Interstitial cystitis (IC), also known as bladder pain syndrome, is a chronic inflammatory disease that affects the bladder. The symptoms of IC vary, including feeling an urgent need for immediate urination and of needing to urinate often, as well as bladder or pelvic pain. Despite its high incidence, no molecular diagnostic methods are available for IC, and the molecular pathogenesis is unknown. microRNAs (miRNA) can regulate expression of RNA transcripts in cells and aberrant expression of miRNAs is associated with several human diseases. Here, we investigated the molecular pathogenesis of IC based on miRNA expression signatures. RNA sequencing of miRNA levels in IC tissues and comparison with levels in normal bladder tissue and bladder cancer revealed dysregulated expression of 366 miRNAs (203 and 163 down- and upregulated miRNAs, respectively). In particular, miR-320 family miRNAs(miR-320a, miR-320b, miR-320c, miR-320d and miR-320e) had downregulated expression in IC tissues. Genome-wide gene expression analyses and in silico database analyses showed that three transcription factors, E2F-1, E2F-2 and TUB, are regulated by miR-320 family miRNAs. Immunostaining of IC tissues confirmed that these transcription factors are overexpressed in IC tissues. Novel approaches that identify aberrantly expressed miRNA regulatory networks in IC could provide new prognostic markers and therapeutic targets for this disease.
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van de Merwe JP, Nordling J, Bouchelouche P, Bouchelouche K, Cervigni M, Daha LK, et al. Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC proposal. Eur Urol. 2008;53:60–7.
Macdiarmid SA, Sand PK. Diagnosis of interstitial cystitis/ painful bladder syndrome in patients with overactive bladder symptoms. Rev Urol. 2007;9:9–16.
Dawson, TE & Jamison, J Intravesical treatments for painful bladder syndrome/ interstitial cystitis. Cochrane Database Syst Rev. 2007;4:Cd006113.
Kim HJ. Update on the pathology and diagnosis of interstitial cystitis/bladder pain syndrome: a review. Int Neurourol J. 2016;20:13–7.
Chancellor MB, Yoshimura N. Treatment of interstitial cystitis. Urology. 2004;63:85–92.
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell . 2004;116:281–97.
Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009;19:92–105.
Wiemer EA. The role of microRNAs in cancer: no small matter. Eur J Cancer. 2007;43:1529–44.
Nelson KM, Weiss GJ. MicroRNAs and cancer: past, present, and potential future. Mol Cancer Ther. 2008;7:3655–60.
Rebane A, Akdis CA. MicroRNAs: essential players in the regulation of inflammation. J Allergy Clin Immunol. 2013;132:15–26.
Ha TY. MicroRNAs in human diseases: from cancer to cardiovascular disease. Immune Netw. 2011;11:135–54.
Qu Z, Li W, Fu B. MicroRNAs in autoimmune diseases. Biomed Res Int. 2014;2014:527895.
Dissanayake E, Inoue Y. MicroRNAs in allergic disease. Curr Allergy Asthma Rep. 2016;16:67.
Fuse M, Kojima S, Enokida H, Chiyomaru T, Yoshino H, Nohata N, et al. Tumor suppressive microRNAs (miR-222 and miR-31) regulate molecular pathways based on microRNA expression signature in prostate cancer. J Hum Genet. 2012;57:691–9.
Goto Y, Kojima S, Nishikawa R, Kurozumi A, Kato M, Enokida H, et al. MicroRNA expression signature of castration-resistant prostate cancer: the microRNA-221/222 cluster functions as a tumour suppressor and disease progression marker. Br J Cancer. 2015;113:1055–65.
Goto Y, Kurozumi A, Arai T, Nohata N, Kojima S, Okato A, et al. Impact of novel miR-145-3p regulatory networks on survival in patients with castration-resistant prostate cancer. Br J Cancer. 2017;117:409–20.
Itesako T, Seki N, Yoshino H, Chiyomaru T, Yamasaki T, Hidaka H, et al. The microRNA expression signature of bladder cancer by deep sequencing: the functional significance of the miR-195/497 cluster. PLoS ONE. 2014;9:e84311.
Goto Y, Kurozumi A, Nohata N, Kojima S, Matsushita R, Yoshino H, et al. The microRNA signature of patients with sunitinib failure: regulation of UHRF1 pathways by microRNA-101 in renal cell carcinoma. Oncotarget . 2016;7:59070–86.
Koshizuka K, Nohata N, Hanazawa T, Kikkawa N, Arai T, Okato A, et al. Deep sequencing-based microRNA expression signatures in head and neck squamous cell carcinoma: dual strands of pre-miR-150 as antitumor miRNAs. Oncotarget . 2017;8:30288–304.
Arai T, Okato A, Kojima S, Idichi T, Koshizuka K, Kurozumi A, et al. Regulation of spindle and kinetochore-associated protein 1 by antitumor miR-10a-5p in renal cell carcinoma. Cancer Sci. 2017;108:2088–101.
Matsushita R, Seki N, Chiyomaru T, Inoguchi S, Ishihara T, Goto Y, et al. Tumour-suppressive microRNA-144-5p directly targets CCNE1/2 as potential prognostic markers in bladder cancer. Br J Cancer. 2015;113:282–9.
