Hepatitis B virus‑X protein regulates high mobility group box 1 to promote the formation of hepatocellular carcinoma

Wu,Dehai; Liang,Hao; Wang,Hao; Duan,Changhu; Yazdani,Hamza; Zhou,Jinan; Pan,Yujia; Shan,Baga; Su,Zhilei; Wei,Jinping; Cui,Tiangang; Tai,Sheng

doi:10.3892/ol.2018.9178

Hepatitis B virus‑X protein regulates high mobility group box 1 to promote the formation of hepatocellular carcinoma

Authors:
- Dehai Wu
- Hao Liang
- Hao Wang
- Changhu Duan
- Hamza Yazdani
- Jinan Zhou
- Yujia Pan
- Baga Shan
- Zhilei Su
- Jinping Wei
- Tiangang Cui
- Sheng Tai
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Affiliations: General Surgery Department 1, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China, General Surgery Department 1, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China, Biochemistry Department, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
Published online on: July 19, 2018 https://doi.org/10.3892/ol.2018.9178
Pages: 4418-4426
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Hepatitis B virus (HBV) infection is a risk factor for hepatocellular carcinoma (HCC). HBV X protein (HBx) is an important carcinogen for HBV‑induced HCC. When the HBx gene is integrated into the host cell genome, it is difficult to eradicate. The identification of an effective target to inhibit the oncogenic function of HBx is therefore critically important. The present study demonstrated that HBx, particularly truncated HBx, was expressed in several HBV‑derived cell lines (e.g., Hep3B and SNU423). By analyzing data from The Cancer Genome Atlas, it was revealed that high expression of high mobility group box 1 (HMGB1) was associated with the process and prognosis of HCC. In vitro experiments confirmed that HBx could regulate the expression of HMGB1 and knockdown of HMGB1 could decrease the ability of HBx to promote cellular proliferation. HBx could also upregulate six transcription factors (GATA binding protein 3, Erb‑B2 receptor tyrosine kinase 3, heat shock transcription factor 1, nuclear factor κB subunit 1, TATA‑box binding protein and Kruppel‑like factor 4), which could directly regulate HMGB1. By analyzing genes that are co‑expressed with HMGB1, several signaling pathways associated with the development of HCC were identified. HBx and HMGB1 were revealed to be involved in these pathways, which may be the mechanism by which HBx promotes HCC by regulating HMGB1. These findings suggested that HMGB1 may be an effective target for inhibiting HBV‑induced HCC.

