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http://dx.doi.org/10.5483/BMBRep.2021.54.12.084

Hepatitis B virus X protein enhances liver cancer cell migration by regulating calmodulin-associated actin polymerization  

Kim, Mi-jee (Department of Microbiology & Molecular Biology, College of Biological Science and Biotechnology, Chungnam National University)
Kim, Jinchul (Department of Microbiology & Molecular Biology, College of Biological Science and Biotechnology, Chungnam National University)
Im, Jin-su (Department of Microbiology & Molecular Biology, College of Biological Science and Biotechnology, Chungnam National University)
Kang, Inho (Department of Microbiology & Molecular Biology, College of Biological Science and Biotechnology, Chungnam National University)
Ahn, Jeong Keun (Department of Microbiology & Molecular Biology, College of Biological Science and Biotechnology, Chungnam National University)
Publication Information
BMB Reports / v.54, no.12, 2021 , pp. 614-619 More about this Journal
Abstract
Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC), which is a highly aggressive cancer. HBV X protein (HBx), one of four HBV gene products, plays pivotal roles in the development and metastasis of HCC. It has been reported that HBx induces liver cancer cell migration and reorganizes actin cytoskeleton, however the molecular basis for actin cytoskeleton reorganization remains obscure. In this study, we for the first time report that HBx promotes actin polymerization and liver cancer cell migration by regulating calcium modulated protein, calmodulin (CaM). HBx physically interacts with CaM to control the level of phosphorylated cofilin, an actin depolymerizing factor. Mechanistically, HBx interacts with CaM, liberates Hsp90 from its inhibitory partner CaM, and increases the activity of Hsp90, thus activating LIMK1/cofilin pathway. Interestingly, the interaction between HBx and CaM is calcium-dependent and requires the CaM binding motif on HBx. These results indicate that HBx modulates CaM which plays a regulatory role in Hsp90/LIMK1/cofilin pathway of actin reorganization, suggesting a new mechanism of HBV-induced HCC metastasis specifically derived by HBx.
Keywords
Actin polymerization; CaM; Cell migration; Cofilin; HBx;
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1 Dushek O, Mueller S, Soubies S et al (2008) Effects of intracellular calcium and actin cytoskeleton on TCR mobility measured by fluorescence recovery. PLoS One 3, e3913   DOI
2 Chen P, Zeng M, Zhao Y and Fang X (2014) Upregulation of Limk1 caused by microRNA-138 loss aggravates the metastasis of ovarian cancer by activation of Limk1/cofilin signaling. Oncol Rep 32, 2070-2076   DOI
3 Mizuno K (2013) Signaling mechanisms and functional roles of cofilin phosphorylation and dephosphorylation. Cell Signal 25, 457-469   DOI
4 Whitesell L and Lindquist SL (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5, 761-772   DOI
5 Sidera K, Gaitanou M, Stellas D, Matsas R and Patsavoudi E (2008) A critical role for HSP90 in cancer cell invasion involves interaction with the extracellular domain of HER-2. J Biol Chem 283, 2031-2041   DOI
6 Galazkiewicz B, Mossakowska M, Osinska H and Dabrowska R (1985) Polymerization of G-actin by caldesmon. FEBS Lett 184, 144-149   DOI
7 Nishida E, Koyasu S, Sakai H and Yahara I (1986) Calmodulin-regulated binding of the 90-kDa heat shock protein to actin filaments. J Biol Chem 261, 16033-16036   DOI
8 Yamniuk AP and Vogel HJ (2004) Calmodulin's flexibility allows for promiscuity in its interactions with target proteins and peptides. Mol Biotechnol 27, 33-57   DOI
9 Minami Y, Kawasaki H, Suzuki K and Yahara I (1993) The calmodulin-binding domain of the mouse 90-kDa heat shock protein. J Biol Chem 268, 9604-9610   DOI
