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BMC Cancer
Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Research article

Increased MiR-221 expression in hepatocellular carcinoma tissues and its role in enhancing cell growth and inhibiting apoptosis in vitro

Authors: Minhua Rong, Gang Chen, Yiwu Dang

Published in: BMC Cancer | Issue 1/2013

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Abstract

Background

MiR-221 is over-expressed in human hepatocellular carcinoma (HCC), but its clinical significance and function in HCC remains uncertain. The aim of the study was to investigate the relationship between miR-221 overexpression and clinicopathological parameters in HCC formalin-fixed paraffin-embedded (FFPE) tissues, and the effect of miR-221 inhibitor and mimic on different HCC cell lines in vitro.

Methods

MiR-221 expression was detected using real time RT-qPCR in FFPE HCC and the adjacent noncancerous liver tissues. The relationship between miR-221 level and clinicopathological features was also analyzed. Furthermore, miR-221 inhibitor and mimic were transfected into HCC cell lines HepB3, HepG2 and SNU449. The effects of miR-221 on cell growth, cell cycle, caspase activity and apoptosis were also investigated by spectrophotometry, fluorimetry, fluorescence microscopy and flow cytometry, respectively.

Results

The relative expression of miR-221 in clinical TNM stages III and IV was significantly higher than that in the stages I and II. The miR-221 level was also upregulated in the metastatic group compared to the nonmetastatic group. Furthermore, miR-221 over-expression was related to the status of tumor capsular infiltration in HCC clinical samples. Functionally, cell growth was inhibited, cell cycle was arrested in G1/S-phase and apoptosis was increased by miR-221 inhibitor in vitro. Likewise, miR-221 mimic accelerated the cell growth.