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1	Hernandez-Gea V, Toffanin S, Friedman SL and Llovet JM: Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology. 144:512–527. 2013. View Article : Google Scholar : PubMed/NCBI
2	Lu JW, Yang WY, Tsai SM, Lin YM, Chang PH, Chen JR, Wang HD, Wu JL, Jin SL and Yuh CH: Liver-specific expressions of HBx and src in the p53 mutant trigger hepatocarcinogenesis in zebrafish. PLoS One. 8:e769512013. View Article : Google Scholar : PubMed/NCBI
3	Chen JY, Chen YJ, Yen CJ, Chen WS and Huang WC: HBx sensitizes hepatocellular carcinoma cells to lapatinib by up-regulating ErbB3. Oncotarget. 7:473–489. 2016.PubMed/NCBI
4	Liu XY, Tang SH, Wu SL, Luo YH, Cao MR, Zhou HK, Jiang XW, Shu JC, Bie CQ, Huang SM, et al: Epigenetic modulation of insulin-like growth factor-II overexpression by hepatitis B virus X protein in hepatocellular carcinoma. Am J Cancer Res. 5:956–978. 2015.PubMed/NCBI
5	Zhao J, Wu J, Cai H, Wang D, Yu L and Zhang WH: E3 Ubiquitin ligase Siah-1 is Down-regulated and fails to target natural HBx truncates for degradation in hepatocellular carcinoma. J Cancer. 7:418–426. 2016. View Article : Google Scholar : PubMed/NCBI
6	Hu JJ, Song W, Zhang SD, Shen XH, Qiu XM, Wu HZ, Gong PH, Lu S, Zhao ZJ, He ML and Fan H: HBx-upregulated lncRNA UCA1 promotes cell growth and tumorigenesis by recruiting EZH2 and repressing p27Kip1/CDK2 signaling. Sci Rep. 6:235212016. View Article : Google Scholar : PubMed/NCBI
7	Amaddeo G, Cao Q, Ladeiro Y, Imbeaud S, Nault JC, Jaoui D, Gaston Mathe Y, Laurent C, Laurent A, Bioulac-Sage P, et al: Integration of tumour and viral genomic characterizations in HBV-related hepatocellular carcinomas. Gut. 64:820–829. 2015. View Article : Google Scholar : PubMed/NCBI
8	Levrero M and Zucman-Rossi J: Mechanisms of HBV-induced hepatocellular carcinoma. J Hepatol. 64 Suppl 1:S84–S101. 2016. View Article : Google Scholar : PubMed/NCBI
9	Geng M, Xin X, Bi LQ, Zhou LT and Liu XH: Molecular mechanism of hepatitis B virus X protein function in hepatocarcinogenesis. World J Gastroenterol. 21:10732–10738. 2015. View Article : Google Scholar : PubMed/NCBI
10	Tarocchi M, Polvani S, Marroncini G and Galli A: Molecular mechanism of hepatitis B virus-induced hepatocarcinogenesis. World J Gastroenterol. 20:11630–11640. 2014. View Article : Google Scholar : PubMed/NCBI
11	Zhu M, Guo J, Li W, Xia H, Lu Y, Dong X, Chen Y, Xie X, Fu S and Li M: HBx induced AFP receptor expressed to activate PI3K/AKT signal to promote expression of Src in liver cells and hepatoma cells. BMC Cancer. 15:3622015. View Article : Google Scholar : PubMed/NCBI
12	Ding SL, Yang ZW, Wang J, Zhang XL, Chen XM and Lu FM: Integrative analysis of aberrant Wnt signaling in hepatitis B virus-related hepatocellular carcinoma. World J Gastroenterol. 21:6317–6328. 2015. View Article : Google Scholar : PubMed/NCBI
13	Chan C, Wang Y, Chow PK, Chung AY, Ooi LL and Lee CG: Altered binding site selection of p53 transcription cassettes by hepatitis B virus X protein. Mol Cell Biol. 33:485–497. 2013. View Article : Google Scholar : PubMed/NCBI
14	Ng KY, Chai S, Tong M, Guan XY, Lin CH, Ching YP, Xie D, Cheng AS and Ma S: C-terminal truncated hepatitis B virus X protein promotes hepatocellular carcinogenesis through induction of cancer and stem cell-like properties. Oncotarget. 7:24005–24017. 2016. View Article : Google Scholar : PubMed/NCBI
15	Kang R, Chen R, Zhang Q, Hou W, Wu S, Cao L, Huang J, Yu Y, Fan XG, Yan Z, et al: HMGB1 in health and disease. Mol Aspects Med. 40:1–116. 2014. View Article : Google Scholar : PubMed/NCBI
16	Cato L, Stott K, Watson M and Thomas JO: The interaction of HMGB1 and linker histones occurs through their acidic and basic tails. J Mol Biol. 384:1262–1272. 2008. View Article : Google Scholar : PubMed/NCBI
17	El Mezayen R, El Gazzar M, Seeds MC, McCall CE, Dreskin SC and Nicolls MR: Endogenous signals released from necrotic cells augment inflammatory responses to bacterial endotoxin. Immunol Lett. 111:36–44. 2007. View Article : Google Scholar : PubMed/NCBI
18	Yang C, Peng L and Su J: Two HMGB1 genes from grass carp Ctenopharyngodon idella mediate immune responses to viral/bacterial PAMPs and GCRV challenge. Dev Comp Immunol. 39:133–146. 2013. View Article : Google Scholar : PubMed/NCBI
