miRNAs, along with other non-coding RNAs, can guide cancer treatment and management by offering insight into, for example, tumors with a higher likelihood of recurrence and that may be resistant to certain chemotherapeutic agents. It is evident from this review that there is a need for additional work at the cellular level to explore associations that have been reported between miRNAs and recurrence. Specifically, there is a paucity of work exploring (i) the effects of miRNAs implicated in recurrence on the invasive phenotype and (ii) targets, regulators, and pathways through which these miRNAs may act. Identifying these molecules can help in developing novel treatments, as is the case with FGFR3. There is also a need for more work to identify molecules regulating and regulated by miRNAs that are implicated in response to chemotherapy. Once gene targets implicated in recurrence and treatment response are identified, the pathways in which they are involved should be further explored, since these may aid in bladder cancer treatment. Pathways that are important for additional investigation include Hippo, Wnt, and fatty acid metabolism, and promising gene targets include YAP and PTEN, in addition to the well-researched FGFR3.
Though this review focuses on miRNAs, there are other non-coding RNAs, such as long non-coding RNAs and circular RNAs, that have similarly been implicated in BCa resistance and recurrence and which should be explored further, especially since these networks also involved miRNAs [51,130,131,132]. This includes Cdr1as, a circular RNA that mediates bladder cancer chemotherapeutic response via miR-1270 [132] and circ-BPTF, which promotes recurrence through interaction with miR-31-5p [133]. Likewise, the circular non-coding RNA serum biomarkers circFARSA, circSHKBP1, and circBANP were found to be able to discriminate patients with recurrent BCa [134]. In addition, the long non-coding RNA FOXD2-AS1 was found to promote bladder cancer progression and recurrence through a feedback loop with Akt [135]. In a study of the TCGA BCa dataset, Zhang et al. [136] identified a biomarker signature composed of 14 long non-coding RNA to predict recurrence free survival in BCa. These studies illustrate the roles, and potential utility, of other non-coding RNA in aiding BCa treatment.
Ultimately, studies looking at miRNAs, their gene targets and associated pathways, and even other non-coding RNAs can serve as biomarkers for recurrence and resistance. This information can be used to develop cell-free assays (involving either urine or serum/plasma) and offer simple, noninvasive methods to identify patients likely to recur and those who may exhibit chemoresistance to specific drugs. This is clinically relevant as a key component of BCa management centers around prevention of progression of NMIBC to muscle-invasive disease. It is important to note that there is existing work exploring liquid biopsies as a tool in bladder cancer recurrence: this includes Urovysion, Xpert, and more preliminary findings looking at miRNAs that may be useful [15,137,138]. In addition, there are clinical trials investigating the potential of biomarkers to aid in treatment decisions. Recently, a clinical trial conducted by the SWOG Cancer Research Network reported on a gene-expression biomarker called the COXEN GC score [139]. This test aims to predict tumor response to drug treatment. Likewise, the active BISCAY trial (NCT02546661), is attempting to use protein and tumor antibody biomarkers in an effort to identify patients that are likely to repond to treatment. Also, the TOMBOLA trial (NCT04138628) measures circulating tumor DNA in an effort to identify early metastasis and thus aid in initiating early immunotherapy. Collectively these works illustrate the coming age of biomarkers aiding in clinical decision-making.
Management strategies for NMIBC such as intravesical instillation of bacillus Calmette-Guérin (BCG), intravesical chemotherapies, and even systemic immunotherapies such as pembrolizumab play an important role in reducing risk of progression to muscle-invasive disease, but are dependent on individuals’ response to these therapies, which can vary based on patient- and tumor-level factors. Determining a patient’s response to treatment presents a significant challenge and although progress has been made, currently there are no molecular biomarkers used in the clinical setting to predict response to these therapies [140].
Tumor-specific factors that can affect progression from NMIBC to MIBC include variant histology, which is defined as BCa with histology other than typical urothelial carcinoma (i.e., micropapillary, nested, plasmacytoid, neuroendocrine, or sarcomatoid tumors). NMIBCs with variant histology are associated with increased risk of upstaging to muscle-invasive disease, tend to respond less to minimally invasive treatment modalities such as intravesical instillation of BCG, and are more frequently managed with guideline-directed yet highly morbid procedures such as radical cystectomy when compared to typical urothelial carcinomas [141,142]. Interestingly, work has been done to understand how surgical margin further affects survival following radical cystectomy [143]. Though it is understood that NMIBC with variant histology represents higher risk disease [144], certain variant histologic subtypes carry higher risk than others, and debate exists on how tumor histology should guide the aggressiveness of treatment (i.e., intravesical therapies vs. cystectomy). Moreover, identification of variant histology is dependent on pathologists’ interpretation and therefore intrinsically subjective. As such, adjunctive tests may provide additional predictive value to the physician making treatment decisions. Other biomarker-based tools in bladder cancer management include Controlling Nutritional Status (CONUT) [145] and molecules such as PD-L1 [146]. MiRNAs offer important information pertaining to molecules and signaling pathways that can be regulated to effectively manage bladder cancer in conjunction with additional tools. Little is known about which miRNAs may serve as predictors of variant histology and subsequent disease progression among patients who have tumors with variant histology [12,147]. Identifying such miRNAs may aid physicians in making treatment decisions for the management of non-muscle invasive BCa.
In summary, further understanding of miRNAs and their potential to serve as biomarkers for identification of high-risk patients who may respond poorly to conservative therapies, or whose pathways may lead to the development of targeted therapies that can prevent the morbidity associated with radical cystectomy, may contribute to improved patient outcomes and decreased morbidity associated with the management of BCa.

Author Contributions

