Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Molecular pathogenesis of interstitial cystitis based on microRNA expression signature: miR-320 family-regulated molecular pathways and targets

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2

References

  1. 1.

    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.

    Article  PubMed  Google Scholar 

  2. 2.

    Macdiarmid SA, Sand PK. Diagnosis of interstitial cystitis/ painful bladder syndrome in patients with overactive bladder symptoms. Rev Urol. 2007;9:9–16.

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Dawson, TE & Jamison, J Intravesical treatments for painful bladder syndrome/ interstitial cystitis. Cochrane Database Syst Rev. 2007;4:Cd006113.

  4. 4.

    Kim HJ. Update on the pathology and diagnosis of interstitial cystitis/bladder pain syndrome: a review. Int Neurourol J. 2016;20:13–7.

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Chancellor MB, Yoshimura N. Treatment of interstitial cystitis. Urology. 2004;63:85–92.

    Article  PubMed  Google Scholar 

  6. 6.

    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell . 2004;116:281–97.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009;19:92–105.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Wiemer EA. The role of microRNAs in cancer: no small matter. Eur J Cancer. 2007;43:1529–44.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Nelson KM, Weiss GJ. MicroRNAs and cancer: past, present, and potential future. Mol Cancer Ther. 2008;7:3655–60.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Rebane A, Akdis CA. MicroRNAs: essential players in the regulation of inflammation. J Allergy Clin Immunol. 2013;132:15–26.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Ha TY. MicroRNAs in human diseases: from cancer to cardiovascular disease. Immune Netw. 2011;11:135–54.

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Qu Z, Li W, Fu B. MicroRNAs in autoimmune diseases. Biomed Res Int. 2014;2014:527895.

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Dissanayake E, Inoue Y. MicroRNAs in allergic disease. Curr Allergy Asthma Rep. 2016;16:67.

    Article  PubMed  Google Scholar 

  14. 14.

    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.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    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.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    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.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    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.

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    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.

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    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.

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    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.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    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.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    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.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Lee TI, Young RA. Transcriptional regulation and its misregulation in disease. Cell . 2013;152:1237–51.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Attwooll C, Lazzerini Denchi E, Helin K. The E2F family: specific functions and overlapping interests. EMBO J. 2004;23:4709–16.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    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.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    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.

    Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    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.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    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.

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Shi C, Zhang Z. MicroRNA-320 suppresses cervical cancer cell viability, migration and invasion via directly targeting FOXM1. Oncol Lett. 2017;14:3809–16.

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    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.

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    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.

    Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    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.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    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.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Carroll K, Gomez C, Shapiro L. Tubby proteins: the plot thickens. Nat Rev Mol Cell Biol. 2004;5:55–63.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Mukhopadhyay S, Jackson PK. The tubby family proteins. Genome Biol. 2011;12:225.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    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.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Noben-Trauth K, Naggert JK, North MA, Nishina PM. A candidate gene for the mouse mutation tubby. Nature. 1996;380:534–8.

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by KAKENHI grants 17K16779(B) and 15K10801(C).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Naohiko Seki.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Further reading

Search

Quick links