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Abstract: Bladder cancer is among the most common cancers globally, with significant mortality associated with more advanced disease. Early detection and diagnostic accuracy are thus fundamental to the clinical pathway for managing bladder cancer. MicroRNA (miRNA) are small, non-coding segments of RNA that regulate gene expression and have been implicated in the process of carcinogenesis. Dysregulation and aberrant expression of miRNAs have been shown to have both oncogenic and tumor suppressive effects. A vast number of miRNAs, across the entire field of cancer biology, have already been identified and characterized, and many of these have been associated with bladder cancer. These miRNAs have furthered our understanding of the genetic profile of bladder cancer, and ultimately, may be utilized in the detection, prognosis, and treatment of this disease. This chapter focuses on the role of miRNA in the pathogenesis of metastatic bladder cancer and overviews many of the miRNA thought to be associated with bladder cancer. Additionally, this chapter explores the clinical utilities of miRNAs in bladder cancer to serve as biomarkers and guide individualized treatment.

Keywords: metastamirs in bladder cancer; metastatic bladder cancer; microRNA in metastatic bladder cancer; miRNAs as prognostic indicators in bladder cancer; therapeutic utility of miRNAs in bladder cancer

INTRODUCTION

There is an ongoing paradigm shift in cancer treatment. The clinical pathways for treating cancer have grown increasingly individualized and the treatments themselves increasingly targeted. Central to these advances is a better understanding of the genetics and the biomolecular mechanisms of different cancers. In practice, characterizing the distinct oncologic profiles of specific tumors has allowed for more personalized therapies. Elucidating the factors that contribute to tumor promotion and suppression is paramount to constructing and understanding these profiles. One of these factors, microRNA (miRNA) is thought to play a major role in gene expression and in the development of cancer.

MiRNAs are small, non-coding segments of RNA approximately 19–22 nucleotides in length. MiRNA regulate messenger RNA (mRNA) in a post-transcriptional, or pre-translational, fashion (1, 2). Approximately 30% of all human genes and 60% of mRNA are regulated by miRNA (3). While miRNAs are evidently responsible for supporting normal human biological functioning, aberrant expression of these non-coding RNA segments may contribute to the pathogenesis of cancer and other diseases (4). Dysregulation of miRNA can trigger both tumor promotion and suppression via a multitude of biomolecular processes and pathways. Alterations to these pathways may significantly impact cancer phenotype, including cell migration and invasion, epithelial-to-mesenchymal transition (EMT) and angiogenesis—all factors that can contribute to metastatic potential (5). MiRNAs that are associated with the promotion or suppression of metastatic potential, when differentially expressed, are known as “metastamiRs” (6). The role of metastamiRs in the detection, prognosis and treatment of cancer continues to be investigated.

In addition to regulating gene expression at the cellular level, miRNAs are often exported from the cell and act as signaling molecules (7). MiRNA is widespread in the human body in both tissue and fluids, and it is relatively stable. The availability and stability of miRNA in easily accessible specimens, such as urine and blood, largely enables the feasibility of miRNA research (8). Basic research into identifying miRNA, their targets, and their downstream oncologic effects, as well as translational research into how these findings can be applied clinically, is ongoing. MiRNA as a non-invasive biomarker presents multiple uses, from detecting cancer to predicting and monitoring treatment response (8–10). Furthermore, the prospective use of miRNAs in personalizing care by identifying individual chemosensitivities to various chemotherapeutic agents, based on the specific genetics of individual tumors, would change the landscape of cancer management (11–13). The clinical utility of miRNA would be particularly welcome in the realm of bladder cancer—a cancer that traditionally requires multiple invasive procedures to diagnose as well as to surveille, with early detection and accurate staging vital for long-term survival. This chapter will explore the current knowledge base surrounding miRNA in bladder cancer metastasis and the proposed clinical applications of miRNA in this disease.

THE ROLE OF MICRORNAS IN THE METASTATIC PHENOTYPE OF BLADDER CANCER

Bladder cancer is the 10^th most common cancer in the world and accounts for 3% of cancer diagnoses globally. In more developed regions of the world, such as Western Europe and the US, bladder cancer is particularly prevalent. In the US, bladder cancer is the 6^th most common cancer and represents 4.6% of all cancer diagnoses, clearly outpacing global averages (14). In 2022, approximately 81,000 new cases of bladder cancer will be diagnosed and 17,000 people will die from the disease in the US (15). Ninety percent (90%) of bladder cancer cases are urothelial in origin (UCC or TCC) with additional variants (such as squamous cell carcinoma and adenocarcinoma) being very rare and associated with a worse prognosis. While the overall 5-year survival rate for bladder cancer in the US is 77%, for metastatic bladder cancer the survival rate is about 5% (14). Thus, early detection and diagnosis is vital in addressing bladder cancer before progression to more advanced disease states. Herein we discuss the potential role of miRNAs in revolutionizing how bladder cancer is detected, staged, monitored, and treated.

METASTAMIRS IN BLADDER CANCER

There has been extensive research into the role of miRNAs in bladder cancer, and numerous metastamiRs have been implicated in its progression. Metastasis-promoting miRNAs in bladder cancer downregulate tumor suppressors like PTEN and facilitate increased expression of oncogenes such as the MMP family to facilitate increased cell migration and invasion. Conversely, metastasis-suppressing miRNAs in bladder cancer downregulate genes such as TGFβ1 and E2F3 to inhibit cellular proliferation, migration, and invasion. Tables 1 and 2 provide a summary of specific metastamiRs in bladder cancer and their identified targets and functions (16–94). These tables are far from an all-inclusive list, as the body of research is extraordinarily vast and can be discordant. For example, several studies have reported that miR-200c promotes cell migration and invasion; however, alternate studies posit that downregulation of miR-200c leads to increased cell migration, invasion, and is associated with lung metastases (16–22). While these contradictory findings may be a result of differing methodology or perhaps differences due to tissue origin in the respective studies, the definitive function of miR-200c remains unclear and requires further investigation. Nevertheless, these studies continue to highlight the diverse and multifaceted nature of bladder cancer and how dysregulation of seemingly opposite pathways can still lead to metastasis.