Conceptualization, S.D., J.H., T.S. and K.R.-C.; data curation, S.D. and J.H.; formal analysis, T.S.; writing—original draft preparation, S.D., J.H. and T.S.; writing—review and editing, T.S. and K.R.-C.; supervision, K.R.-C. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Available upon request.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin. 2018, 68, 7–30. [Google Scholar] [CrossRef]
  2. Matulewicz, R.S.; Steinberg, G.D. Non-muscle-invasive Bladder Cancer: Overview and Contemporary Treatment Landscape of Neoadjuvant Chemoablative Therapies. Rev. Urol. 2020, 22, 43–51. [Google Scholar]
  3. Knowles, M.A.; Hurst, C.D. Molecular biology of bladder cancer: New insights into pathogenesis and clinical diversity. Nat. Rev. Cancer 2015, 15, 25–41. [Google Scholar] [CrossRef]
  4. Lindskrog, S.V.; Prip, F.; Lamy, P.; Taber, A.; Groeneveld, C.S.; Birkenkamp-Demtröder, K.; Jensen, J.B.; Strandgaard, T.; Nordentoft, I.; Christensen, E.; et al. An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer. Nat. Commun. 2021, 12, 2301. [Google Scholar] [CrossRef]
  5. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014, 507, 315–322. [Google Scholar] [CrossRef] [Green Version]
  6. Damrauer, J.S.; Hoadley, K.A.; Chism, D.D.; Fan, C.; Tiganelli, C.J.; Wobker, S.E.; Yeh, J.J.; Milowsky, M.I.; Iyer, G.; Parker, J.S.; et al. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc. Natl. Acad. Sci. USA 2014, 111, 3110–3115. [Google Scholar] [CrossRef] [Green Version]
  7. Fong, M.H.Y.; Feng, M.; McConkey, D.J.; Choi, W. Update on bladder cancer molecular subtypes. Transl. Androl. Urol. 2020, 9, 2881–2889. [Google Scholar] [CrossRef]
  8. Kamoun, A.; de Reyniès, A.; Allory, Y.; Sjödahl, G.; Robertson, A.G.; Seiler, R.; Hoadley, K.A.; Groeneveld, C.S.; Al-Ahmadie, H.; Choi, W.; et al. A Consensus Molecular Classification of Muscle-invasive Bladder Cancer. Eur. Urol. 2020, 77, 420–433. [Google Scholar] [CrossRef]
  9. Ward, D.G.; Gordon, N.S.; Boucher, R.H.; Pirrie, S.J.; Baxter, L.; Ott, S.; Silcock, L.; Whalley, C.M.; Stockton, J.D.; Beggs, A.D.; et al. Targeted deep sequencing of urothelial bladder cancers and associated urinary DNA: A 23-gene panel with utility for non-invasive diagnosis and risk stratification. BJU Int. 2019, 124, 532–544. [Google Scholar] [CrossRef] [Green Version]
  10. Traczyk-Borszynska, M.; Borkowska, E.; Jablonowski, Z.; Jedrzejczyk, A.; Pietrusinski, M.; Kaluzewski, B.; Sosnowski, M.; Borowiec, M. Genetic diversity of urinary bladder cancer and the risk of recurrence based on mutation analysis. Neoplasma 2016, 63, 952–960. [Google Scholar] [CrossRef]
  11. Yin, X.H.; Jin, Y.H.; Cao, Y.; Wong, Y.; Weng, H.; Sun, C.; Deng, J.H.; Zeng, X.T. Development of a 21-miRNA Signature Associated with the Prognosis of Patients with Bladder Cancer. Front. Oncol. 2019, 9, 729. [Google Scholar] [CrossRef] [PubMed]
  12. Usuba, W.; Urabe, F.; Yamamoto, Y.; Matsuzaki, J.; Sasaki, H.; Ichikawa, M.; Takizawa, S.; Aoki, Y.; Niida, S.; Kato, K.; et al. Circulating miRNA panels for specific and early detection in bladder cancer. Cancer Sci. 2019, 110, 408–419. [Google Scholar] [CrossRef]
  13. Enokida, H.; Yoshino, H.; Matsushita, R.; Nakagawa, M. The role of microRNAs in bladder cancer. Investig. Clin. Urol. 2016, 57 (Suppl. 1), S60–S76. [Google Scholar] [CrossRef] [Green Version]
  14. Long, J.D.; Sullivan, T.B.; Humphrey, J.; Logvinenko, T.; Summerhayes, K.A.; Kozinn, S.; Harty, N.; Summerhayes, I.C.; Libertino, J.A.; Holway, A.H.; et al. A non-invasive miRNA based assay to detect bladder cancer in cell-free urine. Am. J. Transl. Res. 2015, 7, 2500–2509. [Google Scholar] [PubMed]
  15. Urabe, F.; Matsuzaki, J.; Ito, K.; Takamori, H.; Tsuzuki, S.; Miki, J.; Kimura, T.; Egawa, S.; Nakamura, E.; Matsui, Y.; et al. Serum microRNA as liquid biopsy biomarker for the prediction of oncological outcomes in patients with bladder cancer. Int. J. Urol. Off. J. Jpn. Urol. Assoc. 2022, 29, 968–976. [Google Scholar] [CrossRef] [PubMed]
  16. Hou, G.; Xu, W.; Jin, Y.; Wu, J.; Pan, Y.; Zhou, F. MiRNA-217 accelerates the proliferation and migration of bladder cancer via inhibiting KMT2D. Biochem. Biophys. Res. Commun. 2019, 519, 747–753. [Google Scholar] [CrossRef]
  17. Feng, C.; Sun, P.; Hu, J.; Feng, H.; Li, M.; Liu, G.; Pan, Y.; Feng, Y.; Xu, Y.; Feng, K.; et al. miRNA-556-3p promotes human bladder cancer proliferation, migration and invasion by negatively regulating DAB2IP expression. Int. J. Oncol. 2017, 50, 2101–2112. [Google Scholar] [CrossRef] [Green Version]
  18. Vlachos, I.S.; Zagganas, K.; Paraskevopoulou, M.D.; Georgakilas, G.; Karagkouni, D.; Vergoulis, T.; Dalamagas, T.; Hatzigeorgiou, A.G. DIANA-miRPath v3.0: Deciphering microRNA function with experimental support. Nucleic Acids Res. 2015, 43, W460–W466. [Google Scholar] [CrossRef]
  19. Vlachos, I.S.; Paraskevopoulou, M.D.; Karagkouni, D.; Georgakilas, G.; Vergoulis, T.; Kanellos, I.; Anastasopoulos, I.-L.; Maniou, S.; Karathanou, K.; Kalfakakou, D.; et al. DIANA-TarBase v7.0: Indexing more than half a million experimentally supported miRNA:mRNA interactions. Nucleic Acids Res. 2015, 43, D153–D159. [Google Scholar] [CrossRef]
  20. Du, L.; Jiang, X.; Duan, W.; Wang, R.; Wang, L.; Zheng, G.; Yan, K.; Wang, L.; Li, J.; Zhang, X.; et al. Cell-free microRNA expression signatures in urine serve as novel noninvasive biomarkers for diagnosis and recurrence prediction of bladder cancer. Oncotarget 2017, 8, 40832–40842. [Google Scholar] [CrossRef] [Green Version]
  21. Juracek, J.; Stanik, M.; Vesela, P.; Radova, L.; Dolezel, J.; Svoboda, M.; Slaby, O. Tumor expression of miR-34a-3p is an inde-pendent predictor of recurrence in non-muscle-invasive bladder cancer and promising additional factor to improve predictive value of EORTC nomogram. Urol. Oncol. 2019, 37, 184.e1–184.e7. [Google Scholar] [CrossRef]
  22. Andrew, A.S.; Marsit, C.J.; Schned, A.R.; Seigne, J.D.; Kelsey, K.T.; Moore, J.H.; Perreard, L.; Karagas, M.R.; Sempere, L.F. Expression of tumor suppressive microRNA-34a is associated with a reduced risk of bladder cancer recurrence. Int. J. Cancer 2015, 137, 1158–1166. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Blanca, A.; Sanchez-Gonzalez, A.; Requena, M.J.; Carrasco-Valiente, J.; Gomez-Gomez, E.; Cheng, L.; Cimadamore, A.; Mon-tironi, R.; Lopez-Beltran, A. Expression of miR-100 and miR-138 as prognostic biomarkers in non-muscle-invasive bladder cancer. APMIS Acta Pathol. Microbiol. Immunol. Scand. 2019, 127, 545–553. [Google Scholar] [CrossRef] [PubMed]
  24. Wang, T.; Yang, Y.; Wang, Z.; Zhang, X.; Li, D.; Wei, J. A SNP of miR-146a is involved in bladder cancer relapse by affecting the function of bladder cancer stem cells via the miR-146a signallings. J. Cell. Mol. Med. 2020, 24, 8545–8556. [Google Scholar] [CrossRef] [PubMed]
  25. Ma, L.; Xu, Z.; Xu, C.; Jiang, X. MicroRNA-148a represents an independent prognostic marker in bladder cancer. Tumor Biol. 2016, 37, 7915–7920. [Google Scholar] [CrossRef]
