MicroRNA-154 as a prognostic factor in bladder cancer inhibits cellular malignancy by targeting RSF1 and RUNX2

Zhao,Xin; Ji,Zhigang; Xie,Yi; Liu,Guanghua; Li,Hanzhong

doi:10.3892/or.2017.5992

MicroRNA-154 as a prognostic factor in bladder cancer inhibits cellular malignancy by targeting RSF1 and RUNX2

Authors:
- Xin Zhao
- Zhigang Ji
- Yi Xie
- Guanghua Liu
- Hanzhong Li
View Affiliations

Affiliations: Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
Published online on: September 25, 2017 https://doi.org/10.3892/or.2017.5992
Pages: 2727-2734
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Recent studies have demonstrated that microRNA-154 (miR-154) is involved in tumorigenesis, progression, invasion and metastasis in several types of human cancer. However, whether it plays a role in bladder cancer (BC) is unclear. The aim of the present study was to determine miR-154 levels in human BC tissues and investigate the correlation between miR-154 levels and clinicopathological characteristics as well as patient outcome. Using RT-qPCR, we found that the expression levels of miR-154 were significantly lower in BC tissues compared to adjacent normal tissues. We also demonstrated that downregulation of miR-154 was associated with advanced clinicopathological features and worse prognoses for patients with BC. Using a variety of integrated approaches, we demonstrated that both runt-related transcription factor 2 (RUNX2) and remodeling and spacing factor 1 (RSF1) were miR-154 targets. Notably, there was an inverse correlation between RSF1, RUNX2 and miR-154 expression in BC tissues. The biological functions of miR-154 were examined in vitro using Cell Counting Kit-8 (CCK-8), wound healing, and Transwell assays with T24 human bladder carcinoma cells transfected with miR-154 mimics or negative controls. These assays demonstrated that miR-154 significantly suppressed proliferation, migration and invasion of T24 cells (P<0.05). Furthermore, overexpression of RSF1 and RUNX2 rescued miR-154-induced inhibition of these aggressive behaviors. Our results indicated that miR-154, and its downstream targets RSF1 and RUNX2, are promising options for future BC therapies.