Conclusions

Expression of miR-221 in FFPE tissues could provide predictive significance for prognosis of HCC patients. Moreover, miR-221 inhibitor could be useful to suppress proliferation and induce apoptosis in HCC cells. Thus miR-221 might be a critical targeted therapy strategy for HCC.
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Literature
1.
Kudo M: Hepatocellular carcinoma in 2011 and beyond: from the pathogenesis to molecular targeted therapy. Oncology. 2011, 81 (Suppl 1): 1-10.CrossRefPubMed
2.
Meguro M, Mizuguchi T, Kawamoto M, Hirata K: The molecular pathogenesis and clinical implications of hepatocellular carcinoma. Int J Hepatol. 2011, 2011: 818672-CrossRefPubMedPubMedCentral
3.
Yamazaki K, Masugi Y, Sakamoto M: Molecular pathogenesis of hepatocellular carcinoma: altering transforming growth factor-beta signaling in hepatocarcinogenesis. Dig Dis. 2011, 29: 284-288. 10.1159/000327560.CrossRefPubMed
4.
Parkin DM, Bray F, Ferlay J, Pisani P: Estimating the world cancer burden: Globocan 2000. Int J Cancer. 2001, 94: 153-156. 10.1002/ijc.1440.CrossRefPubMed
5.
Zemel R, Issachar A, Tur-Kaspa R: The role of oncogenic viruses in the pathogenesis of hepatocellular carcinoma. Clin Liver Dis. 2011, 15: 261-279. 10.1016/j.cld.2011.03.001. vii-xCrossRefPubMed
6.
Vertemati M, Moscheni C, Petrella D, Lamperti L, Cossa M, Gambacorta M, Goffredi M, Vizzotto L: Morphometric analysis of hepatocellular nodular lesions in HCV cirrhosis. Pathol Res Pract. 2012, 208: 240-244. 10.1016/j.prp.2012.02.007.CrossRefPubMed
7.
Hu Z, Zhao W: Novel insights into the molecular mechanisms of alpha-fetoprotein expression and malignant phenotypes of hepatocellular carcinoma. Cell Mol Immunol. 2012, 9: 7-8. 10.1038/cmi.2011.30.CrossRefPubMed
8.
9.
Aravalli RN, Steer CJ, Cressman EN: Molecular mechanisms of hepatocellular carcinoma. Hepatology. 2008, 48: 2047-2063. 10.1002/hep.22580.CrossRefPubMed
10.
Katzenellenbogen M, Mizrahi L, Pappo O, Klopstock N, Olam D, Barash H, Domany E, Galun E, Goldenberg D: Molecular mechanisms of the chemopreventive effect on hepatocellular carcinoma development in Mdr2 knockout mice. Mol Cancer Ther. 2007, 6: 1283-1291. 10.1158/1535-7163.MCT-06-0420.CrossRefPubMed
11.
Zinkin NT, Grall F, Bhaskar K, Otu HH, Spentzos D, Kalmowitz B, Wells M, Guerrero M, Asara JM, Libermann TA, Afdhal NH: Serum proteomics and biomarkers in hepatocellular carcinoma and chronic liver disease. Clin Cancer Res. 2008, 14: 470-477. 10.1158/1078-0432.CCR-07-0586.CrossRefPubMed
12.
Hu L, Chen G, Yu H, Qiu X: Clinicopathological significance of RASSF1A reduced expression and hypermethylation in hepatocellular carcinoma. Hepatol Int. 2010, 4: 423-432. 10.1007/s12072-010-9164-8.CrossRefPubMedPubMedCentral
13.
Chen G, Luo D: Expression of decoy receptor 3 in liver tissue microarrays. Natl Med J India. 2008, 21: 275-278.PubMed
14.
Chen G, Dang YW, Luo DZ, Feng ZB, Tang XL: Expression of heparanase in hepatocellular carcinoma has prognostic significance: a tissue microarray study. Oncol Res. 2008, 17: 183-189. 10.3727/096504008785114138.CrossRefPubMed
15.
Giorgio A: Percutaneous radiofrequency ablation of hepatocellular carcinoma on cirrhosis: state of the art and future perspectives. Recent Pat Anticancer Drug Discov. 2010, 5: 69-76.CrossRefPubMed
16.
Lencioni R, Cioni D, Crocetti L, Bartolozzi C: Percutaneous ablation of hepatocellular carcinoma: state-of-the-art. Liver Transpl. 2004, 10: S91-97. 10.1002/lt.20043.CrossRefPubMed
17.