  26. Jiang, X.; Du, L.; Wang, L.; Li, J.; Liu, Y.; Zheng, G.; Qu, A.; Zhang, X.; Pan, H.; Yang, Y.; et al. Serum microRNA expression signatures identified from genome-wide microRNA profiling serve as novel noninvasive biomarkers for diagnosis and recurrence of bladder cancer. Int. J. Cancer 2015, 136, 854–862. [Google Scholar] [CrossRef]
  27. Zhang, X.; Zhang, Y.; Liu, X.; Fang, A.; Wang, J.; Yang, Y.; Wang, L.; Du, L.; Wang, C. Direct quantitative detection for cell-free miR-155 in urine: A potential role in diagnosis and prognosis for non-muscle invasive bladder cancer. Oncotarget 2016, 7, 3255. [Google Scholar] [CrossRef] [Green Version]
  28. Li, Z.; Lin, C.; Zhao, L.; Zhou, L.; Pan, X.; Quan, J.; Peng, X.; Li, W.; Li, H.; Xu, J.; et al. Oncogene miR-187-5p is associated with cellular proliferation, migration, invasion, apoptosis and an increased risk of recurrence in bladder cancer. Biomed. Pharmacother. 2018, 105, 461–469. [Google Scholar] [CrossRef]
  29. Yun, S.J.; Jeong, P.; Kim, W.-T.; Kim, T.H.; Lee, Y.-S.; Song, P.H.; Choi, Y.-H.; Kim, I.Y.; Moon, S.-K.; Kim, W.-J. Cell-free microRNAs in urine as diagnostic and prognostic biomarkers of bladder cancer. Int. J. Oncol. 2012, 41, 1871–1878. [Google Scholar] [CrossRef] [Green Version]
  30. Yang, Y.; Qu, A.; Liu, J.; Wang, R.; Liu, Y.; Li, G.; Duan, W.; Fang, Q.; Jiang, X.; Wang, L.; et al. Serum miR-210 Contributes to Tumor Detection, Stage Prediction and Dynamic Surveillance in Patients with Bladder Cancer. PLoS ONE 2015, 10, e0135168. [Google Scholar] [CrossRef]
  31. Wang, J.; Zhang, X.; Wang, L.; Dong, Z.; Du, L.; Yang, Y.; Guo, Y.; Wang, C. Downregulation of urinary cell-free mi-croRNA-214 as a diagnostic and prognostic biomarker in bladder cancer. J. Surg. Oncol. 2015, 111, 992–999. [Google Scholar] [CrossRef]
  32. Kim, S.M.; Kang, H.W.; Kim, W.T.; Kim, Y.J.; Yun, S.J.; Lee, S.C.; Kim, W.J. Cell-Free microRNA-214 From Urine as a Biomarker for Non-Muscle-Invasive Bladder Cancer. Korean J. Urol. 2013, 54, 791–796. [Google Scholar] [CrossRef] [Green Version]
  33. Tsikrika, F.D.; Avgeris, M.; Levis, P.K.; Tokas, T.; Stravodimos, K.; Scorilas, A. miR-221/222 cluster expression improves clinical stratification of non-muscle invasive bladder cancer (TaT1) patients’ risk for short-term relapse and progression. Genes Chro-Mosomes Cancer 2018, 57, 150–161. [Google Scholar] [CrossRef]
  34. Li, Z.; Zhou, L.; Lin, C.; Pan, X.; Xie, J.; Zhao, L.; Quan, J.; Xu, J.; Guan, X.; Xu, W.; et al. MiR-302b regulates cell functions and acts as a potential biomarker to predict recurrence in bladder cancer. Life Sci. 2018, 209, 15–23. [Google Scholar] [CrossRef]
  35. Shee, K.; Seigne, J.D.; Karagas, M.R.; Marsit, C.J.; Hinds, J.W.; Schned, A.R.; Pettus, J.R.; Armstrong, D.A.; Miller, T.W.; Andrew, A.S.; et al. Identification of Let-7f-5p as a novel bi-omarker of recurrence in non-muscle invasive bladder cancer. Cancer Biomark. Sect. Dis. Mark. 2020, 29, 101–110. [Google Scholar] [CrossRef]
  36. Wang, C.; Tang, Z.; Zhang, Z.; Liu, T.; Zhang, J.; Huang, H.; Li, Y. MiR-7-5p suppresses invasion via downregulation of the autophagy-related gene ATG7 and increases chemoresistance to cisplatin in BCa. Bioengineered 2022, 13, 7328–7339. [Google Scholar] [CrossRef]
  37. Tao, J.; Lu, Q.; Wu, D.; Li, P.; Xu, B.; Qing, W.; Wang, M.; Zhang, Z.; Zhang, W. microRNA-21 modulates cell proliferation and sensitivity to doxorubicin in bladder cancer cells. Oncol. Rep. 2011, 25, 1721–1729. [Google Scholar]
  38. Xiao, J.; Niu, S.; Zhu, J.; Lv, L.; Deng, H.; Pan, D.; Shen, D.; Xu, C.; Shen, Z.; Tao, T. miR-22-3p enhances multi-chemoresistance by targeting NET1 in bladder cancer cells. Oncol. Rep. 2018, 39, 2731–2740. [Google Scholar] [CrossRef] [Green Version]
  39. Meng, W.; Efstathiou, J.; Singh, R.; McElroy, J.; Volinia, S.; Cui, R.; Cui, R.; Ibrahim, A.; Johnson, B.; Gupta, N.; et al. MicroRNA Biomarkers for Patients with Mus-cle-Invasive Bladder Cancer Undergoing Selective Bladder-Sparing Trimodality Treatment. Int. J. Radiat. Oncol. Biol. Phys. 2019, 104, 197–206. [Google Scholar] [CrossRef]
  40. Deng, Y.; Bai, H.; Hu, H. rs11671784 G/A variation in miR-27a decreases chemo-sensitivity of bladder cancer by decreasing miR-27a and increasing the target RUNX-1 expression. Biochem. Biophys. Res. Commun. 2015, 458, 321–327. [Google Scholar] [CrossRef]
  41. Hwang, T.I.S.; Chen, P.C.; Tsai, T.F.; Lin, J.F.; Chou, K.Y.; Ho, C.Y.; Chen, H.E.; Chang, A.C. Hsa-miR-30a-3p overcomes the acquired protective autophagy of bladder cancer in chemotherapy and suppresses tumor growth and muscle invasion. Cell Death Dis. 2022, 13, 390. [Google Scholar] [CrossRef] [PubMed]
  42. Xu, T.; Qin, L.; Zhu, Z.; Wang, X.; Liu, Y.; Fan, Y.; Zhong, S.; Wang, X.; Zhang, X.; Xia, L.; et al. MicroRNA-31 functions as a tumor suppressor and increases sensitivity to mitomycin-C in urothelial bladder cancer by targeting integrin α5. Oncotarget 2016, 7, 27445–27457. [Google Scholar] [CrossRef] [PubMed]
  43. Liu, X.; Liu, X.; Wu, Y.; Fang, Z.; Wu, Q.; Wu, C.; Hao, Y.; Yang, X.; Zhao, J.; Li, J.; et al. MicroRNA-34a Attenuates Metastasis and Chemoresistance of Bladder Cancer Cells by Targeting the TCF1/LEF1 Axis. Cell Physiol. Biochem. 2018, 48, 87–98. [Google Scholar] [CrossRef]
  44. Vinall, R.L.; Ripoll, A.Z.; Wang, S.; Pan, C.X.; deVere White, R.W. MiR-34a chemosensitizes bladder cancer cells to cisplatin treatment regardless of p53-Rb pathway status. Int. J. Cancer 2012, 130, 2526–2538. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Li, H.; Yu, G.; Shi, R.; Lang, B.; Chen, X.; Xia, D.; Xiao, H.; Guo, X.; Guan, W.; Ye, Z.; et al. Cisplatin-induced epigenetic activation of miR-34a sensitizes bladder cancer cells to chemotherapy. Mol. Cancer 2014, 13, 8. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Liu, J.; Wang, H.; Wang, Y.; Li, Z.; Pan, Y.; Liu, Q.; Yang, M.; Wang, J. Repression of the miR-93-enhanced sensitivity of bladder carcinoma to chemotherapy involves the regulation of LASS2. OncoTargets Ther. 2016, 9, 1813–1822. [Google Scholar]
  47. Luan, T.; Fu, S.; Huang, L.; Zuo, Y.; Ding, M.; Li, N.; Chen, J.; Wang, H.; Wang, J. MicroRNA-98 promotes drug resistance and regulates mitochondrial dynamics by targeting LASS2 in bladder cancer cells. Exp. Cell Res. 2018, 373, 188–197. [Google Scholar] [CrossRef]
  48. Bu, Q.; Fang, Y.; Cao, Y.; Chen, Q.; Liu, Y. Enforced expression of miR-101 enhances cisplatin sensitivity in human bladder cancer cells by modulating the cyclooxygenase-2 pathway. Mol. Med. Rep. 2014, 10, 2203–2209. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. Li, B.; Xie, D.; Zhang, H. MicroRNA-101-3p advances cisplatin sensitivity in bladder urothelial carcinoma through targeted silencing EZH2. J. Cancer 2019, 10, 2628–2634. [Google Scholar] [CrossRef] [Green Version]
  50. Cao, J.; Wang, Q.; Wu, G.; Li, S.; Wang, Q. miR-129-5p inhibits gemcitabine resistance and promotes cell apoptosis of bladder cancer cells by targeting Wnt5a. Int. Urol. Nephrol. 2018, 50, 1811–1819. [Google Scholar] [CrossRef]
