MicroRNA-33a promotes cell proliferation and inhibits apoptosis by targeting PPARα in human hepatocellular carcinoma

Chang,Weiping; Zhang,Lei; Xian,Yao; Yu,Zhaoxiang

doi:10.3892/etm.2017.4236

MicroRNA-33a promotes cell proliferation and inhibits apoptosis by targeting PPARα in human hepatocellular carcinoma

Authors:
- Weiping Chang
- Lei Zhang
- Yao Xian
- Zhaoxiang Yu
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Affiliations: Department of General Surgery, The First Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi 710077, P.R. China, Department of Nutrition, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
Published online on: March 20, 2017 https://doi.org/10.3892/etm.2017.4236
Pages: 2507-2514

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Abstract

MicroRNA-33a (miR-33a) is dysregulated in a number of human cancers, where it functions as an oncogenic miRNA. However, the clinical significance of miR‑33a and its underlying molecular pathways regarding the progression of hepatocellular carcinoma (HCC) are currently unknown. In the present study, it was observed that the level of miR‑33a expression was significantly increased in HCC tissues, relative to adjacent non‑tumor tissues. Increased miR‑33a expression was significantly correlated with poor prognostic features of HCC, including larger tumor size, higher Edmondson-Steiner grading and higher tumor‑node-metastasis tumor stage. Furthermore, high levels of miR‑33a expression were associated with decreases in the 5-year overall survival rate and recurrence‑free survival of patients with HCC. In addition, functional experiments indicated that overexpression of miR‑33a led to increased proliferation and reduced apoptosis of the HCC cell line Huh7, while knockdown of miR‑33a decreased proliferation and induced apoptosis in the HCC cell line HepG2. Furthermore, peroxisome proliferator activated receptor alpha (PPARα) was identified as a direct target of miR-33a in HCC. Upregulation of miR‑33a was found to reduce the levels of PPARα expression in Huh7 cells, while inhibition of miR‑33a lead to a downregulation in PPARα expression in HepG2 cells. Collectively, these results suggest that miR-33a regulates the proliferation and apoptosis of HCC cells, and is a potential prognostic marker of HCC.