Raoul JL, Sangro B, Forner A, Mazzaferro V, Piscaglia F, Bolondi L, Lencioni R: Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: available evidence and expert opinion on the use of transarterial chemoembolization. Cancer Treat Rev. 2011, 37: 212-220. 10.1016/j.ctrv.2010.07.006.CrossRefPubMed
18.
Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G, Donehower RC, Fitch T, Picus J, Erlichman C: Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol. 2005, 23: 6657-6663. 10.1200/JCO.2005.14.696.CrossRefPubMed
19.
Thomas MB, Morris JS, Chadha R, Iwasaki M, Kaur H, Lin E, Kaseb A, Glover K, Davila M, Abbruzzese J: Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma. J Clin Oncol. 2009, 27: 843-850. 10.1200/JCO.2008.18.3301.CrossRefPubMed
20.
Zhu AX, Blaszkowsky LS, Ryan DP, Clark JW, Muzikansky A, Horgan K, Sheehan S, Hale KE, Enzinger PC, Bhargava P, Stuart K: Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006, 24: 1898-1903. 10.1200/JCO.2005.04.9130.CrossRefPubMed
21.
Faivre S, Raymond E, Boucher E, Douillard J, Lim HY, Kim JS, Zappa M, Lanzalone S, Lin X, Deprimo S, et al: Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: an open-label, multicentre, phase II study. Lancet Oncol. 2009, 10: 794-800. 10.1016/S1470-2045(09)70171-8.CrossRefPubMed
22.
Palmer DH: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008, 359: 2498-author reply 2498–2499PubMed
23.
Copur MS: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008, 359: 2498-author reply 2498–2499PubMed
24.
Spinzi G, Paggi S: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008, 359: 2497-2498. author reply 2498–2499CrossRefPubMed
25.
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008, 359: 378-390. 10.1056/NEJMoa0708857.CrossRefPubMed
26.
Winter J, Diederichs S: MicroRNA biogenesis and cancer. Methods Mol Biol. 2011, 676: 3-22. 10.1007/978-1-60761-863-8_1.CrossRefPubMed
27.
28.
Hummel R, Hussey DJ, Haier J: MicroRNAs: predictors and modifiers of chemo- and radiotherapy in different tumour types. Eur J Cancer. 2010, 46: 298-311. 10.1016/j.ejca.2009.10.027.CrossRefPubMed
29.
Augello C, Vaira V, Caruso L, Destro A, Maggioni M, Park YN, Montorsi M, Santambrogio R, Roncalli M, Bosari S: MicroRNA profiling of hepatocarcinogenesis identifies C19MC cluster as a novel prognostic biomarker in hepatocellular carcinoma. Liver Int. 2012, 32: 772-782. 10.1111/j.1478-3231.2012.02795.x.CrossRefPubMed
30.
Negrini M, Gramantieri L, Sabbioni S, Croce CM: microRNA involvement in hepatocellular carcinoma. Anticancer Agents Med Chem. 2011, 11: 500-521. 10.2174/187152011796011037.CrossRefPubMed
31.
Sato F, Hatano E, Kitamura K, Myomoto A, Fujiwara T, Takizawa S, Tsuchiya S, Tsujimoto G, Uemoto S, Shimizu K: MicroRNA profile predicts recurrence after resection in patients with hepatocellular carcinoma within the Milan Criteria. PLoS One. 2011, 6: e16435-10.1371/journal.pone.0016435.CrossRefPubMedPubMedCentral
32.
Diao S, Zhang JF, Wang H, He ML, Lin MC, Chen Y, Kung HF: Proteomic identification of microRNA-122a target proteins in hepatocellular carcinoma. Proteomics. 2010, 10: 3723-3731. 10.1002/pmic.201000050.CrossRefPubMed
33.
Burchard J, Zhang C, Liu AM, Poon RT, Lee NP, Wong KF, Sham PC, Lam BY, Ferguson MD, Tokiwa G, et al: microRNA-122 as a regulator of mitochondrial metabolic gene network in hepatocellular carcinoma. Mol Syst Biol. 2010, 6: 402-CrossRefPubMedPubMedCentral
34.
Huang XH, Wang Q, Chen JS, Fu XH, Chen XL, Chen LZ, Li W, Bi J, Zhang LJ, Fu Q, et al: Bead-based microarray analysis of microRNA expression in hepatocellular carcinoma: miR-338 is downregulated. Hepatol Res. 2009, 39: 786-794. 10.1111/j.1872-034X.2009.00502.x.CrossRefPubMed