TABLE 1 Summary of metastasis-promoting miRNAs involved in bladder cancer with impacted pathways, targets, and resulting oncologic outcome

miRNA	Target/Regulator	Function	Reference
miR-10b	KLF4, HOXD10	Promotes cell migration and invasion	(23)
miR-21	PTEN	Promotes invasion and migration via upregulation of PI3K/AKT and AKT/STAG3 pathways. Enhances resistance to doxorubicin	(24, 25)
miR-92b	DAB2IP	Promotes cell migration, invasion and EMT	(26)
miR-129-5p	SOX4	Promotes cell migration and invasion	(27)
miR-137	PAQR3	Promotes cell migration and invasion	(28)
miR-146b	ETS2, MMP2, AUF1	Promotes cell invasion	(29)
miR-182-5p	RECK, Smad4	Promotes cell migration and invasion	(30)
miR-200a	PTEN, Dicer/cJun, MMP-2	Promotes cell invasion by downregulating Dicer and its respective downstream targets, leading to MMP-2 upregulation	(31)
miR-492	GJB4	Promotes cell migration and invasion	(32)
miR-495	PTEN	Promotes cell invasion	(33)
miR-516a	MMP9, PHLPP2, SMURF1	Promotes cell migration and invasion via AKT/FOXO3A/SMURF1 pathway and inhibition of MMP-9 degradation	(34)
miR-556-3p	DAB2IP	Promotes cell proliferation and colony formation via upregulation of Ras-ERK pathways, cell migration and invasion	(35)
miR-3622a	LASS2	Promotes cell invasion	(36)
miR-3648	TCF21, KISS1	Promotes cell migration and invasion	(37)
miR-4295	BTG1	Promotes cell proliferation and migration	(38)

TABLE 2 Summary of metastasis-suppressing miRNAs involved in BC with impacted pathways, targets, and resulting oncologic outcome

miRNA	Target/Regulator	Function	Reference
miR-15	BMI1	Inhibits cell migration and invasion.	(39)
miR-22	E2F3, Snail, MAPK	Inhibits cell migration, invasion and EMT.	(40, 41)
miR-24	CARMA3	Inhibits cell invasion and EMT.	(42)
miR-26a-5p, -26b-5p	PLOD2	Inhibits cell migration and invasion.	(43)
miR-34a-5p	TCF1, LEF1, DNMT3B, MMP-2	Inhibits cell migration and invasion. Enhances epirubicin sensitivity.	(44–46)
miR-101	FZD4, c-FOS, VEGF-C	Inhibits cell migration and invasion. Increases cisplatin sensitivity.	(47–50)
miR-124-3p	ITGA3	Inhibits cell migration, invasion, and EMT via downregulation of FAK/PI3K/AKT pathway.	(51)
miR-125b-5p	SIRT7, MALAT1, MMP13, HK2	Inhibits proliferation, cell migration, and invasion via the PI3K/AKT pathway. Promotes apoptosis.	(52–54)
miR-132	TGFβ1	Inhibits cell migration, invasion and EMT via TGFβ1/SMAD2 pathway.	(55)
miR-138	ZEB2	Inhibits cell migration and invasion.	(56)
miR-140-3p	FOXQ1	Inhibits cell invasion.	(57)
miR-145	N-cadherin, MMP9	Inhibits cell migration and invasion.	(58)
miR-146a-3p	PTTG1	Inhibits cell migration and invasion.	(59)
miR-154	ATG7	Inhibits cell migration and invasion.	(60)
miR-186	VEGF-C	Inhibits cell migration, invasion, angiogenesis.	(61)
miR-194-5p	E2F3	Inhibits cell migration and invasion.	(62)
miR-199a-5p	CCR7, MMP9	Inhibits cell migration, invasion, EMT.	(63)
miR-200b	TGF-β1	Inhibits cell migration and invasion. Enhances cisplatin sensitivity.	(64, 65)
miR-203a	SIX4	Inhibits cell migration, invasion and EMT.	(66)
miR-204	ROBO4	Inhibits cell migration and invasion.	(67)
miR-210-3p	FGFRL1	Inhibits cell invasion.	(68)
miR-223	WDR62	Inhibits cell migration and invasion.	(69)
miR-300	SP1/MMP9 pathway	Inhibits cell migration.	(70)
miR-325-3p	MT3	Inhibits cell migration, invasion, and EMT.	(71)
miR-338-3p	ETS1	Inhibits cell proliferation, metastasis and EMT.	(72)
miR-370	SOX12	Inhibits cell migration and invasion.	(73)
miR-372/373	CUL4B	Inhibits cell migration and invasion via downregulation of PI3K/AKT pathway.	(74)
miR-375-3p	FZD8	Inhibits cell migration.	(75)
miR-379-5p	MDM2	Inhibits cell migration and invasion.	(76)
miR-381-3p	BMI1, Rho/ROCK, CCNA2, MET	Inhibits cell invasion, migration and EMT.	(77, 78)
miR-429	MMP2, E-cadherin	Inhibits cell migration, invasion, and EMT via E-cadherin upregulation.	(79, 80)
miR-485-5p	HMGA2	Inhibits cell invasion and metastatic potential. Inhibits cancer cell adhesion and EMT.	(81, 82)
miR-486-5p	ROCK, CD44, MMP9	Inhibits cell migration. Enhances cisplatin sensitivity.	(83)
miR-497	Vimentin, α-SMA, E-cadherin, E2F3	Inhibits cell migration, invasion, and EMT by downregulating vimentin and α-SMA and upregulating E-cadherin.	(84, 85)
miR-502-5p	CCND1, NOP14, DNMT3B	Inhibits cell migration.	(86)
miR-539	IGF-1R	Inhibits cell proliferation and invasion.	(87)
miR-612	ME1	Inhibits cell migration, invasion, and EMT.	(88)
miR-613	SphK1	Inhibits cell migration, invasion, and EMT.	(89)
miR-621	TRIM29, Wnt/β-catenin	Inhibits cell proliferation and metastatic potential by downregulation of the Wnt/β-catenin pathway.	(90)
miR-1182	hTERT	Inhibits cell proliferation and invasion. Enhances cisplatin sensitivity.	(91)
miR-1280	ROCK1	Inhibits cell proliferation, migration and invasion.	(92)
miR-3619-5p	β-catenin, CDK2	Inhibits cell migration, invasion, and reduces metastatic potential by upregulating p21.	(93)
miR-4324	RACGAP1	Inhibits cell colony formation, migration, invasion and EMT. Enhances doxorubicin sensitivity.	(94)

