miR‑152 regulates TGF‑β1‑induced epithelial‑mesenchymal transition by targeting HPIP in tubular epithelial cells

Ning,Ya‑Xian; Wang,Xiao‑Yuan; Wang,Jian‑Qin; Zeng,Rong; Wang,Gou‑Qin

doi:10.3892/mmr.2018.8842

miR‑152 regulates TGF‑β1‑induced epithelial‑mesenchymal transition by targeting HPIP in tubular epithelial cells

Authors:
- Ya‑Xian Ning
- Xiao‑Yuan Wang
- Jian‑Qin Wang
- Rong Zeng
- Gou‑Qin Wang
View Affiliations

Affiliations: Department of Nephrology, Lanzhou University Second Hospital, Lanzhou, Gansu 730000, P.R. China, Department of Rheumatology, Lanzhou University Second Hospital, Lanzhou, Gansu 730000, P.R. China
Published online on: April 3, 2018 https://doi.org/10.3892/mmr.2018.8842
Pages: 7973-7979

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Renal fibrosis is a common pathological feature of chronic kidney diseases, and their development and progression are influenced by epigenetic modifications including aberrant microRNA (miRNA or miR) expression. miRNAs have been demonstrated to modulate the aggressiveness of various cancers and have emerged as possible therapeutic agents for the management of renal fibrosis. Transforming growth factor β1 (TGF‑β1)‑induced epithelial‑mesenchymal transition (EMT) of tubular epithelial cells serves a role in the initiation and progression of renal fibrosis. Furthermore, recent results indicated that the progression of EMT is reversible. The present study aimed to clarify the role of miR‑152 in EMT of the tubular epithelial cell line HK‑2, stimulated by TGF‑β1, using in vitro transfection with a miR‑152 mimic and to further investigate the underlying mechanism of miR‑152 activity. In the present study, miR‑152 expression was significantly reduced in TGF‑β1‑treated HK‑2 cells, accompanied by an increased expression of hematopoietic pre‑B‑cell leukemia transcription factor (PBX)‑interacting protein (HPIP). Additionally, miR‑152 overexpression inhibited TGF‑β1‑induced EMT and suppressed HPIP expression by directly targeting the 3' untranslated region of HPIP in HK‑2 cells. Furthermore, upregulation of HPIP reversed miR‑152‑mediated inhibitory effects on the EMT. Collectively, the results suggest that downregulation of miR‑152 initiates the dedifferentiation of renal tubules and progression of renal fibrosis, which may provide important targets for prevention strategies of renal fibrosis.