10 Monteith GR, McAndrew D, Faddy HM and Roberts-Thomson SJ (2007) Calcium and cancer: targeting Ca2+ transport. Nat Rev Cancer 7, 519-530   DOI
11 Kim SY, Kim JC, Kim JK et al (2008) Hepatitis B virus X protein enhances NFkappaB activity through cooperating with VBP1. BMB Rep 41, 158-163   DOI
12 Rottner K and Stradal TE (2011) Actin dynamics and turnover in cell motility. Curr Opin Cell Biol 23, 569-578   DOI
13 Li W, Miao X, Qi Z, Zeng W, Liang J and Liang Z (2010) Hepatitis B virus X protein upregulates HSP90alpha expression via activation of c-Myc in human hepatocarcinoma cell line, HepG2. Virol J 7, 45   DOI
14 Nishimura Y, Yoshioka K, Bernard O, Bereczky B and Itoh K (2006) A role of LIM kinase 1/cofilin pathway in regulating endocytic trafficking of EGF receptor in human breast cancer cells. Histochem Cell Biol 126, 627-638   DOI
15 Elsaraj SM and Bhullar RP (2008) Regulation of platelet Rac1 and Cdc42 activation through interaction with calmodulin. Biochim Biophys Acta 1783, 770-778   DOI
16 Villalobo A and Berchtold MW (2020) The role of calmodulin in tumor cell migration, invasiveness, and metastasis. International J Mol Sci 21, 765   DOI
17 Iizuka N, Tamesa T, Sakamoto K, Miyamoto T, Hamamoto Y and Oka M (2006) Different molecular pathways determining extrahepatic and intrahepatic recurrences of hepatocellular carcinoma. Oncol Rep 16, 1137-1142
18 Chemin I and Zoulim F (2009) Hepatitis B virus induced hepatocellular carcinoma. Cancer Lett 286, 52-59   DOI
19 Perz JF, Armstrong GL, Farrington LA, Hutin YJ and Bell BP (2006) The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 45, 529-538   DOI
20 Ou DP, Tao YM, Tang FQ and Yang LY (2007) The hepatitis B virus X protein promotes hepatocellular carcinoma metastasis by upregulation of matrix metalloproteinases. Int J Cancer 120, 1208-1214   DOI
21 Lambrechts A, Van Troys M and Ampe C (2004) The actin cytoskeleton in normal and pathological cell motility. Int J Biochem Cell Biol 36, 1890-1909   DOI
22 Kapur R, Shi J, Ghosh J et al (2016) ROCK1 via LIM kinase regulates growth, maturation and actin based functions in mast cells. Oncotarget 7, 16936-16947   DOI
23 Baheti AD, Dunham GM, Ingraham CR et al (2016) Clinical implications for imaging of vascular invasion in hepatocellular carcinoma. Abdom Radiol (NY) 41, 1800-1810   DOI
24 Zhang X, Zhang H and Ye L (2006) Effects of hepatitis B virus X protein on the development of liver cancer. J Lab Clin Med 147, 58-66   DOI
25 Alqahtani A, Khan Z, Alloghbi A, Ahmed TSS, Ashraf M, and Hammouda DM (2019) Hepatocellular carcinoma: molecular mechanisms and targeted therapies. Medicina 55, 526   DOI
26 Min JS, Kim JC, Kim JA, Kang I and Ahn JK (2018) SIRT2 reduces actin polymerization and cell migration through deacetylation and degradation of HSP90. Biochim Biophys Acta Mol Cell Res 1865, 1230-1238   DOI
27 Li R, Soosairajah J, Harari D et al (2006) Hsp90 increases LIM kinase activity by promoting its homo-dimerization. FASEB J 20, 1218-1220   DOI
28 Vetter SW and Leclerc E (2003) Novel aspects of calmodulin target recognition and activation. Eur J Biochem 270, 404-414   DOI
29 Motavaf M, Safari S, Saffari Jourshari M and Alavian SM (2013) Hepatitis B virus-induced hepatocellular carcinoma: the role of the virus x protein. Acta Virol 57, 389-396   DOI
30 Chen S, Dong Z, Yang P et al (2017) Hepatitis B virus X protein stimulates high mobility group box 1 secretion and enhances hepatocellular carcinoma metastasis. Cancer Lett 394, 22-32   DOI
31 Yap KL, Kim J, Truong K, Sherman M, Yuan T and Ikura M (2000) Calmodulin target database. J Struct Funct Genomics 1, 8-14   DOI
32 Yang N, Higuchi O, Ohashi K et al (1998) Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature 393, 809-812   DOI
33 Hartzell CA, Jankowska KI, Burkhardt JK and Lewis RS (2016) Calcium influx through CRAC channels controls actin organization and dynamics at the immune synapse. eLife 5, e14850   DOI