Diagnostic and therapeutic utility of miRNAs in bladder cancer

Diagnosis of bladder cancer utilizes urine cytology and cystoscopic biopsies of bladder tissue. Further biopsies are occasionally needed for staging and differentiation between muscle invasive (MIBC) and non-muscle invasive bladder cancer (NMIBC) as well as to detect response to intravesical treatment and recurrence. These diagnostic procedures are not without risk, as patients undergoing bladder biopsies require induction with general anesthesia, and the surgeries themselves can cause bleeding, urinary tract infections (UTI), as well as damage to the prostate, bladder, or urethra. Given the physical risks of these procedures, the emotional toll on patients, and the financial burden of diagnosis, an alternative, less invasive diagnostic test utilizing miRNAs would rectify several of these existing issues.

miRNAs as diagnostic biomarkers

A urine-based diagnostic test utilizing miRNAs as biomarkers for bladder cancer would be an ideal clinical tool, given the ease and non-invasive nature of specimen collection. Several pilot studies have investigated the feasibility of detecting miRNAs in urine to diagnose bladder cancer (95–100), and a meta-analysis found that urine-based miRNA assays were more sensitive than urine cytology in diagnosis of bladder cancer (101). Implementing a urine-based miRNA test in the pathway of bladder cancer management could prove invaluable if it lessens the burden of repetitive invasive testing as required in NMIBC. Furthermore, tissue-based miRNA profiles may have a role in bladder cancer diagnostics as well. Patients often require repeat resections to ensure the presence of muscle in the specimen—the differentiator between NMIBC and MIBC. To this end, a tissue-based miRNA test could preclude the need for repeat resection if the presence of specific miRNAs in the initial specimen can predict muscle invasion (20) or risk of recurrence.

Utilizing miRNAs to screen and assess treatment response in bladder cancer

Treatment algorithms differ between NMIBC and MIBC. While bladder tumor resections, intravesical chemotherapy, and immunotherapy are mainstay treatments for NMIBC, surgical removal of the bladder via radical cystectomy and urinary diversion, often after neoadjuvant cisplatin-based chemotherapy, is the standard of care for MIBC (102–103). However, roughly 60% of all patients subjected to neoadjuvant chemotherapy fail to have an adequate response to systemic treatment and still have invasive disease upon cystectomy (104). Thus, a large percentage of patients with MIBC receiving neoadjuvant chemotherapy are subjected to the morbid side-effects of these chemotherapeutic agents, while not benefiting from any considerable response. Furthermore, completion of systemic therapy in this population serves to delay definitive management via surgery.

Utilizing a biomarker to identify patients who are likely to respond to chemotherapy prior to its initiation could transform the utility of neoadjuvant treatment by both minimizing unnecessary chemotherapy exposure and expediting surgery for those who are unlikely to respond. Current research suggests miRNAs may be particularly suited for this purpose. For example, miR-101, -1182, -200b and -486-5p are all implicated in tumor suppression and have been associated with cisplatin sensitivity (47, 48–50, 65, 83, 91). As such, these miRNAs could potentially be utilized to screen patients as likely responders to cisplatin-based neoadjuvant chemotherapy and would thus allow for the more appropriate provision of systemic chemotherapeutics. Furthermore, miRNAs could be used in this capacity to not just dictate the utility of cisplatin-based therapy but may also identify other chemotherapeutic options for those deemed unlikely to respond to cisplatin, thus personalizing treatment and optimizing the likelihood of response.

miRNAs as prognostic indicators in bladder cancer

While there are no current prognostic calculators for bladder cancer that utilize miRNA, there is potential for miRNAs to act in this realm. Xie et al. identified five miRNAs in a systematic review and meta-analysis that could potentially be useful in prognostics, citing high levels of miR-21 and miR-222 and low levels of miR-214 were associated with low overall survival. Furthermore, they detailed high levels of miR-143 and miR-155 were associated with poor progression-free survival (105). More recently, Yin et al. proposed a 21-signature miRNA profile to determine prognosis in BC patients (106).

MiRNAs may specifically be useful in addressing the need for a prognostic indicator for risk of disease progression. This would be particularly helpful in those who have low stage/grade disease and therefore are—based on conventional indicators—stratified as having a low risk of progression. That is, those with low stage disease who are determined to be at high risk of progression would benefit from more frequent clinical surveillance, thus providing earlier detection of disease progression, and allowing for better therapeutic options and outcomes.

UPPER TRACT UROTHELIAL CARCINOMA

Upper tract urothelial carcinoma (UTUC) refers to urothelial cancer of the renal collecting system, including the renal pelvis and the ureter. While the role of miRNAs in UTUC is far less elucidated than in UCC (bladder cancer), several studies have identified miRNAs that are dysregulated in UTUC. A serum miRNA analysis by Tao et al. found significantly different expression patterns of 13 miRNAs between UTUC patients and cancer-free patients (107). Another study by Hsu et al. identified miR-145-5p as downregulated in UTUC tissue, and a modulator of cell migration and invasion through its regulation of ARF6 (108). Furthermore, rescue of miR-145-5p expression yielded a suppression of EMT markers through its correlation with an increase in E-cadherin levels and a decrease in MMP7 and N-cadherin (108). EMT was also noted to be inhibited by miR-30a-5p in a study comparing UTUC tissue to adjacent normal tissue after nephroureterectomy for UTUC (109). In addition, Browne et al. identified several miRNAs that were associated with an invasive phenotype in UTUC, including miRs-10b-5p, -26a-5p, -31-5p, and -146b-5p (110). Lastly, Ke et al. found that miR-210 was overexpressed in UTUC compared to benign urothelium and proposed miR-210 involvement in promoting UTUC carcinogenesis and tumor progression (111).

While there is a paucity of literature regarding the role of miRNAs in UTUC in comparison to that of bladder cancer, several miRNAs have been identified with potential for therapeutic and diagnostic targeting. While further research is necessary, these miRNAs show promise in bladder cancer and UTUC alike to both further advance and refine the clinical management of these malignancies.

CONCLUSION

The clinical pathways and algorithms used for diagnosing and treating cancer are in the midst of a seismic shift and continue to rapidly evolve. An emphasis on individualized care—targeted therapy—is at the forefront of these changes. The ability to increasingly characterize a tumor based on its genetics has opened the door for improved diagnosis, prognostication, and treatment. While there are many factors found in the genetic profile of a cell that may aid its transformation into a cancer, abundant research across the spectrum of cancer biology has explored miRNA and how these short, non-coding RNA segments regulate gene expression. The potential clinical applications of miRNA are vast. MiRNAs as biomarkers could revolutionize how cancer is detected, monitored, and treated. For example, reliable urine miRNA biomarkers in bladder cancer could negate the need for the multiple invasive procedures. Further, establishing a miRNA profile for a specific tumor may elucidate its chemosensitivities, and in turn, enable personalized, targeted chemotherapy. Bladder cancer is particularly deadly in its advanced and metastatic stages and using the genetics of a tumor to refine therapeutic options could greatly alleviate the mortality burden. MiRNA research, for bladder cancer and beyond, holds great promise.