Yonemori K, Seki N, Idichi T, Kurahara H, Osako Y, Koshizuka K, et al. The microRNA expression signature of pancreatic ductal adenocarcinoma by RNA sequencing: anti-tumour functions of the microRNA-216 cluster. Oncotarget . 2017;8:70097–115.
Jin H, Xie Q, Guo X, Xu J, Wang A, Li J, et al. p63alpha protein up-regulates heat shock protein 70 expression via E2F1 transcription factor 1, promoting Wasf3/Wave3/MMP9 signaling and bladder cancer invasion. J Biol Chem. 2017;292:15952–63.
Jiang Y, Han Y, Sun C, Han C, Han N, Zhi W, et al. Rab23 is overexpressed in human bladder cancer and promotes cancer cell proliferation and invasion. Tumour Biol. 2016;37:8131–8.
Shang C, Zhang H, Guo Y, Hong Y, Liu Y, Xue Y. MiR-320a down-regulation mediates bladder carcinoma invasion by targeting ITGB3. Mol Biol Rep. 2014;41:2521–7.
Borah S, Xi L, Zaug AJ, Powell NM, Dancik GM, Cohen SB, et al. Cancer. TERT promoter mutations and telomerase reactivation in urothelial cancer. Science. 2015;347:1006–10.
Lee TI, Young RA. Transcriptional regulation and its misregulation in disease. Cell . 2013;152:1237–51.
Attwooll C, Lazzerini Denchi E, Helin K. The E2F family: specific functions and overlapping interests. EMBO J. 2004;23:4709–16.
Gaubatz S, Lindeman GJ, Ishida S, Jakoi L, Nevins JR, Livingston DM, et al. E2F4 and E2F5 play an essential role in pocket protein-mediated G1 control. Mol Cell. 2000;6:729–35.
Sanchez Freire V, Burkhard FC, Kessler TM, Kuhn A, Draeger A, Monastyrskaya K. MicroRNAs may mediate the down-regulation of neurokinin-1 receptor in chronic bladder pain syndrome. Am J Pathol. 2010;176:288–303.
Wu YY, Chen YL, Jao YC, Hsieh IS, Chang KC, Hong TM. miR-320 regulates tumor angiogenesis driven by vascular endothelial cells in oral cancer by silencing neuropilin 1. Angiogenesis. 2014;17:247–60.
Vishnubalaji R, Hamam R, Yue S, Al-Obeed O, Kassem M, Liu FF, et al. MicroRNA-320 suppresses colorectal cancer by targeting SOX4, FOXM1, and FOXQ1. Oncotarget. 2016;7:35789–802.
Shi C, Zhang Z. MicroRNA-320 suppresses cervical cancer cell viability, migration and invasion via directly targeting FOXM1. Oncol Lett. 2017;14:3809–16.
Pan C, Gao H, Zheng N, Gao Q, Si Y, Zhao Y. MiR-320 inhibits the growth of glioma cells through downregulating PBX3. Biol Res. 2017;50:31.
Okato A, Goto Y, Kurozumi A, Kato M, Kojima S, Matsushita R, et al. Direct regulation of LAMP1 by tumor-suppressive microRNA-320a in prostate cancer. Int J Oncol. 2016;49:111–22.
Wang X, Wu J, Lin Y, Zhu Y, Xu X, Xu X, et al. MicroRNA-320c inhibits tumorous behaviors of bladder cancer by targeting Cyclin-dependent kinase 6. J Exp Clin Cancer Res. 2014;33:69.
Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013;153:307–19.
Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-Andre V, Sigova AA, et al. Super-enhancers in the control of cell identity and disease. Cell . 2013;155:934–47.
Kaga K, Inoue KI, Kaga M, Ichikawa T, Yamanishi T. Expression profile of urothelial transcription factors in bladder biopsies with interstitial cystitis. Int J Urol. 2017;24:632–8.
Chen HZ, Tsai SY, Leone G. Emerging roles of E2Fs in cancer: an exit from cell cycle control. Nat Rev Cancer. 2009;9:785–97.
Wu J, Sabirzhanov B, Stoica BA, Lipinski MM, Zhao Z, Zhao S, et al. Ablation of the transcription factors E2F1-2 limits neuroinflammation and associated neurological deficits after contusive spinal cord injury. Cell Cycle. 2015;14:3698–712.
Carroll K, Gomez C, Shapiro L. Tubby proteins: the plot thickens. Nat Rev Mol Cell Biol. 2004;5:55–63.
Mukhopadhyay S, Jackson PK. The tubby family proteins. Genome Biol. 2011;12:225.
Boggon TJ, Shan WS, Santagata S, Myers SC, Shapiro L. Implication of tubby proteins as transcription factors by structure-based functional analysis. Science. 1999;286:2119–25.
Noben-Trauth K, Naggert JK, North MA, Nishina PM. A candidate gene for the mouse mutation tubby. Nature. 1996;380:534–8.
This study was supported by KAKENHI grants 17K16779(B) and 15K10801(C).
Conflict of interest
The authors declare that they have no conflict of interest.
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Arai, T., Fuse, M., Goto, Y. et al. Molecular pathogenesis of interstitial cystitis based on microRNA expression signature: miR-320 family-regulated molecular pathways and targets. J Hum Genet 63, 543–554 (2018). https://doi.org/10.1038/s10038-018-0419-x
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