Mitogen-activated protein kinase kinase 3 induces cell cycle arrest via p38 activation mediated Bmi-1 downregulation in hepatocellular carcinoma

Wang,Lin; Chen,Chen; Feng,Shuzhi; Lei,Ping; Tian,Jianli

doi:10.3892/mmr.2015.4564

Mitogen-activated protein kinase kinase 3 induces cell cycle arrest via p38 activation mediated Bmi-1 downregulation in hepatocellular carcinoma

Authors:
- Lin Wang
- Chen Chen
- Shuzhi Feng
- Ping Lei
- Jianli Tian
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Affiliations: Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin 300052, P.R. China
Published online on: November 13, 2015 https://doi.org/10.3892/mmr.2015.4564
Pages: 243-248

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Abstract

The underlying molecular pathogenesis of hepatocellular carcinoma (HCC) remains poorly understood. Mitogen-activated protein kinase kinase 3 (MKK3), has been reported as a novel tumor suppressor in breast cancer. However, its potential suppressive role in HCC has not been evaluated. In the current study, the biologic functions of MKK3 in HCC were investigated and a previously unreported cell cycle regulation mechanism was observed. MKK3 overexpression suppressed HepG2 and PLC‑PRF‑5 cell proliferation and induced cell cycle arrest in the two cell lines. In addition, MKK3 overexpression upregulated the cyclin-dependent kinase inhibitors, p16 INK4A and p15 INK4B in HCC cells. Their negative regulator, Bim‑1, was downregulated following MKK3 overexpression. Moreover, MKK3 activated p38 in HCC cells and SB203580, a p38 inhibitor, reversed the tumor suppressive effect of MKK3. In conclusion, the results identify MKK3 as a tumor suppressor and highlighted the significance of p38 pathway aberration in HCC.