  51. Li, B.; Zhang, H. Knockdown of microRNA-130b improves doxorubicin sensitivity in bladder urothelial carcinoma by nega-tively regulating cylindromatosis expression. Arch. Med. Sci. AMS 2021, 17, 1038–1043. [Google Scholar] [CrossRef] [Green Version]
  52. Wang, H.; Li, Q.; Niu, X.; Wang, G.; Zheng, S.; Fu, G.; Wang, Z. miR-143 inhibits bladder cancer cell proliferation and enhances their sensitivity to gemcitabine by repressing IGF-1R signaling. Oncol. Lett. 2017, 13, 435–440. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Deng, H.; Lv, L.; Li, Y.; Zhang, C.; Meng, F.; Pu, Y.; Xiao, J.; Qian, L.; Zhao, W.; Liu, Q.; et al. miR-193a-3p regulates the multi-drug resistance of bladder cancer by targeting the LOXL4 gene and the oxidative stress pathway. Mol. Cancer 2014, 13, 234. [Google Scholar] [CrossRef]
  54. Lv, L.; Li, Y.; Deng, H.; Zhang, C.; Pu, Y.; Qian, L.; Xiao, J.; Zhao, W.; Liu, Q.; Zhang, D.; et al. MiR-193a-3p promotes the multi-chemoresistance of bladder cancer by targeting the HOXC9 gene. Cancer Lett. 2015, 357, 105–113. [Google Scholar] [CrossRef] [PubMed]
  55. Deng, H.; Lv, L.; Li, Y.; Zhang, C.; Meng, F.; Pu, Y.; Xiao, J.; Qian, L.; Zhao, W.; Liu, Q.; et al. The miR-193a-3p regulated PSEN1 gene suppresses the mul-ti-chemoresistance of bladder cancer. Biochim. Biophys. Acta 2015, 1852, 520–528. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Li, Y.; Deng, H.; Lv, L.; Zhang, C.; Qian, L.; Xiao, J.; Zhao, W.; Liu, Q.; Zhang, D.; Wang, Y.; et al. The miR-193a-3p-regulated ING5 gene activates the DNA damage response pathway and inhibits multi-chemoresistance in bladder cancer. Oncotarget 2015, 6, 10195–10206. [Google Scholar] [CrossRef] [Green Version]
  57. Zhou, J.; Duan, H.; Xie, Y.; Ning, Y.; Zhang, X.; Hui, N.; Wang, C.; Zhang, J.; Zhou, J. MiR-193a-5p Targets the Coding Region of AP-2α mRNA and Induces Cisplatin Resistance in Bladder Cancers. J. Cancer 2016, 7, 1740–1746. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Shindo, T.; Niinuma, T.; Nishiyama, N.; Shinkai, N.; Kitajima, H.; Kai, M.; Maruyama, R.; Tokino, T.; Masumori, N.; Suzuki, H. Epigenetic silencing of miR-200b is associated with cisplatin resistance in bladder cancer. Oncotarget 2018, 9, 24457–24469. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  59. Liu, J.; Bi, J.; Li, Z.; Li, Z.; Liu, X.; Kong, C. miR-214 reduces cisplatin resistance by targeting netrin-1 in bladder cancer cells. Int. J. Mol. Med. 2018, 41, 1765–1773. [Google Scholar] [CrossRef] [Green Version]
  60. Li, P.; Yang, X.; Cheng, Y.; Zhang, X.; Yang, C.; Deng, X.; Li, P.; Tao, J.; Yang, H.; Wei, J.; et al. MicroRNA-218 Increases the Sensitivity of Bladder Cancer to Cisplatin by Targeting Glut1. Cell Physiol. Biochem. Int. J. Exp. Cell Physiol. Biochem. Pharmacol. 2017, 41, 921–932. [Google Scholar] [CrossRef]
  61. Zeng, L.P.; Hu, Z.M.; Li, K.; Xia, K. miR-222 attenuates cisplatin-induced cell death by targeting the PPP2R2A/Akt/mTOR Axis in bladder cancer cells. J. Cell Mol. Med. 2016, 20, 559–567. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Li, R.; Zheng, J.Z.; Huang, X. Suppression of HAX-1 induced by miR-325 resensitizes bladder cancer cells to cisplatin-induced apoptosis. Eur. Rev. Med. Pharmacol. Sci. 2020, 24, 9303–9314. [Google Scholar] [PubMed]
  63. Yu, M.; Ozaki, T.; Sun, D.; Xing, H.; Wei, B.; An, J.; Yang, J.; Gao, Y.; Liu, S.; Kong, C.; et al. HIF-1α-dependent miR-424 induction confers cisplatin resistance on bladder cancer cells through down-regulation of pro-apoptotic UNC5B and SIRT4. J. Exp. Clin. Cancer Res. 2020, 39, 108. [Google Scholar] [CrossRef] [PubMed]
  64. Chen, D.; Xie, S.; Wu, Y.; Cui, Y.; Cai, Y.; Lan, L.; Yang, H.; Chen, J.; Chen, W. Reduction of Bladder Cancer Chemosensitivity Induced by the Effect of HOXA-AS3 as a ceRNA for miR-455-5p That Upregulates Notch1. Front. Oncol. 2020, 10, 572672. [Google Scholar] [CrossRef]
  65. Salimian, J.; Baradaran, B.; Azimzadeh Jamalkandi, S.; Moridikia, A.; Ahmadi, A. MiR-486-5p enhances cisplatin sensitivity of human muscle-invasive bladder cancer cells by induction of apoptosis and down-regulation of metastatic genes. Urol. Oncol. 2020, 38, 738.e9–738.e21. [Google Scholar] [CrossRef]
  66. Chen, M.K.; Zhou, J.H.; Wang, P.; Ye, Y.L.; Liu, Y.; Zhou, J.W.; Chen, Z.J.; Yang, J.K.; Liao, D.Y.; Liang, Z.J.; et al. BMI1 activates P-glycoprotein via transcription repression of miR-3682-3p and enhances chemoresistance of bladder cancer cell. Aging 2021, 13, 18310–18330. [Google Scholar] [CrossRef]
  67. Du, B.; Js, S. Targeting Epithelial-Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer. Molecules 2016, 21, 965. Available online: https://pubmed.ncbi.nlm.nih.gov/27455225/ (accessed on 28 November 2022). [CrossRef] [Green Version]
  68. Lu, W.; Kang, Y. Epithelial-mesenchymal plasticity in cancer progression and metastasis. Dev. Cell 2019, 49, 361–374. [Google Scholar] [CrossRef]
  69. Baumgart, E.; Cohen, M.S.; Silva Neto, B.; Jacobs, M.A.; Wotkowicz, C.; Rieger-Christ, K.M.; Biolo, A.; Zeheb, R.; Loda, M.; Libertino, J.A.; et al. Identification and prognostic significance of an epithelial-mesenchymal transition expression profile in human bladder tumors. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2007, 13, 1685–1694. [Google Scholar] [CrossRef] [Green Version]
  70. Tan, S.; Kang, Y.; Li, H.; He, H.Q.; Zheng, L.; Wu, S.Q.; Ai, K.; Zhang, L.; Xu, R.; Zhang, X.-Z.; et al. circST6GALNAC6 suppresses bladder cancer metastasis by sponging miR-200a-3p to modulate the STMN1/EMT axis. Cell Death Dis. 2021, 12, 168. [Google Scholar] [CrossRef]
  71. Li, W.J.; Li, G.; Liu, Z.W.; Chen, Z.Y.; Pu, R. LncRNA LINC00355 promotes EMT and metastasis of bladder cancer cells through the miR-424-5p/HMGA2 axis. Neoplasma 2021, 68, 1225–1235. [Google Scholar] [CrossRef]
  72. Liu, L.; Qiu, M.; Tan, G.; Liang, Z.; Qin, Y.; Chen, L.; Chen, H.; Liu, J. miR-200c Inhibits invasion, migration and proliferation of bladder cancer cells through down-regulation of BMI-1 and E2F3. J. Transl. Med. 2014, 12, 305. [Google Scholar] [CrossRef] [Green Version]
  73. Chen, M.F.; Zeng, F.; Qi, L.; Zu, X.B.; Wang, J.; Liu, L.F.; Li, Y. Transforming growth factor-β1 induces epithelial-mesenchymal transition and increased expression of matrix metalloproteinase-16 via miR-200b downregulation in bladder cancer cells. Mol. Med. Rep. 2014, 10, 1549–1554. [Google Scholar] [CrossRef]
  74. Mei, Y.; Zheng, J.; Xiang, P.; Liu, C.; Fan, Y. Prognostic value of the miR-200 family in bladder cancer: A systematic review and meta-analysis. Medicine 2020, 99, e22891. [Google Scholar] [CrossRef]
  75. Wu, Y.S.; Ho, J.Y.; Yu, C.P.; Cho, C.J.; Wu, C.L.; Huang, C.S.; Gao, H.W.; Yu, D.S. Ellagic Acid Resensitizes Gemcita-bine-Resistant Bladder Cancer Cells by Inhibiting Epithelial-Mesenchymal Transition and Gemcitabine Transporters. Cancers 2021, 13, 2032. [Google Scholar] [CrossRef]