Conflict of Interest: The authors declare no potential conflicts of interest with respect to research, authorship and/or publication of this chapter.

Copyright and Permission Statement: The authors confirm that the materials included in this chapter do not violate copyright laws. Where relevant, appropriate permissions have been obtained from the original copyright holder(s), and all original sources have been appropriately acknowledged or referenced.

REFERENCES

1. Carthew RW, Sontheimer EJ. Origins and Mechanisms of miRNAs and siRNAs. Cell. 2009;136:642–55. https://doi.org/10.1016/j.cell.2009.01.035
2. Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet. 2008;9:102–14. https://doi.org/10.1038/nrg2290
3. Zhang C. MicroR. Nomics: a newly emerging approach for disease biology. Physiol Genomics. 2008;33:139–47. https://doi.org/10.1152/physiolgenomics.00034.2008
4. Tüfekci KU, Öner MG, Meuwissen RLJ, Genç Ş. The Role of MicroRNAs in Human Diseases. In: Yousef M, Allmer J, editors. miRNomics: MicroRNA Biology and Computational Analysis [Internet]. Totowa, NJ: Humana Press; 2014 [cited 2022 Jan 24]. p. 33–50. (Methods in Molecular Biology). https://doi.org/10.1007/978-1-62703-748-8_3
5. Peng Y, Croce CM. The role of MicroRNAs in human cancer. Signal Transduct Target Ther. 2016;1:15004. https://doi.org/10.1038/sigtrans.2015.4
6. Hurst DR, Edmonds MD, Welch DR. Metastamir - the field of metastasis-regulatory microRNA is spreading. Cancer Res. 2009;69(19):7495–8. https://doi.org/10.1158/0008-5472.CAN-09-2111
7. Makarova JA, Shkurnikov MU, Wicklein D, Lange T, Samatov TR, Turchinovich AA, et al. Intracellular and extracellular microRNA: An update on localization and biological role. Prog Histochem Cytochem. 2016;51(3):33–49. https://doi.org/10.1016/j.proghi.2016.06.001
8. Armstrong DA, Green BB, Seigne JD, Schned AR, Marsit, CJ. MicroRNA molecular profiling from matched tumor and bio-fluids in bladder cancer. Mol Cancer 2015:14:194. https://doi.org/10.1186/s12943-015-0466-2
9. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–8. https://doi.org/10.1038/nature03702
10. Hanke M, Hoefig K, Merz H, Feller AC, Kausch I, Jocham D, et al. A robust methodology to study urine microRNA as tumor marker: microRNA-126 and microRNA-182 are related to urinary bladder cancer. Urol Oncol. 2010:28;655–61. https://doi.org/10.1016/j.urolonc.2009.01.027
11. Tao J, Lu Q, Wu D, Li P, Xu B, Qing W, et al. microRNA-21 modulates cell proliferation and sensitivity to doxorubicin in bladder cancer cells. Oncol Rep. 2011;25(6):1721–9.
12. Kozinn SI, Harty NJ, Delong JM, Deliyiannis C, Logvinenko T, Summerhayes IC, et al. MicroRNA Profile to Predict Gemcitabine Resistance in Bladder Carcinoma Cell Lines. Genes Cancer. 2013;4:61–9. https://doi.org/10.1177/1947601913484495
13. Chen M. miR-150 modulates cisplatin chemosensitivity and invasiveness of muscle-invasive bladder cancer cells via targeting PDCD4 in vitro. Med Sci Monit. 2014;20:1850–7. https://doi.org/10.12659/MSM.891340
14. Saginala K, Barsouk A, Aluru JS, Rawla P, Padala SA, Barsouk A. Epidemiology of Bladder Cancer. Med Sci (Basel). 2020;8(1):15. https://doi.org/10.3390/medsci8010015
15. American Cancer Society | Cancer Facts & Statistics [Internet]. American Cancer Society | Cancer Facts & Statistics. [cited 2022 Feb 1]. Available from: http://cancerstatisticscenter.cancer.org/
16. Cheng Y, Zhang X, Li P, Yang C, Tang J, Deng X, et al. MiR-200c promotes bladder cancer cell migration and invasion by directly targeting RECK. Onco Targets Ther. 2016;9:5091–9. https://doi.org/10.2147/OTT.S101067
17. Jin H, Xue L, Mo L, Zhang D, Guo X, Xu J, et al. Downregulation of miR-200c stabilizes XIAP mRNA and contributes to invasion and lung metastasis of bladder cancer. Cell Adh Migr. 2019;13(1):236–48. https://doi.org/10.1080/19336918.2019.1633851
18. Yuan D, Zheng S, Wang L, Li J, Yang J, Wang B, et al. MiR-200c inhibits bladder cancer progression by targeting lactate dehydrogenase A. Oncotarget. 2017;8(40):67663–9. https://doi.org/10.18632/oncotarget.18801
19. Huang H, Jin H, Zhao H, Wang J, Li X, Yan H, et al. RhoGDIβ promotes Sp1/MMP-2 expression and bladder cancer invasion through perturbing miR-200c-targeted JNK2 protein translation. Mol Oncol. 2017;11(11):1579–94. https://doi.org/10.1002/1878-0261.12132
20. Wszolek MF, Rieger-Christ KM, Kenney PA, Gould JJ, Silva Neto B, Lavoie AK, et al. A MicroRNA expression profile defining the invasive bladder tumor phenotype. Urol Oncol. 2011;29(6):794–801.e1. https://doi.org/10.1016/j.urolonc.2009.08.024
21. Liu L, Qiu M, Tan G, Liang Z, Qin Y, Chen L, et al. 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. https://doi.org/10.1186/s12967-014-0305-z
22. Tran MN, Choi W, Wszolek MF, Navai N, Lee I-LC, Nitti G, et al. The p63 Protein Isoform ΔNp63α Inhibits Epithelial-Mesenchymal Transition in Human Bladder Cancer Cells. J Biol Chem. 2013;288(5):3275–88. https://doi.org/10.1074/jbc.M112.408104