View Figures

View References

1	Babjuk M, Böhle A, Burger M, Capoun O, Cohen D, Compérat EM, Hernández V, Kaasinen E, Palou J, Rouprêt M, et al: EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016. Eur Urol. 71:447–461. 2017. View Article : Google Scholar : PubMed/NCBI
2	Burger M, Catto JW, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, Kassouf W, Kiemeney LA, La Vecchia C, Shariat S, et al: Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 63:234–241. 2013. View Article : Google Scholar : PubMed/NCBI
3	Stenzl A, Cowan NC, De Santis M, Kuczyk MA, Merseburger AS, Ribal MJ, Sherif A and Witjes JA: European Association of Urology (EAU): Treatment of muscle-invasive and metastatic bladder cancer: Update of the EAU guidelines. Eur Urol. 59:1009–1018. 2011. View Article : Google Scholar : PubMed/NCBI
4	Ye F, Wang L, Castillo-Martin M, McBride R, Galsky MD, Zhu J, Boffetta P, Zhang DY and Cordon-Cardo C: Biomarkers for bladder cancer management: Present and future. Am J Clin Exp Urol. 2:1–14. 2014.PubMed/NCBI
5	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
6	Chang SJ, Weng SL, Hsieh JY, Wang TY, Chang MD and Wang HW: MicroRNA-34a modulates genes involved in cellular motility and oxidative phosphorylation in neural precursors derived from human umbilical cord mesenchymal stem cells. BMC Med Genomics. 4:652011. View Article : Google Scholar : PubMed/NCBI
7	Cui X, Kong C, Zhu Y, Zeng Y, Zhang Z, Liu X, Zhan B, Piao C and Jiang Z: miR-130b, an onco-miRNA in bladder cancer, is directly regulated by NF-κB and sustains NF-κB activation by decreasing Cylindromatosis expression. Oncotarget. 7:48547–48561. 2016. View Article : Google Scholar : PubMed/NCBI
8	Song T, Zhang X, Yang G, Song Y and Cai W: Decrement of miR-199a-5p contributes to the tumorigenesis of bladder urothelial carcinoma by regulating MLK3/NF-κB pathway. Am J Transl Res. 7:2786–2794. 2015.PubMed/NCBI
9	Calin GA and Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 6:857–866. 2006. View Article : Google Scholar : PubMed/NCBI
10	Lee JY, Ryu DS, Kim WJ and Kim SJ: Aberrantly expressed microRNAs in the context of bladder tumorigenesis. Investig Clin Urol. 57 Suppl 1:S52–S59. 2016. View Article : Google Scholar : PubMed/NCBI
11	Zhang Y, Zhang Z, Li Z, Gong D, Zhan B, Man X and Kong C: MicroRNA-497 inhibits the proliferation, migration and invasion of human bladder transitional cell carcinoma cells by targeting E2F3. Oncol Rep. 36:1293–1300. 2016. View Article : Google Scholar : PubMed/NCBI
12	Shin SS, Park SS, Hwang B, Kim WT, Choi YH, Kim WJ and Moon SK: MicroRNA-106a suppresses proliferation, migration, and invasion of bladder cancer cells by modulating MAPK signaling, cell cycle regulators, and Ets-1-mediated MMP-2 expression. Oncol Rep. 36:2421–2429. 2016. View Article : Google Scholar : PubMed/NCBI
13	Zhu C, Shao P, Bao M, Li P, Zhou H, Cai H, Cao Q, Tao L, Meng X, Ju X, et al: miR-154 inhibits prostate cancer cell proliferation by targeting CCND2. Urol Oncol. 32:31.e9–31.e16. 2014. View Article : Google Scholar
14	Xin C, Zhang H and Liu Z: miR-154 suppresses colorectal cancer cell growth and motility by targeting TLR2. Mol Cell Biochem. 387:271–277. 2014. View Article : Google Scholar : PubMed/NCBI
15	Lin X, Yang Z, Zhang P, Liu Y and Shao G: miR-154 inhibits migration and invasion of human non-small cell lung cancer by targeting ZEB2. Oncol Lett. 12:301–306. 2016.PubMed/NCBI
16	Wang L, Wu L and Wu J: Downregulation of miR-154 in human glioma and its clinicopathological and prognostic significance. J Int Med Res. 44:994–1001. 2016. View Article : Google Scholar : PubMed/NCBI
17	Kai Y, Qiang C, Xinxin P, Miaomiao Z and Kuailu L: Decreased miR-154 expression and its clinical significance in human colorectal cancer. World J Surg Oncol. 13:1952015. View Article : Google Scholar : PubMed/NCBI
18	Baranwal S and Alahari SK: miRNA control of tumor cell invasion and metastasis. Int J Cancer. 126:1283–1290. 2010.PubMed/NCBI
19	Xiong F, Liu K, Zhang F, Sha K, Wang X, Guo X and Huang N: MiR-204 inhibits the proliferation and invasion of renal cell carcinoma by inhibiting RAB22A expression. Oncol Rep. 35:3000–3008. 2016. View Article : Google Scholar : PubMed/NCBI
20	Zhou J, Dai W and Song J: miR-1182 inhibits growth and mediates the chemosensitivity of bladder cancer by targeting hTERT. Biochem Biophys Res Commun. 470:445–452. 2016. View Article : Google Scholar : PubMed/NCBI
21	Xu H, Fei D, Zong S and Fan Z: MicroRNA-154 inhibits growth and invasion of breast cancer cells through targeting E2F5. Am J Transl Res. 8:2620–2630. 2016.PubMed/NCBI