View Figures

View References

1	Webster AC, Nagler EV, Morton RL and Masson P: Chronic kidney disease. Lancet. 389:1238–1252. 2017. View Article : Google Scholar : PubMed/NCBI
2	Wing MR, Ramezani A, Gill HS, Devaney JM and Raj DS: Epigenetics of progression of chronic kidney disease: Fact or fantasy? Semin Nephrol. 33:363–374. 2013. View Article : Google Scholar : PubMed/NCBI
3	Li Z, Liu X, Wang B, Nie Y, Wen J, Wang Q and Gu C: Pirfenidone suppresses MAPK signaling pathway to reverse epithelial-mesenchymal transition and renal fibrosis. Nephrology (Carlton). 22:589–597. 2017. View Article : Google Scholar : PubMed/NCBI
4	Bani-Hani AH, Campbell MT, Meldrum DR and Meldrum KK: Cytokines in epithelial-mesenchymal transition: A new insight into obstructive nephropathy. J Urol. 180:461–468. 2008. View Article : Google Scholar : PubMed/NCBI
5	Liu Y: Epithelial to mesenchymal transition in renal fibrogenesis: Pathologic significance, molecular mechanism, and therapeutic intervention. J Am Soc Nephrol. 15:1–12. 2004. View Article : Google Scholar : PubMed/NCBI
6	Winter J, Jung S, Keller S, Gregory RI and Diederichs S: Many roads to maturity: MicroRNA biogenesis pathways and their regulation. Nat Cell Biol. 11:228–234. 2009. View Article : Google Scholar : PubMed/NCBI
7	Chen Y, Song YX and Wang ZN: The microRNA-148/152 family: Multi-faceted players. Mol Cancer. 12:432013. View Article : Google Scholar : PubMed/NCBI
8	Miao CG, Yang YY, He X, Huang C, Huang Y, Qin D, Du CL and Li J: MicroRNA-152 modulates the canonical Wnt pathway activation by targeting DNA methyltransferase 1 in arthritic rat model. Biochimie. 106:149–156. 2014. View Article : Google Scholar : PubMed/NCBI
9	Wu Y, Huang A, Li T, Su X, Ding H, Li H, Qin X, Hou L, Zhao Q, Ge X, et al: miR-152 reduces human umbilical vein endothelial cell proliferation and migration by targeting ADAM17. FEBS Lett. 588:2063–2069. 2014. View Article : Google Scholar : PubMed/NCBI
10	Chandrasekaran K, Karolina DS, Sepramaniam S, Armugam A, Wintour EM, Bertram JF and Jeyaseelan K: Role of microRNAs in kidney homeostasis and disease. Kidney Int. 81:617–627. 2012. View Article : Google Scholar : PubMed/NCBI
11	Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y and Goodall GJ: The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 10:593–601. 2008. View Article : Google Scholar : PubMed/NCBI
12	Park SM, Gaur AB, Lengyel E and Peter ME: The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 22:894–907. 2008. View Article : Google Scholar : PubMed/NCBI
13	Chen CH, Cheng CY, Chen YC, Sue YM, Liu CT, Cheng TH, Hsu YH and Chen TH: MicroRNA-328 inhibits renal tubular cell epithelial-to-mesenchymal transition by targeting the CD44 in pressure-induced renal fibrosis. PLoS One. 9:e998022014. View Article : Google Scholar : PubMed/NCBI
14	Kato M, Zhang J, Wang M, Lanting L, Yuan H, Rossi JJ and Natarajan R: MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors. Proc Natl Acad Sci USA. 104:3432–3437. 2007. View Article : Google Scholar : PubMed/NCBI
15	Yin S, Zhang Q, Yang J, Lin W, Li Y, Chen F and Cao W: TGFβ-incurred epigenetic aberrations of miRNA and DNA methyltransferase suppress Klotho and potentiate renal fibrosis. Biochim Biophys Acta. 1864:1207–1216. 2017. View Article : Google Scholar : PubMed/NCBI
16	Huang Y, Tong J, He F, Yu X, Fan L, Hu J, Tan J and Chen Z: miR-141 regulates TGF-β1-induced epithelial-mesenchymal transition through repression of HIPK2 expression in renal tubular epithelial cells. Int J Mol Med. 35:311–318. 2015. View Article : Google Scholar : PubMed/NCBI
17	Lan A, Qi Y and Du J: Akt2 mediates TGF-β1-induced epithelial to mesenchymal transition by deactivating GSK3β/snail signaling pathway in renal tubular epithelial cells. Cell Physiol Biochem. 34:368–382. 2014. View Article : Google Scholar : PubMed/NCBI
18	Li SS, Liu QF, He AL and Wu FR: Tranilast attenuates TGF-β1-induced epithelial-mesenchymal transition in the NRK-52E cells. Pak J Pharm Sci. 27:51–55. 2014.PubMed/NCBI
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
20	Feng Y, Li L, Zhang X, Zhang Y, Liang Y, Lv J, Fan Z, Guo J, Hong T, Ji B, et al: Hematopoietic pre-B cell leukemia transcription factor interacting protein is overexpressed in gastric cancer and promotes gastric cancer cell proliferation, migration, and invasion. Cancer Sci. 106:1313–1322. 2015. View Article : Google Scholar : PubMed/NCBI
21	Hudson BG, Tryggvason K, Sundaramoorthy M and Neilson EG: Alport's syndrome, Goodpasture's syndrome, and type IV collagen. N Engl J Med. 348:2543–2556. 2003. View Article : Google Scholar : PubMed/NCBI