23. Xiao H, Li H, Yu G, Xiao W, Hu J, Tang K, et al. MicroRNA-10b promotes migration and invasion through KLF4 and HOXD10 in human bladder cancer. Oncol Rep. 2014;31(4):1832–8. https://doi.org/10.3892/or.2014.3048
24. Lin F, Yin H-B, Li X-Y, Zhu G-M, He W-Y, Gou X. Bladder cancer cell-secreted exosomal miR-21 activates the PI3K/AKT pathway in macrophages to promote cancer progression. Int J Oncol. 2019;56(1):151–64. https://doi.org/10.3892/ijo.2019.4933
25. Tao J, Lu Q, Wu D, Li P, Xu B, Qing W, et al. microRNA-21 modulates cell proliferation and sensitivity to doxorubicin in bladder cancer cells. Oncol Rep. 2011;25(6):1721–9.
26. Huang J, Wang B, Hui K, Zeng J, Fan J, Wang X, et al. miR-92b targets DAB2IP to promote EMT in bladder cancer migration and invasion. Oncol Rep. 2016;36(3):1693–701. https://doi.org/10.3892/or.2016.4940
27. Liao C, Long Z, Zhang X, Cheng J, Qi F, Wu S, et al. LncARSR sponges miR-129-5p to promote proliferation and metastasis of bladder cancer cells through increasing SOX4 expression. Int J Biol Sci. 2020;16(1):1–11. https://doi.org/10.7150/ijbs.39461
28. Xiu Y, Liu Z, Xia S, Jin C, Yin H, Zhao W, et al. MicroRNA-137 Upregulation Increases Bladder Cancer Cell Proliferation and Invasion by Targeting PAQR3. PLOS One. 2014;9(10):e109734. https://doi.org/10.1371/journal.pone.0109734
29. Zhu J, Xu C, Ruan L, Wu J, Li Y, Zhang X. MicroRNA-146b Overexpression Promotes Human Bladder Cancer Invasion via Enhancing ETS2-Mediated mmp2 mRNA Transcription. Mol Ther Nucleic Acids. 2019;16:531–42. https://doi.org/10.1016/j.omtn.2019.04.007
30. Hirata H, Ueno K, Shahryari V, Tanaka Y, Tabatabai ZL, Hinoda Y, et al. Oncogenic miRNA-182-5p Targets Smad4 and RECK in Human Bladder Cancer. PLoS One. 2012;7(11):e51056. https://doi.org/10.1371/journal.pone.0051056
31. Yang R, Xu J, Hua X, Tian Z, Xie Q, Li J, et al. Overexpressed miR-200a promotes bladder cancer invasion through direct regulating Dicer/miR-16/JNK2/MMP-2 axis. Oncogene. 2020;39(9):1983–96. https://doi.org/10.1038/s41388-019-1120-z
32. Wang K, Lü H, Qu H, Xie Q, Sun T, Gan O, et al. miR-492 Promotes Cancer Progression by Targeting GJB4 and Is a Novel Biomarker for Bladder Cancer. Onco Targets Ther. 2019;12:11453–64. https://doi.org/10.2147/OTT.S223448
33. Tan M, Mu X, Liu Z, Tao L, Wang J, Ge J, et al. microRNA-495 promotes bladder cancer cell growth and invasion by targeting phosphatase and tensin homolog. Biochem Biophys Res Commun. 2017;483(2):867–73. https://doi.org/10.1016/j.bbrc.2017.01.019
34. Chang Y, Jin H, Li H, Ma J, Zheng Z, Sun B, et al. MiRNA-516a promotes bladder cancer metastasis by inhibiting MMP9 protein degradation via the AKT/FOXO3A/SMURF1 axis. Clin Transl Med. 2020;10(8):e263. https://doi.org/10.1002/ctm2.263
35. Feng C, Sun P, Hu J, Feng H, Li M, Liu G, et al. miRNA-556-3p promotes human bladder cancer proliferation, migration and invasion by negatively regulating DAB2IP expression. Int J Oncol. 2017;50(6):2101–12. https://doi.org/10.3892/ijo.2017.3969
36. Fu S, Luan T, Jiang C, Huang Y, Li N, Wang H, et al. miR-3622a promotes proliferation and invasion of bladder cancer cells by downregulating LASS2. Gene. 2019;701:23–31. https://doi.org/10.1016/j.gene.2019.02.083
37. Sun W, Li S, Yu Y, Jin H, Xie Q, Hua X, et al. MicroRNA-3648 Is Upregulated to Suppress TCF21, Resulting in Promotion of Invasion and Metastasis of Human Bladder Cancer. Mol Ther Nucleic Acids. 2019;16:519–30. https://doi.org/10.1016/j.omtn.2019.04.006
38. Nan Y-H, Wang J, Wang Y, Sun P-H, Han Y-P, Fan L, et al. MiR-4295 promotes cell growth in bladder cancer by targeting BTG1. Am J Transl Res. 2016;8(11):4892–901.
39. Zhang L, Wang C-Z, Ma M, Shao G-F. MiR-15 suppressed the progression of bladder cancer by targeting BMI1 oncogene via PI3K/AKT signaling pathway. Eur Rev Med Pharmacol Sci. 2019;23(20):8813–22.
40. Guo J, Zhang J, Yang T, Zhang W, Liu M. MiR-22 suppresses the growth and metastasis of bladder cancer cells by targeting E2F3. Int J Clin Exp Pathol. 2020;13(3):587–96.
41. Xu M, Li J, Wang X, Meng S, Shen J, Wang S, et al. MiR-22 suppresses epithelial-mesenchymal transition in bladder cancer by inhibiting Snail and MAPK1/Slug/vimentin feedback loop. Cell Death Dis. 2018;9(2):209. https://doi.org/10.1038/s41419-017-0206-1
42. Zhang S, Zhang C, Liu W, Zheng W, Zhang Y, Wang S, et al. MicroRNA-24 upregulation inhibits proliferation, metastasis and induces apoptosis in bladder cancer cells by targeting CARMA3. International J Oncol. 2015;47(4):1351–60. https://doi.org/10.3892/ijo.2015.3117
43. Miyamoto K, Seki N, Matsushita R, Yonemori M, Yoshino H, Nakagawa M, et al. Tumour-suppressive miRNA-26a-5p and miR-26b-5p inhibit cell aggressiveness by regulating PLOD2 in bladder cancer. Br J Cancer. 2016;115(3):354–63. https://doi.org/10.1038/bjc.2016.179
44. Chou K-Y, Chang A-C, Tsai T-F, Lin Y-C, Chen H-E, Ho C-Y, et al. MicroRNA 34a 5p serves as a tumor suppressor by regulating the cell motility of bladder cancer cells through matrix metalloproteinase 2 silencing. Oncol Rep. 2021;45(3):911–20. https://doi.org/10.3892/or.2020.7910