35.
Ura S, Honda M, Yamashita T, Ueda T, Takatori H, Nishino R, Sunakozaka H, Sakai Y, Horimoto K, Kaneko S: Differential microRNA expression between hepatitis B and hepatitis C leading disease progression to hepatocellular carcinoma. Hepatology. 2009, 49: 1098-1112. 10.1002/hep.22749.CrossRefPubMed
36.
Li S, Fu H, Wang Y, Tie Y, Xing R, Zhu J, Sun Z, Wei L, Zheng X: MicroRNA-101 regulates expression of the v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS) oncogene in human hepatocellular carcinoma. Hepatology. 2009, 49: 1194-1202. 10.1002/hep.22757.CrossRefPubMed
37.
Gramantieri L, Fornari F, Callegari E, Sabbioni S, Lanza G, Croce CM, Bolondi L, Negrini M: MicroRNA involvement in hepatocellular carcinoma. J Cell Mol Med. 2008, 12: 2189-2204. 10.1111/j.1582-4934.2008.00533.x.CrossRefPubMedPubMedCentral
38.
Wang Y, Lee AT, Ma JZ, Wang J, Ren J, Yang Y, Tantoso E, Li KB, Ooi LL, Tan P, Lee CG: Profiling microRNA expression in hepatocellular carcinoma reveals microRNA-224 up-regulation and apoptosis inhibitor-5 as a microRNA-224-specific target. J Biol Chem. 2008, 283: 13205-13215. 10.1074/jbc.M707629200.CrossRefPubMed
39.
Varnholt H, Drebber U, Schulze F, Wedemeyer I, Schirmacher P, Dienes HP, Odenthal M: MicroRNA gene expression profile of hepatitis C virus-associated hepatocellular carcinoma. Hepatology. 2008, 47: 1223-1232.CrossRefPubMed
40.
Gramantieri L, Ferracin M, Fornari F, Veronese A, Sabbioni S, Liu CG, Calin GA, Giovannini C, Ferrazzi E, Grazi GL, et al: Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma. Cancer Res. 2007, 67: 6092-6099. 10.1158/0008-5472.CAN-06-4607.CrossRefPubMed
41.
Murakami Y, Yasuda T, Saigo K, Urashima T, Toyoda H, Okanoue T, Shimotohno K: Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene. 2006, 25: 2537-2545. 10.1038/sj.onc.1209283.CrossRefPubMed
42.
Karakatsanis A, Papaconstantinou I, Gazouli M, Lyberopoulou A, Polymeneas G, Voros D: Expression of microRNAs, miR-21, miR-31, miR-122, miR-145, miR-146a, miR-200c, miR-221, miR-222, and miR-223 in patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma and its prognostic significance. Mol Carcinog. 2011, 10.1002/mc.21864.
43.
Fu X, Wang Q, Chen J, Huang X, Chen X, Cao L, Tan H, Li W, Zhang L, Bi J, et al: Clinical significance of miR-221 and its inverse correlation with p27Kip(1) in hepatocellular carcinoma. Mol Biol Rep. 2011, 38: 3029-3035. 10.1007/s11033-010-9969-5.CrossRefPubMed
44.
Pineau P, Volinia S, McJunkin K, Marchio A, Battiston C, Terris B, Mazzaferro V, Lowe SW, Croce CM, Dejean A: miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci U S A. 2010, 107: 264-269. 10.1073/pnas.0907904107.CrossRefPubMed
45.
Gramantieri L, Fornari F, Ferracin M, Veronese A, Sabbioni S, Calin GA, Grazi GL, Croce CM, Bolondi L, Negrini M: MicroRNA-221 targets Bmf in hepatocellular carcinoma and correlates with tumor multifocality. Clin Cancer Res. 2009, 15: 5073-5081. 10.1158/1078-0432.CCR-09-0092.CrossRefPubMedPubMedCentral
46.
Wong QW, Lung RW, Law PT, Lai PB, Chan KY, To KF, Wong N: MicroRNA-223 is commonly repressed in hepatocellular carcinoma and potentiates expression of Stathmin1. Gastroenterology. 2008, 135: 257-269. 10.1053/j.gastro.2008.04.003.CrossRefPubMed
47.
Fornari F, Gramantieri L, Ferracin M, Veronese A, Sabbioni S, Calin GA, Grazi GL, Giovannini C, Croce CM, Bolondi L, Negrini M: MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene. 2008, 27: 5651-5661. 10.1038/onc.2008.178.CrossRefPubMed
48.