22	Zeisberg M, Strutz F and Muller GA: Renal fibrosis: An update. Curr Opin Nephrol Hypertens. 10:315–320. 2001. View Article : Google Scholar : PubMed/NCBI
23	Ng YY, Huang TP, Yang WC, Chen ZP, Yang AH, Mu W, Nikolic-Paterson DJ, Atkins RC and Lan HY: Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats. Kidney Int. 54:864–876. 1998. View Article : Google Scholar : PubMed/NCBI
24	Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F and Kalluri R: BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med. 9:964–968. 2003. View Article : Google Scholar : PubMed/NCBI
25	Thuault S, Valcourt U, Petersen M, Manfioletti G, Heldin CH and Moustakas A: Transforming growth factor-beta employs HMGA2 to elicit epithelial-mesenchymal transition. J Cell Biol. 174:175–183. 2006. View Article : Google Scholar : PubMed/NCBI
26	Bijkerk R, de Bruin RG, van Solingen C, van Gils JM, Duijs JM, van der Veer EP, Rabelink TJ, Humphreys BD and van Zonneveld AJ: Silencing of microRNA-132 reduces renal fibrosis by selectively inhibiting myofibroblast proliferation. Kidney Int. 89:1268–1280. 2016. View Article : Google Scholar : PubMed/NCBI
27	Loboda A, Sobczak M, Jozkowicz A and Dulak J: TGF-β1/Smads and miR-21 in renal fibrosis and inflammation. Mediators Inflamm. 2016:83192832016. View Article : Google Scholar : PubMed/NCBI
28	Chhabra R, Dubey R and Saini N: Cooperative and individualistic functions of the microRNAs in the miR-23a~27a~24-2 cluster and its implication in human diseases. Mol Cancer. 9:2322010. View Article : Google Scholar : PubMed/NCBI
29	Yu G, Jia Z and Dou Z: miR-24-3p regulates bladder cancer cell proliferation, migration, invasion and autophagy by targeting DEDD. Oncol Rep. 37:1123–1131. 2017. View Article : Google Scholar : PubMed/NCBI
30	Roscigno G, Puoti I, Giordano I, Donnarumma E, Russo V, Affinito A, Adamo A, Quintavalle C, Todaro M, Vivanco MD and Condorelli G: MiR-24 induces chemotherapy resistance and hypoxic advantage in breast cancer. Oncotarget. 8:19507–19521. 2017. View Article : Google Scholar : PubMed/NCBI
31	Lin F, Wu X, Zhang H, You X, Zhang Z, Shao R and Huang C: A microrna screen to identify regulators of peritoneal fibrosis in a rat model of peritoneal dialysis. BMC Nephrol. 16:482015. View Article : Google Scholar : PubMed/NCBI
32	Bugide S, David D, Nair A, Kannan N, Samanthapudi VS, Prabhakar J and Manavathi B: Hematopoietic PBX-interacting protein (HPIP) is over expressed in breast infiltrative ductal carcinoma and regulates cell adhesion and migration through modulation of focal adhesion dynamics. Oncogene. 34:4601–4612. 2015. View Article : Google Scholar : PubMed/NCBI
33	van Vuurden DG, Aronica E, Hulleman E, Wedekind LE, Biesmans D, Malekzadeh A, Bugiani M, Geerts D, Noske DP, Vandertop WP, et al: Pre-B-cell leukemia homeobox interacting protein 1 is overexpressed in astrocytoma and promotes tumor cell growth and migration. Neuro Oncol. 16:946–959. 2014. View Article : Google Scholar : PubMed/NCBI
34	Feng Y, Xu X, Zhang Y, Ding J, Wang Y, Zhang X, Wu Z, Kang L, Liang Y, Zhou L, et al: HPIP is upregulated in colorectal cancer and regulates colorectal cancer cell proliferation, apoptosis and invasion. Sci Rep. 5:94292015. View Article : Google Scholar : PubMed/NCBI
35	Shi S, Zhao J, Wang J, Mi D and Ma Z: HPIP silencing inhibits TGF-β1-induced EMT in lung cancer cells. Int J Mol Med. 39:479–483. 2017. View Article : Google Scholar : PubMed/NCBI
36	Zhang GY, Liu AH, Li GM and Wang JR: HPIP silencing prevents epithelial-mesenchymal transition induced by TGF-β1 in human ovarian cancer cells. Oncol Res. 24:33–39. 2016. View Article : Google Scholar : PubMed/NCBI
37	Mai H, Xu X, Mei G, Hong T, Huang J, Wang T, Yan Z, Li Y, Liang Y, Li L, et al: The interplay between HPIP and casein kinase 1alpha promotes renal cell carcinoma growth and metastasis via activation of mTOR pathway. Oncogenesis. 5:e2602016. View Article : Google Scholar : PubMed/NCBI
38	Xu X, Fan Z, Kang L, Han J, Jiang C, Zheng X, Zhu Z, Jiao H, Lin J, Jiang K, et al: Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis. J Clin Invest. 123:630–645. 2013.PubMed/NCBI
39	Bugide S, Gonugunta VK, Penugurti V, Malisetty VL, Vadlamudi RK and Manavathi B: HPIP promotes epithelial-mesenchymal transition and cisplatin resistance in ovarian cancer cells through PI3K/AKT pathway activation. Cell Oncol (Dordr). 40:133–144. 2017. View Article : Google Scholar : PubMed/NCBI