45. Liu X, Liu X, Wu Y, Fang Z, Wu Q, Wu C, et al. MicroRNA-34a Attenuates Metastasis and Chemoresistance of Bladder Cancer Cells by Targeting the TCF1/LEF1 Axis. CPB. 2018;48(1):87–98. https://doi.org/10.1159/000491665
46. Xu K, Chen B, Li B, Li C, Zhang Y, Jiang N, et al. DNMT3B silencing suppresses migration and invasion by epigenetically promoting miR-34a in bladder cancer. Aging (Albany NY). 2020;12(23):23668–83. https://doi.org/10.18632/aging.103820
47. Chen L, Long Y, Han Z, Yuan Z, Liu W, Yang F, et al. MicroRNA-101 inhibits cell migration and invasion in bladder cancer via targeting FZD4. Exp Ther Med. 2019;17(2):1476–85. https://doi.org/10.3892/etm.2018.7084
48. Long Y, Wu Z, Yang X, Chen L, Han Z, Zhang Y, et al. MicroRNA-101 inhibits the proliferation and invasion of bladder cancer cells via targeting c-FOS. Mol Med Rep. 2016;14(3):2651–6. https://doi.org/10.3892/mmr.2016.5534
49. Lei Y, Li B, Tong S, Qi L, Hu X, Cui Y, et al. miR-101 Suppresses Vascular Endothelial Growth Factor C That Inhibits Migration and Invasion and Enhances Cisplatin Chemosensitivity of Bladder Cancer Cells. PLOS One. 2015;10(2):e0117809. https://doi.org/10.1371/journal.pone.0117809
50. 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(4):2203–9. https://doi.org/10.3892/mmr.2014.2455
51. Wang J-R, Liu B, Zhou L, Huang Y-X. MicroRNA-124-3p suppresses cell migration and invasion by targeting ITGA3 signaling in bladder cancer. Cancer Biomark. 2019;24(2):159–72. https://doi.org/10.3233/CBM-182000
52. Han Y, Liu Y, Zhang H, Wang T, Diao R, Jiang Z, et al. Hsa-miR-125b suppresses bladder cancer development by down-regulating oncogene SIRT7 and oncogenic long non-coding RNA MALAT1. FEBS Lett. 2013;587(23):3875–82. https://doi.org/10.1016/j.febslet.2013.10.023
53. Liu S, Chen Q, Wang Y. MiR-125b-5p suppresses the bladder cancer progression via targeting HK2 and suppressing PI3K/AKT pathway. Hum Cell. 2020;33(1):185–94. https://doi.org/10.1007/s13577-019-00285-x
54. Wu D, Ding J, Wang L, Pan H, Zhou Z, Zhou J, et al. microRNA-125b inhibits cell migration and invasion by targeting matrix metallopeptidase 13 in bladder cancer. Oncol Lett. 2013;5(3):829–34. https://doi.org/10.3892/ol.2013.1123
55. Wei XC, Lv ZH. MicroRNA-132 inhibits migration, invasion and epithelial-mesenchymal transition via TGFβ1/Smad2 signaling pathway in human bladder cancer. Onco Targets Ther. 2019;12:5937–45. https://doi.org/10.2147/OTT.S201731
56. Sun D-K, Wang J-M, Zhang P, Wang Y-Q. MicroRNA-138 Regulates Metastatic Potential of Bladder Cancer Through ZEB2. Cell Physiol Biochem. 2015;37(6):2366–74. https://doi.org/10.1159/000438590
57. Wang Y, Chen J, Wang X, Wang K. miR-140-3p inhibits bladder cancer cell proliferation and invasion by targeting FOXQ1. Aging (Albany NY). 2020;12(20):20366–79. https://doi.org/10.18632/aging.103828
58. Zhang X-F, Zhang X-Q, Chang Z-X, Wu C-C, Guo H. microRNA 145 modulates migration and invasion of bladder cancer cells by targeting N cadherin. Mol Med Rep. 2018;17(6):8450–6. https://doi.org/10.3892/mmr.2018.8910
59. Xiang W, Wu X, Huang C, Wang M, Zhao X, Luo G, et al. PTTG1 regulated by miR-146a-3p promotes bladder cancer migration, invasion, metastasis and growth. Oncotarget. 2016;8(1):664–78. https://doi.org/10.18632/oncotarget.13507
60. Zhang J, Mao S, Wang L, Zhang W, Zhang Z, Guo Y, et al. MicroRNA 154 functions as a tumor suppressor in bladder cancer by directly targeting ATG7. Oncol Rep. 2019;41(2):819–28. https://doi.org/10.3892/or.2018.6879
61. He X, Ping J, Wen D. MicroRNA-186 regulates the invasion and metastasis of bladder cancer via vascular endothelial growth factor C. Exp Ther Med. 2017;14(4):3253–8. https://doi.org/10.3892/etm.2017.4908
62. Wang Y, Sun G, Wang C, Guo W, Tang Q. MiR-194-5p inhibits cell migration and invasion in bladder cancer by targeting E2F3. J BUON. 2018;23(5):1492–99.
63. Zhou M, Wang S, Hu L, Liu F, Zhang Q, Zhang D. miR-199a-5p suppresses human bladder cancer cell metastasis by targeting CCR7. BMC Urol. 2016;16:64. https://doi.org/10.1186/s12894-016-0181-3
64. Gao R, Zhang N, Yang J, Zhu Y, Zhang Z, Wang J, 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. 2019;38:111. https://doi.org/10.1186/s13046-019-1102-6
65. Shindo T, Niinuma T, Nishiyama N, Shinkai N, Kitajima H, Kai M, et al. Epigenetic silencing of miR-200b is associated with cisplatin resistance in bladder cancer. Oncotarget. 2018;9(36):24457–69. https://doi.org/10.18632/oncotarget.25326
66. Na XY, Shang XS, Zhao Y, Ren PP, Hu XQ. MiR-203a functions as a tumor suppressor in bladder cancer by targeting SIX4. Neoplasma. 2019;66(02):211–21. https://doi.org/10.4149/neo_2018_180512N312
67. Li Y, Chen R, Li Z, Cheng H, Li X, Li T, et al. miR-204 Negatively Regulates Cell Growth And Metastasis By Targeting ROBO4 In Human Bladder Cancer. Onco Targets Ther. 2019;12:8515–24. https://doi.org/10.2147/OTT.S205023