  76. Xie, Y.; Zhu, S.; Zang, J.; Wu, G.; Wen, Y.; Liang, Y.; Long, Y.; Guo, W.; Zang, C.; Hu, X.; et al. ADNP prompts the cisplatin-resistance of bladder cancer via TGF-β-mediated epithelial-mesenchymal transition (EMT) pathway. J. Cancer 2021, 12, 5114–5124. [Google Scholar] [CrossRef]
  77. Wang, C.; Li, A.; Yang, S.; Qiao, R.; Zhu, X.; Zhang, J. CXCL5 promotes mitomycin C resistance in non-muscle invasive bladder cancer by activating EMT and NF-κB pathway. Biochem. Biophys. Res. Commun. 2018, 498, 862–868. [Google Scholar] [CrossRef]
  78. Zhou, Q.; Chen, S.; Lu, M.; Luo, Y.; Wang, G.; Xiao, Y.; Ju, L.; Wang, X. EFEMP2 suppresses epithelial-mesenchymal transition via Wnt/β-catenin signaling pathway in human bladder cancer. Int. J. Biol. Sci. 2019, 15, 2139–2155. [Google Scholar] [CrossRef]
  79. Huang, H.; Fan, X.; Zhang, X.; Xie, Y.; Ji, Z. LncRNA CARLo-7 facilitates proliferation, migration, invasion, and EMT of bladder cancer cells by regulating Wnt/β-catenin and JAK2/STAT3 signaling pathways. Transl. Androl. Urol. 2020, 9, 2251–2261. [Google Scholar] [CrossRef]
  80. Yang, N.; Gao, J.; Hou, R.; Xu, X.; Yang, N.; Huang, S. Grape Seed Proanthocyanidins Inhibit Migration and Invasion of Bladder Cancer Cells by Reversing EMT through Suppression of TGF-β Signaling Pathway. Oxidative Med. Cell. Longev. 2021, 2021, 1–10. [Google Scholar] [CrossRef]
  81. Yang, J.; Fan, L.; Liao, X.; Cui, G.; Hu, H. CRTAC1 (Cartilage acidic protein 1) inhibits cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) process in bladder cancer by downregulating Yin Yang 1 (YY1) to inactivate the TGF-β pathway. Bioengineered 2021, 12, 9377–9389. [Google Scholar] [CrossRef]
  82. Zhang, Z.; Chen, F.; Zhan, H.; Chen, L.; Deng, Q.; Xiong, T.; Ye, J. lncRNA CASC9 sponges miR-758-3p to promote prolifer-ation and EMT in bladder cancer by upregulating TGF-β2. Oncol. Rep. 2021, 45, 265–277. [Google Scholar] [CrossRef]
  83. Zhang, Z.; Ao, P.; Han, H.; Zhang, Q.; Chen, Y.; Han, J.; Huang, Q.; Huang, H.; Zhuo, D. LncRNA PLAC2 upregulates miR-663 to downregulate TGF-β1 and suppress bladder cancer cell migration and invasion. BMC Urol. 2020, 20, 94. [Google Scholar] [CrossRef]
  84. Huang, C.S.; Tsai, C.H.; Yu, C.P.; Wu, Y.S.; Yee, M.F.; Ho, J.Y.; Yu, D.S. Long Noncoding RNA LINC02470 Sponges Mi-croRNA-143-3p and Enhances SMAD3-Mediated Epithelial-to-Mesenchymal Transition to Promote the Aggressive Properties of Bladder Cancer. Cancers 2022, 14, 968. [Google Scholar] [CrossRef]
  85. Gao, R.; Zhang, N.; Yang, J.; Zhu, Y.; Zhang, Z.; Wang, J.; Xu, X.; Li, Z.; Liu, X.; Li, Z.; et al. Long non-coding RNA ZEB1-AS1 regulates miR-200b/FSCN1 signaling and enhances migration and invasion induced by TGF-β1 in bladder cancer cells. J. Exp. Clin. Cancer Res. CR 2019, 38, 111. [Google Scholar] [CrossRef] [Green Version]
  86. Zhuang, J.; Shen, L.; Yang, L.; Huang, X.; Lu, Q.; Cui, Y.; Zheng, X.; Zhao, X.; Zhang, D.; Huang, R.; et al. TGFβ1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer. Theranostics 2017, 7, 3053–3607. [Google Scholar] [CrossRef]
  87. Vermeulen, K.; Van Bockstaele, D.R.; Berneman, Z.N. The cell cycle: A review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif. 2003, 36, 131–149. [Google Scholar] [CrossRef]
  88. Wang, G.; Zheng, L.; Yu, Z.; Liao, G.; Lu, L.; Xu, R.; Zhao, Z.; Chen, G. Increased cyclin-dependent kinase 6 expression in bladder cancer. Oncol. Lett. 2012, 4, 43–46. [Google Scholar] [CrossRef]
  89. Long, Q.; Ma, A.H.; Zhang, H.; Cao, Z.; Xia, R.; Lin, T.Y.; Sonpavde, G.P.; de Vere White, R.; Guo, J.; Pan, C.-X. Combination of cyclin-dependent kinase and immune check-point inhibitors for the treatment of bladder cancer. Cancer Immunol. Immunother. 2020, 69, 2305–2317. [Google Scholar] [CrossRef]
  90. Wu, S.; Yang, J.; Xu, H.; Wang, X.; Zhang, R.; Lu, W.; Yang, J.; Li, X.; Chen, S.; Zou, Y.; et al. Circular RNA circGLIS3 promotes bladder cancer proliferation via the miR-1273f/SKP1/Cyclin D1 axis. Cell Biol. Toxicol. 2022, 38, 129–146. [Google Scholar] [CrossRef]
  91. Blanca, A.; Requena, M.J.; Alvarez, J.; Cheng, L.; Montironi, R.; Raspollini, M.R.; Reymundo, C.; Lopez-Beltran, A. FGFR3 and Cyclin D3 as urine biomarkers of bladder cancer recurrence. Biomarkers Med. 2016, 10, 243–253. [Google Scholar] [CrossRef]
  92. Shariat, S.F.; Karakiewicz, P.I.; Ashfaq, R.; Lerner, S.P.; Palapattu, G.S.; Cote, R.J.; Sagalowsky, A.I.; Lotan, Y. Multiple bi-omarkers improve prediction of bladder cancer recurrence and mortality in patients undergoing cystectomy. Cancer 2008, 112, 315–325. [Google Scholar] [CrossRef]
  93. March-Villalba, J.A.; Ramos-Soler, D.; Soriano-Sarrió, P.; Hervás-Marín, D.; Martínez-García, L.; Martínez-Jabaloyas, J.M. Immunohistochemical expression of Ki-67, Cyclin D1, p16INK4a, and Survivin as a predictive tool for recurrence and pro-gression-free survival in papillary urothelial bladder cancer pTa/pT1 G2 (WHO 1973). Urol. Oncol. 2019, 37, 158–165. [Google Scholar] [CrossRef]
  94. Jing, W.; Wang, G.; Cui, Z.; Xiong, G.; Jiang, X.; Li, Y.; Li, W.; Han, B.; Chen, S.; Shi, B. FGFR3 Destabilizes PD-L1 via NEDD4 to Control T-cell–Mediated Bladder Cancer Immune Surveillance. Cancer Res 2022, 82, 114–129. [Google Scholar] [CrossRef]
  95. Van Rhijn, B.W.G.; Mertens, L.S.; Mayr, R.; Bostrom, P.J.; Real, F.X.; Zwarthoff, E.C.; Boormans, J.L.; Abas, C.; Geert Jacob Leonard Hubert van Leenders; Götz, S.; et al. FGFR3 Mutation Status and FGFR3 Expression in a Large Bladder Cancer Cohort Treated by Radical Cystectomy: Implications for Anti-FGFR3 Treatment? Eur. Urol. 2020, 78, 682–687. [Google Scholar] [CrossRef]
  96. Kacew, A.; Sweis, R.F. FGFR3 Alterations in the Era of Immunotherapy for Urothelial Bladder Cancer. Front. Immunol. 2020, 11. [Google Scholar] [CrossRef]
  97. Gulìa, C.; Baldassarra, S.; Signore, F.; Rigon, G.; Pizzuti, V.; Gaffi, M.; Briganti, V.; Porrello, A.; Piergentili, R. Role of Non-Coding RNAs in the Etiology of Bladder Cancer. Genes 2017, 8, 339. [Google Scholar] [CrossRef] [Green Version]
  98. Sikic, D.; Taubert, H.; Breyer, J.; Eckstein, M.; Weyerer, V.; Keck, B.; Kubon, J.; Otto, W.; Worst, T.S.; Kriegmair, M.C.; et al. The Prognostic Value of FGFR3 Expression in Patients with T1 Non-Muscle Invasive Bladder Cancer. Cancer Manag. Res. 2021, 13, 6567–6578. [Google Scholar] [CrossRef]
  99. Beukers, W.; van der Keur, K.A.; Kandimalla, R.; Vergouwe, Y.; Steyerberg, E.W.; Boormans, J.L.; Jensen, J.B.; Lorente, J.A.; Real, F.X.; Segersten, U.; et al. FGFR3, TERT and OTX1 as a Urinary Biomarker Combination for Surveillance of Patients with Bladder Cancer in a Large Prospective Multicenter Study. J. Urol. 2017, 197, 1410–1418. [Google Scholar] [CrossRef]
  100. Pal, S.K.; Somford, D.M.; Grivas, P.; Sridhar, S.S.; Gupta, S.; Bellmunt, J.; Sonpavde, G.; Fleming, M.T.; Lerner, S.P.; Loriot, Y.; et al. Targeting FGFR3 alterations with adjuvant infigratinib in invasive urothelial carcinoma: The phase III PROOF 302 trial. Future Oncol. 2022, 18, 2599–2614. [Google Scholar] [CrossRef]