Garofalo M, Di Leva G, Romano G, Nuovo G, Suh SS, Ngankeu A, Taccioli C, Pichiorri F, Alder H, Secchiero P, et al: miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell. 2009, 16: 498-509. 10.1016/j.ccr.2009.10.014.CrossRefPubMedPubMedCentral
49.
Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, Guo J, Zhang Y, Chen J, Guo X, et al: Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 2008, 18: 997-1006. 10.1038/cr.2008.282.CrossRefPubMed
50.
51.
Li J, Wang Y, Yu W, Chen J, Luo J: Expression of serum miR-221 in human hepatocellular carcinoma and its prognostic significance. Biochem Biophys Res Commun. 2011, 406: 70-73. 10.1016/j.bbrc.2011.01.111.CrossRefPubMed
52.
Yuan Q, Loya K, Rani B, Mobus S, Balakrishnan A, Lamle J, Cathomen T, Vogel A, Manns MP, Ott M, et al: MicroRNA-221 overexpression accelerates hepatocyte proliferation during liver regeneration. Hepatology. 2013, 57: 299-310. 10.1002/hep.25984.CrossRefPubMed
53.
Dai R, Li J, Liu Y, Yan D, Chen S, Duan C, Liu X, He T, Li H: miR-221/222 suppression protects against endoplasmic reticulum stress-induced apoptosis via p27(Kip1)- and MEK/ERK-mediated cell cycle regulation. Biol Chem. 2010, 391: 791-801.CrossRefPubMed
54.
Sharma AD, Narain N, Handel EM, Iken M, Singhal N, Cathomen T, Manns MP, Scholer HR, Ott M, Cantz T: MicroRNA-221 regulates FAS-induced fulminant liver failure. Hepatology. 2011, 53: 1651-1661. 10.1002/hep.24243.CrossRefPubMed
55.
Lu Q, Lu C, Zhou GP, Zhang W, Xiao H, Wang XR: MicroRNA-221 silencing predisposed human bladder cancer cells to undergo apoptosis induced by TRAIL. Urol Oncol. 2010, 28: 635-641. 10.1016/j.urolonc.2009.06.005.CrossRefPubMed
56.
Park JK, Kogure T, Nuovo GJ, Jiang J, He L, Kim JH, Phelps MA, Papenfuss TL, Croce CM, Patel T, Schmittgen TD: miR-221 silencing blocks hepatocellular carcinoma and promotes survival. Cancer Res. 2011, 71: 7608-7616. 10.1158/0008-5472.CAN-11-1144.CrossRefPubMedPubMedCentral
57.
Sobin LH, Compton CC: TNM seventh edition: what's new, what's changed: communication from the International Union Against Cancer and the American Joint Committee on Cancer. Cancer. 2010, 116: 5336-5339. 10.1002/cncr.25537.CrossRefPubMed
58.
Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, Sherman M, Schwartz M, Lotze M, Talwalkar J, Gores GJ: Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008, 100: 698-711. 10.1093/jnci/djn134.CrossRefPubMed
59.
Chen G, Kronenberger P, Umelo IA, Teugels E, De Grève J: Quantification of epidermal growth factor receptor T790M mutant transcripts in lung cancer cells by real-time reverse transcriptase-quantitative polymerase chain reaction. Anal Biochem. 2010, 398: 266-268. 10.1016/j.ab.2009.11.034.CrossRefPubMed
60.
Chen G, Kronenberger P, Teugels E, De Grève J: Influence of RT-qPCR primer position on EGFR interference efficacy in lung cancer cells. Biol Proced Online. 2011, 13: 1-10.1186/1480-9222-13-1.CrossRef
61.
Chen G, Kronenberger P, Teugels E, Adaku Umelo I, De Greve J: Targeting the epidermal growth factor receptor in non-small cell lung cancer cells: the effect of combining RNA interference with tyrosine kinase inhibitors or cetuximab. BMC Med. 2012, 10: 28-10.1186/1741-7015-10-28.CrossRefPubMedPubMedCentral
62.
Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 2001, 25: 402-408. 10.1006/meth.2001.1262.CrossRefPubMed
Metadata
Title
Increased MiR-221 expression in hepatocellular carcinoma tissues and its role in enhancing cell growth and inhibiting apoptosis in vitro
Authors
Minhua Rong
Gang Chen
Yiwu Dang
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-21

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