68. Yang X, Shi L, Yi C, Yang Y, Chang L, Song D. MiR-210-3p inhibits the tumor growth and metastasis of bladder cancer via targeting fibroblast growth factor receptor-like 1. Am J Cancer Res. 2017;7(8):1738–53.
69. Sugita S, Yoshino H, Yonemori M, Miyamoto K, Matsushita R, Sakaguchi T, et al. Tumor suppressive microRNA 223 targets WDR62 directly in bladder cancer. Int J Oncol. 2019;54(6):2222–36. https://doi.org/10.3892/ijo.2019.4762
70. Yan H, Li J, Ying Y, Xie H, Chen H, Xu X, et al. MIR-300 in the imprinted DLK1-DIO3 domain suppresses the migration of bladder cancer by regulating the SP1/MMP9 pathway. Cell Cycle. 2018;17(24):2790–801. https://doi.org/10.1080/15384101.2018.1557490
71. Sun S, Liu F, Xian S, Cai D. miR-325-3p Overexpression Inhibits Proliferation and Metastasis of Bladder Cancer Cells by Regulating MT3. Med Sci Monit. 2020;26:e920331-1-e920331-9. https://doi.org/10.12659/MSM.920331
72. Zhang L, Yan R, Zhang S-N, Zhang H-Z, Ruan X-J, Cao Z, et al. MicroRNA-338-3p inhibits the progression of bladder cancer through regulating ETS1 expression. Eur Rev Med Pharmacol Sci. 2019;23(5):1986–95.
73. Wang Y, Ma D-L, Yu C-H, Sha K-F, Zhao M-J, Liu T-J. MicroRNA-370 suppresses SOX12 transcription and acts as a tumor suppressor in bladder cancer. Eur Rev Med Pharmacol Sci. 2020;24(5):2303–12.
74. Liu X, Cui J, Gong L, Tian F, Shen Y, Chen L, et al. The CUL4B-miR-372/373-PIK3CA- AKT axis regulates metastasis in bladder cancer. Oncogene. 2020 Apr;39(17):3588–603. https://doi.org/10.1038/s41388-020-1236-1
75. Li Q, Huyan T, Cai S, Huang Q, Zhang M, Peng H, et al. The role of exosomal miR-375-3p: A potential suppressor in bladder cancer via the Wnt/β-catenin pathway. FASEB J. 2020;34(9):12177–96. https://doi.org/10.1096/fj.202000347R
76. Wu D, Niu X, Tao J, Li P, Lu Q, Xu A, et al. MicroRNA-379-5p plays a tumor-suppressive role in human bladder cancer growth and metastasis by directly targeting MDM2. Oncol Rep. 2017 Jun 1;37(6):3502–8. https://doi.org/10.3892/or.2017.5607
77. Chen D, Cheng L, Cao H, Liu W. Role of microRNA-381 in bladder cancer growth and metastasis with the involvement of BMI1 and the Rho/ROCK axis. BMC Urol. 2021;21:5. https://doi.org/10.1186/s12894-020-00775-3
78. Li J, Ying Y, Xie H, Jin K, Yan H, Wang S, et al. Dual regulatory role of CCNA2 in modulating CDK6 and MET-mediated cell-cycle pathway and EMT progression is blocked by miR-381-3p in bladder cancer. FASEB J. 2019;33(1):1374–88. https://doi.org/10.1096/fj.201800667R
79. Wu C-L, Ho J-Y, Chou S-C, Yu D-S. MiR-429 reverses epithelial-mesenchymal transition by restoring E-cadherin expression in bladder cancer. Oncotarget. 2016;7(18):26593–603. https://doi.org/10.18632/oncotarget.8557
80. Wu C-L, Ho J-Y, Hung S-H, Yu D-S. miR-429 expression in bladder cancer and its correlation with tumor behavior and clinical outcome. Kaohsiung J Med Sci. 2018;34(6):335–40. https://doi.org/10.1016/j.kjms.2018.01.001
81. Chen Z, Li Q, Wang S, Zhang J. miR 485 5p inhibits bladder cancer metastasis by targeting HMGA2. Int J Mol Med. 2015;36(4):1136–42. https://doi.org/10.3892/ijmm.2015.2302
82. Ding X, Wang Y, Ma X, Guo H, Yan X, Chi Q, et al. Expression of HMGA2 in bladder cancer and its association with epithelial-to-mesenchymal transition. Cell Prolif. 2014;47(2):146–51. https://doi.org/10.1111/cpr.12096
83. 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(9):738.e9-738.e21. https://doi.org/10.1016/j.urolonc.2020.05.008
84. Wei Z, Hu X, Liu J, Zhu W, Zhan X, Sun S. MicroRNA-497 upregulation inhibits cell invasion and metastasis in T24 and BIU-87 bladder cancer cells. Mol Med Rep. 2017;16(2):2055–60. https://doi.org/10.3892/mmr.2017.6805
85. Zhang Y, Zhang Z, Li Z, Gong D, Zhan B, Man X, et al. MicroRNA-497 inhibits the proliferation, migration and invasion of human bladder transitional cell carcinoma cells by targeting E2F3. Oncol Rep. 2016;36(3):1293–300. https://doi.org/10.3892/or.2016.4923
86. Ying Y, Li J, Xie H, Yan H, Jin K, He L, et al. CCND1, NOP14 and DNMT3B are involved in miR-502-5p-mediated inhibition of cell migration and proliferation in bladder cancer. Cell Prolif. 2020;53(2):e12751. https://doi.org/10.1111/cpr.12751
87. Liao G, Chen F, Zhong J, Jiang X. MicroRNA 539 inhibits the proliferation and invasion of bladder cancer cells by regulating IGF 1R. Mol Med Rep. 2018;17(4):4917–24. https://doi.org/10.3892/mmr.2018.8497
88. Liu M, Chen Y, Huang B, Mao S, Cai K, Wang L, et al. Tumor-suppressing effects of microRNA-612 in bladder cancer cells by targeting malic enzyme 1 expression. Int J Oncol. 2018;52(6):1923–33. https://doi.org/10.3892/ijo.2018.4342
89. Yu H, Duan P, Zhu H, Rao D. miR-613 inhibits bladder cancer proliferation and migration through targeting SphK1. Am J Transl Res. 2017;9(3):1213–21.
90. Tian H, Wang X, Lu J, Tian W, Chen P. MicroRNA-621 inhibits cell proliferation and metastasis in bladder cancer by suppressing Wnt/β-catenin signaling. Chem Biol Interact. 2019;308:244–51. https://doi.org/10.1016/j.cbi.2019.05.042