  101. Subbiah, V.; Iannotti, N.O.; Gutierrez, M.; Smith, D.C.; Féliz, L.; Lihou, C.F.; Tian, C.; Silverman, I.; Ji, T.; Saleh, M. FIGHT-101, a first-in-human study of potent and selective FGFR 1-3 inhibitor pemigatinib in pan-cancer patients with FGF/FGFR alterations and advanced malignancies. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2022, 33, 522–533. [Google Scholar] [CrossRef]
  102. Teo, M.Y.; Mota, J.M.; Whiting, K.A.; Li, H.A.; Funt, S.A.; Lee, C.H.; Solit, D.B.; Al-Ahmadie, H.; Milowsky, M.I.; Balar, A.; et al. Fibroblast Growth Factor Receptor 3 Alteration Status is Associated with Differential Sensitivity to Platinum-based Chemotherapy in Locally Advanced and Metastatic Urothelial Carcinoma. Eur. Urol. 2020, 78, 907–915. [Google Scholar] [CrossRef]
  103. Xie, X.; Lin, J.; Zhong, Y.; Fu, M.; Tang, A. FGFR3S249C mutation promotes chemoresistance by activating Akt signaling in bladder cancer cells. Exp. Ther. Med. 2019, 18, 1226–1234. [Google Scholar] [CrossRef]
  104. Yang, Z.; Zhang, R.; Ge, Y.; Qin, X.; Kang, X.; Wang, Y.; Zhang, X.; Song, C.; Quan, X.; Wang, H.; et al. Somatic FGFR3 Mutations Distinguish a Subgroup of Mus-cle-Invasive Bladder Cancers with Response to Neoadjuvant Chemotherapy. eBioMedicine 2018, 35, 198–203. [Google Scholar] [CrossRef]
  105. di Martino, E.; Alder, O.; Hurst, C.D.; Knowles, M.A. ETV5 links the FGFR3 and Hippo signalling pathways in bladder cancer. Sci. Rep. 2019, 9, 5740. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Zhao, B.; Li, L.; Lei, Q.; Guan, K.-L. The Hippo-YAP pathway in organ size control and tumorigenesis: An updated version. Genes Dev. 2010, 24, 862–874. [Google Scholar] [CrossRef] [Green Version]
  107. Huang, Z.; Wang, X.; Ma, L.; Guo, Z.; Liu, H.; Du, M.; Chu, H.; Wang, M.; Wang, Z.; Zhang, Z. Genetic variations in Hippo pathway genes influence bladder cancer risk in a Chinese population. Arch. Toxicol. 2020, 94, 785–794. [Google Scholar] [CrossRef]
  108. Xu, J.; Fang, X.; Long, L.; Wang, S.; Qian, S.; Lyu, J. HMGA2 promotes breast cancer metastasis by modulating Hippo-YAP signaling pathway. Cancer Biol. Ther. 2021, 22, 5–11. [Google Scholar] [CrossRef]
  109. Xia, J.; Zeng, M.; Zhu, H.; Chen, X.; Weng, Z.; Li, S. Emerging role of Hippo signalling pathway in bladder cancer. J. Cell. Mol. Med. 2018, 22, 4–15. [Google Scholar] [CrossRef]
  110. Ghasemi, H.; Mousavibahar, S.H.; Hashemnia, M.; Karimi, J.; Khodadadi, I.; Mirzaei, F.; Tavilani, H. Tissue stiffness contrib-utes to YAP activation in bladder cancer patients undergoing transurethral resection. Ann. N. Y. Acad. Sci. 2020, 1473, 48–61. [Google Scholar] [CrossRef]
  111. Shiraishi, Y.; Maehama, T.; Nishio, M.; Otani, J.; Hikasa, H.; Mak, T.W.; Sasaki, T.; Honma, T.; Kondoh, Y.; Osada, H.; et al. N-(3,4-dimethoxyphenethyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine inhibits bladder cancer progression by sup-pressing YAP1/TAZ. Genes Cells Devoted Mol. Cell Mech. 2022, 27, 602–612. [Google Scholar] [CrossRef]
  112. Gao, Y.; Shi, Q.; Xu, S.; Du, C.; Liang, L.; Wu, K.; Wang, K.; Wang, X.; Chang, L.S.; He, D.; et al. Curcumin promotes KLF5 proteasome degradation through down-regulating YAP/TAZ in bladder cancer cells. Int. J. Mol. Sci. 2014, 15, 15173–15187. [Google Scholar] [CrossRef] [Green Version]
  113. Zhuang, C.; Liu, Y.; Fu, S.; Yuan, C.; Luo, J.; Huang, X.; Yang, W.; Xie, W.; Zhuang, C. Silencing of lncRNA MIR497HG via CRISPR/Cas13d Induces Bladder Cancer Progression Through Promoting the Crosstalk Between Hippo/Yap and TGF-β/Smad Signaling. Front. Mol. Biosci. 2020, 7. [Google Scholar] [CrossRef]
  114. Luo, Y.; Zhou, J.; Tang, J.; Zhou, F.; He, Z.; Liu, T.; Liu, T. MINDY1 promotes bladder cancer progression by stabilizing YAP. Cancer Cell Int. 2021, 21, 395. [Google Scholar] [CrossRef]
  115. Daga, M.; Pizzimenti, S.; Dianzani, C.; Cucci, M.A.; Cavalli, R.; Grattarola, M.; Ferrara, B.; Scariot, V.; Trotta, F.; Barrera, G. Ailanthone inhibits cell growth and migration of cisplatin resistant bladder cancer cells through down-regulation of Nrf2, YAP, and c-Myc expression. Phytomedicine 2019, 56, 156–164. [Google Scholar] [CrossRef]
  116. Cucci, M.A.; Grattarola, M.; Dianzani, C.; Damia, G.; Ricci, F.; Roetto, A.; Trotta, F.; Barrera, G.; Pizzimenti, S. Ailanthone increases oxidative stress in CDDP-resistant ovarian and bladder cancer cells by inhibiting of Nrf2 and YAP expression through a post-translational mechanism. Free. Radic. Biol. Med. 2020, 150, 125–135. [Google Scholar] [CrossRef]
  117. Ciamporcero, E.; Daga, M.; Pizzimenti, S.; Roetto, A.; Dianzani, C.; Compagnone, A.; Palmieri, A.; Ullio, C.; Cangemi, L.; Pili, R.; et al. Crosstalk between Nrf2 and YAP contributes to maintaining the antioxidant potential and chemoresistance in bladder cancer. Free Radic. Biol. Med. 2018, 115, 447–457. [Google Scholar] [CrossRef]
  118. Cheng, X.; Lou, K.; Ding, L.; Zou, X.; Huang, R.; Xu, G.; Zou, J.; Zhang, G. Clinical potential of the Hippo-YAP pathway in bladder cancer. Front. Oncol. 2022, 12. [Google Scholar] [CrossRef]
  119. Duchartre, Y.; Kim, Y.-M.; Kahn, M. The Wnt signaling pathway in cancer. Crit. Rev. Oncol. Hematol. 2016, 99, 141–149. [Google Scholar] [CrossRef] [Green Version]
  120. Zhang, M.; Du, H.; Wang, L.; Yue, Y.; Zhang, P.; Huang, Z.; Lv, W.; Ma, J.; Shao, Q.; Ma, M.; et al. Thymoquinone suppresses invasion and metastasis in bladder cancer cells by reversing EMT through the Wnt/β-catenin signaling pathway. Chem. Biol. Interact. 2020, 320, 109022. [Google Scholar] [CrossRef]
  121. Du, S.; Sui, Y.; Ren, W.; Zhou, J.; Du, C. PYCR1 promotes bladder cancer by affecting the Akt/Wnt/β-catenin signaling. J. Bioenerg. Biomembr. 2021, 53, 247–258. [Google Scholar] [CrossRef]
  122. Zhao, X.; Li, G.; Chong, T.; Xue, L.; Luo, Q.; Tang, X.; Zhai, X.; Chen, J.; Zhang, X. TMEM88 exhibits an antiproliferative and anti-invasive effect in bladder cancer by downregulating Wnt/β-catenin signaling. J. Biochem. Mol. Toxicol. 2021, 35, e22835. [Google Scholar] [CrossRef]
  123. Cai, D.; Zhou, Z.; Wei, G.; Wu, P.; Kong, G. Construction and verification of a novel hypoxia-related lncRNA signature related with survival outcomes and immune microenvironment of bladder urothelial carcinoma by weighted gene co-expression network analysis. Front. Genet. 2022, 13. [Google Scholar] [CrossRef]
  124. Shan, G.; Zhou, X.; Gu, J.; Zhou, D.; Cheng, W.; Wu, H.; Wang, Y.; Tang, T.; Wang, X. Downregulated exosomal mi-croRNA-148b-3p in cancer associated fibroblasts enhance chemosensitivity of bladder cancer cells by downregulating the Wnt/β-catenin pathway and upregulating PTEN. Cell Oncol. 2021, 44, 45–59. [Google Scholar] [CrossRef]
  125. Jiménez-Guerrero, R.; Belmonte-Fernández, A.; Flores, M.L.; González-Moreno, M.; Pérez-Valderrama, B.; Romero, F.; Japón, M.Á.; Sáez, C. Wnt/β-Catenin Signaling Contributes to Paclitaxel Resistance in Bladder Cancer Cells with Cancer Stem Cell-Like Properties. Int. J. Mol. Sci. 2021, 23, 450. [Google Scholar] [CrossRef]