19	Zhang Z, Zhu Y, Lai Y, Wu X, Feng Z, Yu Y, Bast RC Jr, Wan X, Xi X and Feng Y: Follicle-stimulating hormone inhibits apoptosis in ovarian cancer cells by regulating the OCT4 stem cell signaling pathway. Int J Oncol. 43:1194–1204. 2013. View Article : Google Scholar : PubMed/NCBI
20	Furuita K, Murata S, Jee JG, Ichikawa S, Matsuda A and Kojima C: Structural feature of bent DNA recognized by HMGB1. J Am Chem Soc. 133:5788–5790. 2011. View Article : Google Scholar : PubMed/NCBI
21	Tang D, Kang R, Livesey KM, Cheh CW, Farkas A, Loughran P, Hoppe G, Bianchi ME, Tracey KJ, Zeh HJ III and Lotze MT: Endogenous HMGB1 regulates autophagy. J Cell Biol. 190:881–892. 2010. View Article : Google Scholar : PubMed/NCBI
22	Sundberg E, Fasth AE, Palmblad K, Harris HE and Andersson U: High mobility group box chromosomal protein 1 acts as a proliferation signal for activated T lymphocytes. Immunobiology. 214:303–309. 2009. View Article : Google Scholar : PubMed/NCBI
23	Zhu H, Huang L, Zhu S, Li X, Li Z, Yu C and Yu X: Regulation of autophagy by systemic admission of microRNA-141 to target HMGB1 in l-arginine-induced acute pancreatitis in vivo. Pancreatology. 16:337–346. 2016. View Article : Google Scholar : PubMed/NCBI
24	Gdynia G, Keith M, Kopitz J, Bergmann M, Fassl A, Weber AN, George J, Kees T, Zentgraf HW, Wiestler OD, et al: Danger signaling protein HMGB1 induces a distinct form of cell death accompanied by formation of giant mitochondria. Cancer Res. 70:8558–8568. 2010. View Article : Google Scholar : PubMed/NCBI
25	Lin Q, Yang XP, Fang D, Ren X, Zhou H, Fang J, Liu X, Zhou S, Wen F, Yao X, et al: High-mobility group box-1 mediates toll-like receptor 4-dependent angiogenesis. Arterioscler Thromb Vasc Biol. 31:1024–1032. 2011. View Article : Google Scholar : PubMed/NCBI
26	Jia L, Clear A, Liu FT, Matthews J, Uddin N, McCarthy A, Hoxha E, Durance C, Iqbal S and Gribben JG: Extracellular HMGB1 promotes differentiation of nurse-like cells in chronic lymphocytic leukemia. Blood. 123:1709–1719. 2014. View Article : Google Scholar : PubMed/NCBI
27	Zhang Z, Lin C, Peng L, Ouyang Y, Cao Y, Wang J, Friedman SL and Guo J: High mobility group box 1 activates Toll like receptor 4 signaling in hepatic stellate cells. Life Sci. 91:207–212. 2012. View Article : Google Scholar : PubMed/NCBI
28	Huang H, Nace GW, McDonald KA, Tai S, Klune JR, Rosborough BR, Ding Q, Loughran P, Zhu X, Beer-Stolz D, et al: Hepatocyte-specific high-mobility group box 1 deletion worsens the injury in liver ischemia/reperfusion: A role for intracellular high-mobility group box 1 in cellular protection. Hepatology. 59:1984–1997. 2014. View Article : Google Scholar : PubMed/NCBI
29	Cheng BQ, Jia CQ, Liu CT, Lu XF, Zhong N, Zhang ZL, Fan W and Li YQ: Serum high mobility group box chromosomal protein 1 is associated with clinicopathologic features in patients with hepatocellular carcinoma. Dig Liver Dis. 40:446–452. 2008. View Article : Google Scholar : PubMed/NCBI
30	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
31	Li Q, Li J, Wen T, Zeng W, Peng C, Yan S, Tan J, Yang K, Liu S, Guo A, et al: Overexpression of HMGB1 in melanoma predicts patient survival and suppression of HMGB1 induces cell cycle arrest and senescence in association with p21 (Waf1/Cip1) up-regulation via a p53-independent, Sp1-dependent pathway. Oncotarget. 5:6387–6403. 2014. View Article : Google Scholar : PubMed/NCBI
32	Zhu M, Guo J, Li W, Xia H, Lu Y, Dong X, Chen Y, Xie X, Fu S and Li M: HBx induced AFP receptor expressed to activate PI3K/AKT signal to promote expression of Src in liver cells and hepatoma cells. BMC Cancer. 15:3622015. View Article : Google Scholar : PubMed/NCBI
33	Wang FP, Li L, Li J, Wang JY, Wang LY and Jiang W: High mobility group box-1 promotes the proliferation and migration of hepatic stellate cells via TLR4-dependent signal pathways of PI3K/Akt and JNK. PLoS One. 8:e643732013. View Article : Google Scholar : PubMed/NCBI
34	Wang Y, Cai J, Zeng X, Chen Y, Yan W, Ouyang Y, Xiao D, Zeng Z, Huang L and Liu A: Downregulation of toll-like receptor 4 induces suppressive effects on hepatitis B virus-related hepatocellular carcinoma via ERK1/2 signaling. BMC Cancer. 15:8212015. View Article : Google Scholar : PubMed/NCBI
35	Tohme S, Yazdani HO, Liu Y, Loughran P, van der Windt DJ, Huang H, Simmons RL, Shiva S, Tai S and Tsung A: Hypoxia mediates mitochondrial biogenesis in hepatocellular carcinoma to promote tumor growth through HMGB1 and TLR9 interaction. Hepatology. 66:182–197. 2017. View Article : Google Scholar : PubMed/NCBI