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1	Forner A, Llovet JM and Bruix J: Hepatocellular carcinoma. Lancet. 379:1245–1255. 2012. View Article : Google Scholar : PubMed/NCBI
2	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
3	Yeoman AD, Al-Chalabi T, Karani JB, Quaglia A, Devlin J, Mieli-Vergani G, Bomford A, O'Grady JG, Harrison PM and Heneghan MA: Evaluation of risk factors in the development of hepatocellular carcinoma in autoimmune hepatitis: Implications for follow-up and screening. Hepatology. 48:863–870. 2008. View Article : Google Scholar : PubMed/NCBI
4	Mohamed AE, Kew MC and Groeneveld HT: Alcohol consumption as a risk factor for hepatocellular carcinoma in urban southern African blacks. Int J Cancer. 51:537–541. 1992. View Article : Google Scholar : PubMed/NCBI
5	Tsukuma H, Hiyama T, Tanaka S, Nakao M, Yabuuchi T, Kitamura T, Nakanishi K, Fujimoto I, Inoue A, Yamazaki H, et al: Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med. 328:1797–1801. 1993. View Article : Google Scholar : PubMed/NCBI
6	Badvie S: Hepatocellular carcinoma. Postgrad Med J. 76:4–11. 2000. View Article : Google Scholar : PubMed/NCBI
7	Alazawi W, Cunningham M, Dearden J and Foster GR: Systematic review: Outcome of compensated cirrhosis due to chronic hepatitis C infection. Aliment Pharmacol Ther. 32:344–355. 2010. View Article : Google Scholar : PubMed/NCBI
8	Llovet JM, Burroughs A and Bruix J: Hepatocellular carcinoma. Lancet. 362:1907–1917. 2003. View Article : Google Scholar : PubMed/NCBI
9	Farazi PA and DePinho RA: Hepatocellular carcinoma pathogenesis: From genes to environment. Nat Rev Cancer. 6:674–687. 2006. View Article : Google Scholar : PubMed/NCBI
10	Roux PP and Blenis J: ERK and p38 MAPK-activated protein kinases: A family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev. 68:320–344. 2004. View Article : Google Scholar : PubMed/NCBI
11	Ono K and Han J: The p38 signal transduction pathway: Activation and function. Cell Signal. 12:1–13. 2000. View Article : Google Scholar : PubMed/NCBI
12	Zarubin T and Han J: Activation and signaling of the p38 MAP kinase pathway. Cell Res. 15:11–18. 2005. View Article : Google Scholar : PubMed/NCBI
13	Wagner EF and Nebreda AR: Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 9:537–549. 2009. View Article : Google Scholar : PubMed/NCBI
14	Cerezo-Guisado MI, del Reino P, Remy G, Kuma Y, Arthur JS, Gallego-Ortega D and Cuenda A: Evidence of p38gamma and p38δ involvement in cell transformation processes. Carcinogenesis. 32:1093–1099. 2011. View Article : Google Scholar : PubMed/NCBI
15	Kyriakis JM and Avruch J: Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev. 81:807–869. 2001.PubMed/NCBI
16	MacNeil AJ, Jiao SC, McEachern LA, Yang YJ, Dennis A, Yu H, Xu Z, Marshall JS and Lin TJ: MAPK kinase 3 is a tumor suppressor with reduced copy number in breast cancer. Cancer Res. 74:162–172. 2014. View Article : Google Scholar
17	Malumbres M and Barbacid M: Cell cycle, CDKs and cancer: A changing paradigm. Nat Rev Cancer. 9:153–166. 2009. View Article : Google Scholar : PubMed/NCBI
18	Tian Y, Wan H and Tan G: Cell cycle-related kinase in carcinogenesis. Oncol Lett. 4:601–606. 2012.PubMed/NCBI
19	Abraham RT: Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev. 15:2177–2196. 2001. View Article : Google Scholar : PubMed/NCBI
20	Murray AW: Recycling the cell cycle: Cyclins revisited. Cell. 116:221–234. 2004. View Article : Google Scholar : PubMed/NCBI
21	Jacobs JJ, Kieboom K, Marino S, DePinho RA and van Lohuizen M: The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature. 397:164–168. 1999. View Article : Google Scholar : PubMed/NCBI
22	Jacobs JJ, Scheijen B, Voncken JW, Kieboom K, Berns A and van Lohuizen M: Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev. 13:2678–2690. 1999. View Article : Google Scholar : PubMed/NCBI
23	Cao R, Tsukada Y and Zhang Y: Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol Cell. 20:845–854. 2005. View Article : Google Scholar : PubMed/NCBI
24	Molofsky AV, He S, Bydon M, Morrison SJ and Pardal R: Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. Genes Dev. 19:1432–1437. 2005. View Article : Google Scholar : PubMed/NCBI
25	Yao XB, Wang XX, Liu H, Zhang SQ and Zhu HL: Silencing Bmi-1 expression by RNA interference suppresses the growth of laryngeal carcinoma cells. Int J Mol Med. 31:1262–1272. 2013.PubMed/NCBI
26	Wu SQ, Xu ZZ, Niu WY, Huang HB and Zhan R: ShRNA-mediated Bmi-1 silencing sensitizes multiple myeloma cells to bortezomib. Int J Mol Med. 34:616–623. 2014.PubMed/NCBI
27	Hanahan D and Weinberg RA: The hallmarks of cancer. Cell. 100:57–70. 2000. View Article : Google Scholar : PubMed/NCBI
28	Hanahan D and Weinberg RA: Hallmarks of Cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
29	Rosenthal DT, Iyer H, Escudero S, Bao L, Wu Z, Ventura AC, Kleer CG, Arruda EM, Garikipati K and Merajver SD: p38 gamma promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture and a novel leading edge behavior. Cancer Res. 71:6338–6349. 2011. View Article : Google Scholar : PubMed/NCBI
30	He J, Liu Z, Zheng Y, Qian J, Li H, Lu Y, Xu J, Hong B, Zhang M, Lin P, et al: p38 MAPK in myeloma cells regulates osteoclast and osteoblast activity and induces bone destruction. Cancer Res. 72:6393–6402. 2012. View Article : Google Scholar : PubMed/NCBI
31	Liu K, Yu D, Cho YY, Bode AM, Ma W, Yao K, Li S, Li J, Bowden GT and Dong Z and Dong Z: Sunlight UV-induced skin cancer relies upon activation of the p38 alpha signaling pathway. Cancer Res. 73:2181–2188. 2013. View Article : Google Scholar : PubMed/NCBI
32	Sakurai T, Kudo M, Umemura A, He G, Elsharkawy AM, Seki E and Karin M: p38 alpha inhibits liver fibrogenesis and consequent hepatocarcinogenesis by curtailing accumulation of reactive oxygen species. Cancer Res. 73:215–224. 2013. View Article : Google Scholar :
33	Zhou Y, Liang Y, Wei J, Chen J and Tang Q: Lentiviral-mediated p38 MAPK RNAi attenuates aldosterone-induced myocyte apoptosis. Mol Med Rep. 8:493–498. 2013.PubMed/NCBI
34	Sun BK, Kim JH, Nguyen HN, Oh S, Kim SY, Choi S, Choi HJ, Lee YJ and Song JJ: MEKK1/MEKK4 are responsible for TRAIL-induced JNK/p38 phosphorylation. Oncol Rep. 25:537–544. 2011.
35	Paillas S, Boissière F, Bibeau F, Denouel A, Mollevi C, Causse A, Denis V, Vezzio-Vié N, Marzi L, Cortijo C, et al: Targeting the p38 MAPK pathway inhibits irinotecan resistance in colon adenocarcinoma. Cancer Res. 71:1041–1049. 2011. View Article : Google Scholar