  126. Jeong, H.; Oh, H.E.; Kim, H.; Lee, J.H.; Lee, E.S.; Kim, Y.S.; Choi, J.W. Upregulation of Fatty Acid Transporters is Associated with Tumor Progression in Non-Muscle-Invasive Bladder Cancer. Pathol. Oncol. Res. 2021, 27, 594705. [Google Scholar] [CrossRef]
  127. Abdelrahman, A.E.; Rashed, H.E.; Elkady, E.; Elsebai, E.A.; El-Azony, A.; Matar, I. Fatty acid synthase, Her2/neu, and E2F1 as prognostic markers of progression in non-muscle invasive bladder cancer. Ann. Diagn. Pathol. 2019, 39, 42–52. [Google Scholar] [CrossRef]
  128. Jiang, B.; Li, E.H.; Lu, Y.Y.; Jiang, Q.; Cui, D.; Jing, Y.F.; Xia, S.J. Inhibition of fatty-acid synthase suppresses P-AKT and induces apoptosis in bladder cancer. Urology 2012, 80, 484.e9–484.e15. [Google Scholar] [CrossRef]
  129. Okamura, S.; Yoshino, H.; Kuroshima, K.; Tsuruda, M.; Osako, Y.; Sakaguchi, T.; Yonemori, M.; Yamada, Y.; Tatarano, S.; Nakagawa, M.; et al. EHHADH contributes to cisplatin resistance through regulation by tumor-suppressive microRNAs in bladder cancer. BMC Cancer 2021, 21, 48. [Google Scholar] [CrossRef]
  130. Chen, J.; Li, Y.; Li, Z.; Cao, L. LncRNA MST1P2/miR-133b axis affects the chemoresistance of bladder cancer to cisplatin-based therapy via Sirt1/p53 signaling. J. Biochem. Mol. Toxicol. 2020, 34, e22452. [Google Scholar] [CrossRef]
  131. Dudek, A.M.; van Kampen, J.G.M.; Witjes, J.A.; Kiemeney, L.A.L.M.; Verhaegh, G.W. LINC00857 expression predicts and mediates the response to platinum-based chemotherapy in muscle-invasive bladder cancer. Cancer Med. 2018, 7, 3342–3350. [Google Scholar] [CrossRef] [PubMed]
  132. Yuan, W.; Zhou, R.; Wang, J.; Han, J.; Yang, X.; Yu, H.; Lu, H.; Zhang, X.; Li, P.; Tao, J.; et al. Circular RNA Cdr1as sensitizes bladder cancer to cisplatin by upregulating APAF1 expression through miR-1270 inhibition. Mol. Oncol. 2019, 13, 1559–1576. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  133. Bi, J.; Liu, H.; Cai, Z.; Dong, W.; Jiang, N.; Yang, M.; Huang, J.; Lin, T. Circ-BPTF promotes bladder cancer progression and recurrence through the miR-31-5p/RAB27A axis. Aging 2018, 10, 1964–1976. [Google Scholar] [CrossRef] [PubMed]
  134. Pan, J.; Xie, X.; Li, H.; Li, Z.; Ren, C.; Ming, L. Detection of serum long non-coding RNA UCA1 and circular RNAs for the diagnosis of bladder cancer and prediction of recurrence. Int. J. Clin. Exp. Pathol. 2019, 12, 2951–2958. [Google Scholar] [PubMed]
  135. Su, F.; He, W.; Chen, C.; Liu, M.; Liu, H.; Xue, F.; Bi, J.; Xu, D.; Zhao, Y.; Huang, J.; et al. The long non-coding RNA FOXD2-AS1 promotes bladder cancer progression and recurrence through a positive feedback loop with Akt and E2F1. Cell Death Dis. 2018, 9, 233. [Google Scholar] [CrossRef] [Green Version]
  136. Zhang, X.; Zhang, M.; Zhang, X.; Zhu, X.; Wang, J. A prognostic index based on a fourteen long non-coding RNA signature to predict the recurrence-free survival for muscle-invasive bladder cancer patients. BMC Med. Inform. Decis. Mak. 2020, 20 (Suppl. 3), 136. [Google Scholar] [CrossRef]
  137. Charpentier, M.; Gutierrez, C.; Guillaudeux, T.; Verhoest, G.; Pedeux, R. Noninvasive Urine-Based Tests to Diagnose or Detect Recurrence of Bladder Cancer. Cancers 2021, 13, 1650. [Google Scholar] [CrossRef]
  138. Lodewijk, I.; Dueñas, M.; Rubio, C.; Munera-Maravilla, E.; Segovia, C.; Bernardini, A.; Teijeira, A.; Paramio, J.M.; Suárez-Cabrera, C. Liquid Biopsy Biomarkers in Bladder Cancer: A Current Need for Patient Diagnosis and Monitoring. Int. J. Mol. Sci. 2018, 19, 2514. [Google Scholar] [CrossRef] [Green Version]
  139. Flaig, T.W.; Tangen, C.M.; Daneshmand, S.; Alva, A.; Lerner, S.P.; Lucia, M.S.; McConkey, D.J.; Theodorescu, D.; Goldkorn, A.; Milowsky, M.I.; et al. A Randomized Phase II Study of Coex-pression Extrapolation (COXEN) with Neoadjuvant Chemotherapy for Bladder Cancer (SWOG S1314; NCT02177695). Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2021, 27, 2435–2441. [Google Scholar] [CrossRef]
  140. Claps, F.; Mir, M.C.; Zargar, H. Molecular markers of systemic therapy response in urothelial carcinoma. Asian J. Urol. 2021, 8, 376–390. [Google Scholar] [CrossRef]
  141. Chang, S.S.; Boorjian, S.A.; Chou, R.; Clark, P.E.; Daneshmand, S.; Konety, B.R.; Pruthi, R.; Quale, D.Z.; Ritch, C.R.; Seigne, J.D.; et al. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline. J. Urol. 2016, 196, 1021–1029. [Google Scholar] [CrossRef] [PubMed]
  142. Porten, S.P.; Willis, D.; Kamat, A.M. Variant histology: Role in management and prognosis of nonmuscle invasive bladder cancer. Curr. Opin. Urol. 2014, 24, 517–523. [Google Scholar] [CrossRef] [PubMed]
  143. Claps, F.; van de Kamp, M.W.; Mayr, R.; Bostrom, P.J.; Boormans, J.L.; Eckstein, M.; Mertens, L.S.; Boevé, E.R.; Neuzillet, Y.; Burger, M.; et al. Risk factors associated with positive surgical margins’ location at radical cystectomy and their impact on bladder cancer survival. World J. Urol. 2021, 39, 4363–4371. [Google Scholar] [CrossRef]
  144. Naspro, R.; Finati, M.; Roscigno, M.; Pellucchi, F.; La Croce, G.; Sodano, M.; Manica, M.; Chinaglia, D.; Da Pozzo, L.F. The impact of histological variants on outcomes after open radical cystectomy for muscle-invasive urothelial bladder cancer: Results from a single tertiary referral centre. World J. Urol. 2021, 39, 1917–1926. [Google Scholar] [CrossRef]
  145. Claps, F.; Mir, M.C.; van Rhijn, B.W.G.; Mazzon, G.; Soria, F.; D’Andrea, D.; Marra, G.; Boltri, M.; Traunero, F.; Massanova, M.; et al. Impact of the controlling nutritional status (CONUT) score on perioperative morbidity and oncological outcomes in patients with bladder cancer treated with radical cystectomy. Urol. Oncol. 2023, 41, 49.e13–49.e22. [Google Scholar] [CrossRef]
  146. Morelli, M.B.; Amantini, C.; Rossi de Vermandois, J.A.; Gubbiotti, M.; Giannantoni, A.; Mearini, E.; Maggi, F.; Nabissi, M.; Marinelli, O.; Santoni, M.; et al. Correlation between High PD-L1 and EMT/Invasive Genes Expression and Reduced Recurrence-Free Survival in Blood-Circulating Tumor Cells from Patients with Non-Muscle-Invasive Bladder Cancer. Cancers 2021, 13, 5989. [Google Scholar] [CrossRef]
  147. Inamoto, T.; Uehara, H.; Akao, Y.; Ibuki, N.; Komura, K.; Takahara, K.; Takai, T.; Uchimoto, T.; Saito, K.; Tanda, N.; et al. A Panel of MicroRNA Signature as a Tool for Predicting Survival of Patients with Urothelial Carcinoma of the Bladder. Dis. Markers 2018, 2018, 5468672. [Google Scholar] [CrossRef]
Ijms 24 00964 g001 550
Figure 1. DIANA miRPath [18] KEGG analysis results identified several pathways that may be related to recurrence in bladder cancer. Relevant pathways, based on predicted gene targets of these miRNAs, include proteoglycans in cancer (92 genes), Hippo signaling (49 genes), cell cycle (69 genes), adherens junctions (32 genes), ECM receptor-interaction (15 genes), fatty acid metabolism (14 genes), and fatty acid biosynthesis (4 genes).