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1	Yates LA, Norbury CJ and Gilbert RJ: The long and short of microRNA. Cell. 153:516–519. 2013. View Article : Google Scholar : PubMed/NCBI
2	He L and Hannon GJ: MicroRNAs: Small RNAs with a big role in gene regulation. Nat Rev Genet. 5:522–531. 2004. View Article : Google Scholar : PubMed/NCBI
3	Calin GA and Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 6:857–866. 2006. View Article : Google Scholar : PubMed/NCBI
4	Osman A: MicroRNAs in health and disease-basic science and clinical applications. Clin Lab. 58:393–402. 2012.PubMed/NCBI
5	Rottiers V and Näär AM: MicroRNAs in metabolism and metabolic disorders. Nat Rev Mol Cell Biol. 13:239–250. 2012. View Article : Google Scholar : PubMed/NCBI
6	Forner A, Llovet JM and Bruix J: Hepatocellular carcinoma. Lancet. 379:1245–1255. 2012. View Article : Google Scholar : PubMed/NCBI
7	Yang N, Ekanem NR, Sakyi CA and Ray SD: Hepatocellular carcinoma and microRNA: New perspectives on therapeutics and diagnostics. Adv Drug Deliv Rev. 81:62–74. 2015. View Article : Google Scholar : PubMed/NCBI
8	Dhanasekaran R, Limaye A and Cabrera R: Hepatocellular carcinoma: Current trends in worldwide epidemiology, risk factors, diagnosis, and therapeutics. Hepat Med. 4:19–37. 2012.PubMed/NCBI
9	Aravalli RN, Steer CJ and Cressman EN: Molecular mechanisms of hepatocellular carcinoma. Hepatology. 48:2047–2063. 2008. View Article : Google Scholar : PubMed/NCBI
10	Tanaka S and Arii S: Molecular targeted therapies in hepatocellular carcinoma. Semin Oncol. 39:486–492. 2012. View Article : Google Scholar : PubMed/NCBI
11	Cirera-Salinas D, Pauta M, Allen RM, Salerno AG, Ramírez CM, Chamorro-Jorganes A, Wanschel AC, Lasuncion MA, Morales-Ruiz M, Suarez Y, et al: Mir-33 regulates cell proliferation and cell cycle progression. Cell Cycle. 11:922–933. 2012. View Article : Google Scholar : PubMed/NCBI
12	Li T, Francl JM, Boehme S and Chiang JY: Regulation of cholesterol and bile acid homeostasis by the cholesterol 7α-hydroxylase/steroid response element-binding protein 2/microRNA-33a axis in mice. Hepatology. 58:1111–1121. 2013. View Article : Google Scholar : PubMed/NCBI
13	Najafi-Shoushtari SH, Kristo F, Li Y, Shioda T, Cohen DE, Gerszten RE and Näär AM: MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science. 328:1566–1569. 2010. View Article : Google Scholar : PubMed/NCBI
14	Ramírez CM, Goedeke L, Rotllan N, Yoon JH, Cirera-Salinas D, Mattison JA, Suárez Y, de Cabo R, Gorospe M and Fernández-Hernando C: MicroRNA 33 regulates glucose metabolism. Mol Cell Biol. 33:2891–2902. 2013. View Article : Google Scholar : PubMed/NCBI
15	Liang C, Yu XJ, Guo XZ, Sun MH, Wang Z, Song Y, Ni QX, Li HY, Mukaida N and Li YY: MicroRNA-33a-mediated downregulation of Pim-3 kinase expression renders human pancreatic cancer cells sensitivity to gemcitabine. Oncotarget. 6:14440–14455. 2015. View Article : Google Scholar : PubMed/NCBI
16	Liang C, Wang Z, Li YY, Yu BH, Zhang F and Li HY: miR-33a suppresses the nuclear translocation of β-catenin to enhance gemcitabine sensitivity in human pancreatic cancer cells. Tumour Biol. 36:9395–9403. 2015. View Article : Google Scholar : PubMed/NCBI
17	Kuo PL, Liao SH, Hung JY, Huang MS and Hsu YL: MicroRNA-33a functions as a bone metastasis suppressor in lung cancer by targeting parathyroid hormone related protein. Biochim Biophys Acta. 1830:3756–3766. 2013. View Article : Google Scholar : PubMed/NCBI
18	Wang H, Sun T, Hu J, Zhang R, Rao Y, Wang S, Chen R, McLendon RE, Friedman AH, Keir ST, et al: miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways. J Clin Invest. 124:4489–4502. 2014. View Article : Google Scholar : PubMed/NCBI
19	Zhang T, Han G, Wang Y, Chen K and Sun Y: MicroRNA expression profiles in supraglottic carcinoma. Oncol Rep. 31:2029–2034. 2014.PubMed/NCBI
20	Zhou Y, Huang Z, Wu S, Zang X, Liu M and Shi J: miR-33a is up-regulated in chemoresistant osteosarcoma and promotes osteosarcoma cell resistance to cisplatin by down-regulating TWIST. J Exp Clin Cancer Res. 33:122014. View Article : Google Scholar : PubMed/NCBI
21	Lendvai G, Jármay K, Karácsony G, Halász T, Kovalszky I, Baghy K, Wittmann T, Schaff Z and Kiss A: Elevated miR-33a and miR-224 in steatotic chronic hepatitis C liver biopsies. World J Gastroenterol. 20:15343–15350. 2014. View Article : Google Scholar : PubMed/NCBI
22	Huang CF, Sun CC, Zhao F, Zhang YD and Li DJ: miR-33a levels in hepatic and serum after chronic HBV-induced fibrosis. J Gastroenterol. 50:480–490. 2015. View Article : Google Scholar : PubMed/NCBI
23	World Medical Association, . World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA. 310:2191–2194. 2013. View Article : Google Scholar : PubMed/NCBI
24	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
25	Shimono Y, Zabala M, Cho RW, Lobo N, Dalerba P, Qian D, Diehn M, Liu H, Panula SP, Chiao E, et al: Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell. 138:592–603. 2009. View Article : Google Scholar : PubMed/NCBI
26	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
27	Zhang N, Chu ES, Zhang J, Li X, Liang Q, Chen J, Chen M, Teoh N, Farrell G, Sung JJ and Yu J: Peroxisome proliferator activated receptor alpha inhibits hepatocarcinogenesis through mediating NF-κB signaling pathway. Oncotarget. 5:8330–8340. 2014. View Article : Google Scholar : PubMed/NCBI
28	Lujambio A and Lowe SW: The microcosmos of cancer. Nature. 482:347–355. 2012. View Article : Google Scholar : PubMed/NCBI
29	Cho WC: MicroRNAs: Potential biomarkers for cancer diagnosis, prognosis and targets for therapy. Int J Biochem Cell Biol. 42:1273–1281. 2010. View Article : Google Scholar : PubMed/NCBI
30	Dávalos A, Goedeke L, Smibert P, Ramírez CM, Warrier NP, Andreo U, Cirera-Salinas D, Rayner K, Suresh U, Pastor-Pareja JC, et al: miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proc Natl Acad Sci USA. 108:9232–9237. 2011. View Article : Google Scholar : PubMed/NCBI
31	Zhou Y, Huang ZF, Wu S, Zang XF, Liu M and Shi J: miR-33a is up-regulated in chemoresistant osteosarcoma and promotes osteosarcoma cell resistance to cisplatin by down-regulating TWIST. J Exp Clin Canc Res. 33:122014. View Article : Google Scholar
32	Ibrahim AF, Weirauch U, Thomas M, Grünweller A, Hartmann RK and Aigner A: MicroRNA replacement therapy for miR-145 and miR-33a is efficacious in a model of colon carcinoma. Cancer Res. 71:5214–5224. 2011. View Article : Google Scholar : PubMed/NCBI
33	Lefebvre P, Chinetti G, Fruchart JC and Staels B: Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest. 116:571–580. 2006. View Article : Google Scholar : PubMed/NCBI
34	Grau R, Punzón C, Fresno M and Iñiguez MA: Peroxisome-proliferator-activated receptor alpha agonists inhibit cyclo-oxygenase 2 and vascular endothelial growth factor transcriptional activation in human colorectal carcinoma cells via inhibition of activator protein-1. Biochem J. 395:81–88. 2006. View Article : Google Scholar : PubMed/NCBI
35	Yokoyama Y, Xin B, Shigeto T, Umemoto M, Kasai-Sakamoto A, Futagami M, Tsuchida S, Al-Mulla F and Mizunuma H: Clofibric acid, a peroxisome proliferator-activated receptor alpha ligand, inhibits growth of human ovarian cancer. Mol Cancer Ther. 6:1379–1386. 2007. View Article : Google Scholar : PubMed/NCBI