91. Zhou J, Dai W, Song J. miR-1182 inhibits growth and mediates the chemosensitivity of bladder cancer by targeting hTERT. Biochem Biophys Res Commun. 2016;470(2):445–52. https://doi.org/10.1016/j.bbrc.2016.01.014
92. Majid S, Dar AA, Saini S, Shahryari V, Arora S, Zaman MS, et al. MicroRNA-1280 Inhibits Invasion and Metastasis by Targeting ROCK1 in Bladder Cancer. PLoS One. 2012;7(10):e46743. https://doi.org/10.1371/journal.pone.0046743
93. Zhang Q, Miao S, Han X, Li C, Zhang M, Cui K, et al. MicroRNA-3619-5p suppresses bladder carcinoma progression by directly targeting β-catenin and CDK2 and activating p21. Cell Death Dis. 2018;9(10):960. https://doi.org/10.1038/s41419-018-0986-y
94. Ge Q, Lu M, Ju L, Qian K, Wang G, Wu C-L, et al. miR-4324-RACGAP1-STAT3-ESR1 feedback loop inhibits proliferation and metastasis of bladder cancer. Int J Cancer. 2019;144(12):3043–55. https://doi.org/10.1002/ijc.32036
95. Long JD, Sullivan TB, Humphrey J, Logvinenko T, Summerhayes KA, Kozinn S, et al. A non-invasive miRNA based assay to detect bladder cancer in cell-free urine. Am J Transl Res. 2015;7(11):2500–9.
96. Juracek J, Peltanova B, Dolezel J, Fedorko M, Pacik D, Radova L, et al. Genome-wide identification of urinary cell-free microRNAs for non-invasive detection of bladder cancer. J Cell Mol Med. 2018;22(3):2033–8. https://doi.org/10.1111/jcmm.13487
97. Zhang D-Z, Lau K-M, Chan ESY, Wang G, Szeto C-C, Wong K, et al. Cell-free urinary microRNA-99a and microRNA-125b are diagnostic markers for the non-invasive screening of bladder cancer. PLoS One. 2014;9(7):e100793. https://doi.org/10.1371/journal.pone.0100793
98. Nekoohesh L, Modarressi MH, Mowla SJ, Sadroddiny E, Etemadian M, Afsharpad M, et al. Expression profile of miRNAs in urine samples of bladder cancer patients. Biomark Med. 2018;12(12):1311–21. https://doi.org/10.2217/bmm-2018-0190
99. Pospisilova S, Pazourkova E, Horinek A, Brisuda A, Svobodova I, Soukup V, et al. MicroRNAs in urine supernatant as potential non-invasive markers for bladder cancer detection. Neoplasma. 2016;63(5):799–808. https://doi.org/10.4149/neo_2016_518
100. Pardini B, Cordero F, Naccarati A, Viberti C, Birolo G, Oderda M, et al. microRNA profiles in urine by next-generation sequencing can stratify bladder cancer subtypes. Oncotarget. 2018;9(29):20658–69. https://doi.org/10.18632/oncotarget.25057
101. Cheng Y, Deng X, Yang X, Li P, Zhang X, Li P, et al. Urine microRNAs as biomarkers for bladder cancer: a diagnostic meta-analysis. Onco Targets Ther. 2015;8:2089–96. https://doi.org/10.2147/OTT.S86908
102. Ripoll J, Ramos M, Montaño J, Pons J, Ameijide A, Franch P. Cancer-specific survival by stage of bladder cancer and factors collected by Mallorca Cancer Registry associated to survival. BMC Cancer. 2021;21:676. https://doi.org/10.1186/s12885-021-08418-y
103. Chang SS, Bochner BH, Chou R, Dreicer R, Kamat AM, Lerner SP, et al. Treatment of Non-Metastatic Muscle-Invasive Bladder Cancer: AUA/ASCO/ASTRO/SUO Guideline. J Urol. 2017;198(3):552–9. https://doi.org/10.1016/j.juro.2017.04.086
104. Zargar H, Espiritu PN, Fairey AS, Mertens LS, Dinney CP, Mir MC, et al. Multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol. 2015;67(2):241–9. https://doi.org/10.1016/j.eururo.2014.09.007
105. Xie Y, Ma X, Chen L, Li H, Gu L, Gao Y, et al. MicroRNAs with prognostic significance in bladder cancer: a systematic review and meta-analysis. Sci Rep. 2017;7(1):5619. https://doi.org/10.1038/s41598-017-05801-3
106. Yin X-H, Jin Y-H, Cao Y, Wong Y, Weng H, Sun C, et al. Development of a 21-miRNA Signature Associated With the Prognosis of Patients With Bladder Cancer. Front Oncol. 2019;9:729. https://doi.org/10.3389/fonc.2019.00729
107. Tao J, Yang X, Li P, Wei J, Deng X, Cheng Y, et al. Identification of circulating microRNA signatures for upper tract urothelial carcinoma detection. Mol Med Rep. 2015;12(5):6752–60. https://doi.org/10.3892/mmr.2015.4257
108. Hsu W-C, Li W-M, Lee Y-C, Huang A-M, Chang L-L, Lin H-H, et al. MicroRNA-145 suppresses cell migration and invasion in upper tract urothelial carcinoma by targeting ARF6. FASEB J. 2020;34(4):5975–92. https://doi.org/10.1096/fj.201902555R
109. Chung Y-H, Li S-C, Kao Y-H, Luo H-L, Cheng Y-T, Lin P-R, et al. MiR-30a-5p Inhibits Epithelial-to-Mesenchymal Transition and Upregulates Expression of Tight Junction Protein Claudin-5 in Human Upper Tract Urothelial Carcinoma Cells. Int J Mol Sci. 2017;18(8):1826. https://doi.org/10.3390/ijms18081826
110. Browne BM, Stensland KD, Patel CK, Sullivan T, Burks EJ, Canes D, et al. MicroRNA Expression Profiles in Upper Tract Urothelial Carcinoma Differentiate Tumor Grade, Stage, and Survival: Implications for Clinical Decision-Making. Urology. 2019;123:93–100. https://doi.org/10.1016/j.urology.2018.10.004
111. Ke H-L, Li W-M, Lin H-H, Hsu W-C, Hsu Y-L, Chang L-L, et al. Hypoxia-regulated MicroRNA-210 Overexpression is Associated with Tumor Development and Progression in Upper Tract Urothelial Carcinoma. Int J Med Sci. 2017;14(6):578–84. https://doi.org/10.7150/ijms.15699