Figure 1. DIANA miRPath [18] KEGG analysis results identified several pathways that may be related to recurrence in bladder cancer. Relevant pathways, based on predicted gene targets of these miRNAs, include proteoglycans in cancer (92 genes), Hippo signaling (49 genes), cell cycle (69 genes), adherens junctions (32 genes), ECM receptor-interaction (15 genes), fatty acid metabolism (14 genes), and fatty acid biosynthesis (4 genes).
Ijms 24 00964 g001
Ijms 24 00964 g002 550
Figure 2. DIANA miRPath KEGG analysis results identified several pathways that may be related to chemoresistance in BCa. Relevant pathways, based on predicted gene targets of these miRNAs, include proteoglycans in cancer (124 genes), Hippo signaling (68 genes), cell cycle (52 genes), TGF-beta signaling (44 genes), adherens junctions (40 genes), ECM receptor-interaction (31 genes), fatty acid metabolism (15 genes), and fatty acid biosynthesis (6 genes).
Figure 2. DIANA miRPath KEGG analysis results identified several pathways that may be related to chemoresistance in BCa. Relevant pathways, based on predicted gene targets of these miRNAs, include proteoglycans in cancer (124 genes), Hippo signaling (68 genes), cell cycle (52 genes), TGF-beta signaling (44 genes), adherens junctions (40 genes), ECM receptor-interaction (31 genes), fatty acid metabolism (15 genes), and fatty acid biosynthesis (6 genes).
Ijms 24 00964 g002
Table
Table 1. miRNAs and associated targets/regulators involved in BCa recurrence.
Table 1. miRNAs and associated targets/regulators involved in BCa recurrence.
miRNATarget/RegulatorFunctionReference
MiR-22-3pNot identifiedElevated miR-22-3p showed reduced recurrence-free survival (RFS).[20]
MiR-34aNot identifiedDownregulation associated with recurrence and poorer prognosis [21]. Higher expression of miR-34a associated with lower likelihood of recurrence. MiR-34a upregulation showed less invasion and colony formation [22].[21,22]
MiR-100FGFR3Reduced miR-100 associated with less recurrence. *[23]
MiR-138Cyclin D3Downregulation of miR-138 linked to recurrence.[23]
MiR-146a-5pTwo separate pathways involving YAP1 and COX2Downregulation associated with recurrence. Subsequent regulation of ALDH1A1 and SOX2.[24]
MiR-148aNot identifiedDownregulation of miR-148a in BC patients linked to recurrence and metastasis.[25]
MiR-152Not identifiedHigher expression of miR-152 linked to lower RFS in NMIBC.[26]
MiR-155Not identifiedMiR-155 upregulation associated with recurrence.[27]
MiR-187-5pNot identifiedOncogene, promotes proliferation and mobility while decreasing apoptosis.[28]
MiR-200a familyNot identifiedReduced miR-200a-3p showed reduced RFS [20]. Lower expression of miR-200a in BCa, and downregulation linked to higher chance of recurrence [29].[20,29]
MiR-210Not identifiedHigher expression of miR-210 found in patients with recurrence.[30]
MiR-214Not identifiedReduced miR-214 expression in BCa urines pre-op compared to post. Linked to RFS [31]. Mir-214 downregulation linked to recurrence [32].[29,30,31,32]
MiR-221/222Not identifiedDownregulated in BCa, but miR-222 is upregulated in high grade/invasive BCas. MiR-222 upregulation (Ta/T1 cancers) linked to recurrence.[33]
MiR-302bEPS8 (potential)Tumor suppressor, lessens proliferation, migration, and invasion. Promotes apoptosis. [34]
Let-7f-5pLIN28Tumor suppressor, represses cell viability and migration.[35]
* p value > 0.05.
Table
Table 2. miRNAs and associated targets/regulators involved in BCa chemoresistance.
Table 2. miRNAs and associated targets/regulators involved in BCa chemoresistance.
miRNATarget/RegulatorFunctionReference
MiR-7-5pATG7Upregulation of miR-7-5p inhibited invasive characteristics. Promotes chemosensitivity.[36]
MiR-21PTENPromotes chemoresistance to doxorubicin and proliferation in transitional cell carcinoma; inhibits doxorubicin-induced apoptosis.[37]
MiR-22-3pNET1MiR-22-3p promotes chemoresistance. More cell viability, colony formation, and less apoptosis with upregulation of miR-22-3p via mimic.[38]
MiR-23aSFRP1 protein and Wnt signaling Linked to chemoradiation response.[39]
MiR-27aSFRP1 protein and Wnt signaling, RUNX-1 Linked to chemoradiation response [39]. Rs11671784 SNP (wherein A is replaced with G) results in reduced chemosensitivity [40].[39,40]
MiR-30a-3pMMP2, MMP9Combination of cisplatin and miR-30a-3p resulted in improved apoptosis and reduced cell viability. Upregulation of miR-30a-3p via mimic lessened migration and invasion.[41]
MiR-31ITGA5MiR-31 promotes chemosensitivity to mitomycin-C and upregulation inhibits proliferation, migration, and invasion. Downregulation associated with higher risk of recurrence in noninvasive UBC.[42]
MiR-34a TCF1, LEF1, Cdk6, SRT-1 (sirtuin), CD44Downregulated in BCa; promotes chemosensitivity to epirubicin [43] and to cisplatin [44,45]. Higher expression of miR-34a represses metastatic characteristics [43,45].[43,44,45]
MiR-93LASS2 (but no direct binding)MiR-93 promotes chemoresistance.[46]
MiR-98LASS2Expressed at higher levels in BCa. Upregulation via mimic resulted in increased proliferation, greater cisplatin and doxorubicin resistance, and repression of apoptosis. [47]
MiR-101COX2MiR-101 promotes chemosensitivity to cisplatin.[48]
MiR-101-3pEZH2, affects MRP1 expressionMiR-101-3p promotes chemosensitivity.[49]
MiR-129-5pWnt5aExpression of miR-129-5p promotes response to gemcitabine. [50]
MiR-130bCYLDInvolved in promoting chemoresistance.[51]
MiR-143IGF-1RMiR-143 promotes chemosensitivity. Upregulation of IGF-1R linked to reduced survival and recurrence.[52]
MiR-193a-3p LOXL4, HOXC9, PSEN1, ING5MiR-193a-3p promotes chemoresistance (oxidative stress pathway) [53,54]. MiR-193a-3p reported to target PSEN1 gene and affect DNA damage response [55]. Interaction with ING5 also occurs through DNA damage response pathway [56].[53,54,55,56]
MiR-193a-5pAL-2αMiR-193a-5p is involved in chemoresistance. Upregulation of miR-193a-5p linked to increased migration and resistance to cisplatin.[57]
MiR-200bIGFBP3, ICAM1, TNFSD10MiR-200b promotes chemosensitivity. More broadly, miR-200 family members (miR-200b, miR-200a, and miR-429) were downregulated in cisplatin-resistant cell lines. [58]
MiR-214Netrin-1Tumor suppressor activity; miR-214 upregulation resulted in reduced colony formation and invasion. MiR-214 promotes chemosensitivity.[59]
MiR-218Glut1MiR-218 promotes chemosensitivity to cisplatin.[60]
MiR-222PPP2R2AMiR-222 is implicated in chemoresistance. Acts through AKT/mTOR and autophagy pathways.[61]
MiR-325HAX-1MiR-325 promotes chemosensitivity.[62]
MiR-424UNC5B and SIRT4Promotes cisplatin resistance via downregulation of UNC5B and SIRT4.[63]
MiR-455-5pRegulated by HOXA-As3Promotes sensitivity to cisplatin, reduces proliferation, and promotes apoptosis.[64]
MiR-486-5pGene expression changes observed in caspase-9, caspase03, P53, SIRT1, OLFM4, SMAD2, Bcl-2, ROCK, CD44, MMP9MiR-486-5p functions as tumor suppressor and promotes chemosensitivity.[65]
miR-3682-3pRegulated by BMI1 and regulates ABCB1BMI1 inhibits miR-3682-3p transcription to induce chemoresistance. Elevated BMI1 is also associated with poorer RFS.[66]
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Das, S.; Hayden, J.; Sullivan, T.; Rieger-Christ, K. The Roles of miRNAs in Predicting Bladder Cancer Recurrence and Resistance to Treatment. Int. J. Mol. Sci. 2023, 24, 964. https://doi.org/10.3390/ijms24020964

AMA Style

Das S, Hayden J, Sullivan T, Rieger-Christ K. The Roles of miRNAs in Predicting Bladder Cancer Recurrence and Resistance to Treatment. International Journal of Molecular Sciences. 2023; 24(2):964. https://doi.org/10.3390/ijms24020964

Chicago/Turabian Style

Das, Sanjna, Joshua Hayden, Travis Sullivan, and Kimberly Rieger-Christ. 2023. "The Roles of miRNAs in Predicting Bladder Cancer Recurrence and Resistance to Treatment" International Journal of Molecular Sciences 24, no. 2: 964. https://doi.org/10.3390/ijms24020964

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