22	Pang X, Huang K, Zhang Q, Zhang Y and Niu J: miR-154 targeting ZEB2 in hepatocellular carcinoma functions as a potential tumor suppressor. Oncol Rep. 34:3272–3279. 2015. View Article : Google Scholar : PubMed/NCBI
23	Zhu C, Li J, Cheng G, Zhou H, Tao L, Cai H, Li P, Cao Q, Ju X, Meng X, et al: miR-154 inhibits EMT by targeting HMGA2 in prostate cancer cells. Mol Cell Biochem. 379:69–75. 2013. View Article : Google Scholar : PubMed/NCBI
24	Shih IeM, Sheu JJ, Santillan A, Nakayama K, Yen MJ, Bristow RE, Vang R, Parmigiani G, Kurman RJ, Trope CG, et al: Amplification of a chromatin remodeling gene, Rsf-1/HBXAP, in ovarian carcinoma. Proc Natl Acad Sci USA. 102:pp. 14004–14009. 2005; View Article : Google Scholar : PubMed/NCBI
25	Cosma MP, Tanaka T and Nasmyth K: Ordered recruitment of transcription and chromatin remodeling factors to a cell cycle- and developmentally regulated promoter. Cell. 97:299–311. 1999. View Article : Google Scholar : PubMed/NCBI
26	Shamay M, Barak O, Doitsh G, Ben-Dor I and Shaul Y: Hepatitis B virus pX interacts with HBXAP, a PHD finger protein to coactivate transcription. J Biol Chem. 277:9982–9988. 2002. View Article : Google Scholar : PubMed/NCBI
27	Maeda D, Chen X, Guan B, Nakagawa S, Yano T, Taketani Y, Fukayama M, Wang TL and Shih IeM: Rsf-1 (HBXAP) expression is associated with advanced stage and lymph node metastasis in ovarian clear cell carcinoma. Int J Gynecol Pathol. 30:30–35. 2011. View Article : Google Scholar : PubMed/NCBI
28	Sheu JJ, Choi JH, Guan B, Tsai FJ, Hua CH, Lai MT, Wang TL and Shih IeM: Rsf-1, a chromatin remodelling protein, interacts with cyclin E1 and promotes tumour development. J Pathol. 229:559–568. 2013. View Article : Google Scholar : PubMed/NCBI
29	Ren J, Chen QC, Jin F, Wu HZ, He M, Zhao L, Yu ZJ, Yao WF, Mi XY, Wang EH, et al: Overexpression of Rsf-1 correlates with pathological type, p53 status and survival in primary breast cancer. Int J Clin Exp Pathol. 7:5595–5608. 2014.PubMed/NCBI
30	Liang PI, Wu LC, Sheu JJ, Wu TF, Shen KH, Wang YH, Wu WR, Shiue YL, Huang HY, Hsu HP, et al: Rsf-1/HBXAP overexpression is independent of gene amplification and is associated with poor outcome in patients with urinary bladder urothelial carcinoma. J Clin Pathol. 65:802–807. 2012. View Article : Google Scholar : PubMed/NCBI
31	Liu Y, Li G, Liu C, Tang Y and Zhang S: RSF1 regulates the proliferation and paclitaxel resistance via modulating NF-κB signaling pathway in nasopharyngeal carcinoma. J Cancer. 8:354–362. 2017. View Article : Google Scholar : PubMed/NCBI
32	Ito Y: RUNX genes in development and cancer: Regulation of viral gene expression and the discovery of RUNX family genes. Adv Cancer Res. 99:33–76. 2008. View Article : Google Scholar : PubMed/NCBI
33	Akech J, Wixted JJ, Bedard K, van der Deen M, Hussain S, Guise TA, van Wijnen AJ, Stein JL, Languino LR, Altieri DC, et al: Runx2 association with progression of prostate cancer in patients: Mechanisms mediating bone osteolysis and osteoblastic metastatic lesions. Oncogene. 29:811–821. 2010. View Article : Google Scholar : PubMed/NCBI
34	Pratap J, Wixted JJ, Gaur T, Zaidi SK, Dobson J, Gokul KD, Hussain S, van Wijnen AJ, Stein JL, Stein GS, et al: Runx2 transcriptional activation of Indian Hedgehog and a downstream bone metastatic pathway in breast cancer cells. Cancer Res. 68:7795–7802. 2008. View Article : Google Scholar : PubMed/NCBI
35	Abdelzaher E and Kotb AF: High Coexpression of Runt-related transcription factor 2 (RUNX2) and p53 independently predicts early tumor recurrence in bladder urothelial carcinoma patients. Appl Immunohistochem Mol Morphol. 24:345–354. 2016. View Article : Google Scholar : PubMed/NCBI
36	Lim M, Zhong C, Yang S, Bell AM, Cohen MB and Roy-Burman P: Runx2 regulates survivin expression in prostate cancer cells. Lab Invest. 90:222–233. 2010. View Article : Google Scholar : PubMed/NCBI
37	Ozaki T, Wu D, Sugimoto H, Nagase H and Nakagawara A: Runt-related transcription factor 2 (RUNX2) inhibits p53-dependent apoptosis through the collaboration with HDAC6 in response to DNA damage. Cell Death Dis. 4:e6102013. View Article : Google Scholar : PubMed/NCBI
38	Chen Y, Gao DY and Huang L: In vivo delivery of miRNAs for cancer therapy: Challenges and strategies. Adv Drug Deliv Rev. 81:128–141. 2015. View Article : Google Scholar : PubMed/NCBI
39	Tang Z, Qiu H, Luo L, Liu N, Zhong J, Kang K and Gou D: miR-34b modulates skeletal muscle cell proliferation and differentiation. J Cell Biochem. Apr 19–2017.(Epub ahead of print). doi: 10.1002/jcb.26079. View Article : Google Scholar