Notch1 promotes hepatitis B virus X protein-induced hepatocarcinogenesis via Wnt/β-catenin pathway

Sun,Qian; Wang,Ronghua; Luo,Jing; Wang,Peng; Xiong,Si; Liu,Man; Cheng,Bin

doi:10.3892/ijo.2014.2537

Notch1 promotes hepatitis B virus X protein-induced hepatocarcinogenesis via Wnt/β-catenin pathway

Authors:
- Qian Sun
- Ronghua Wang
- Jing Luo
- Peng Wang
- Si Xiong
- Man Liu
- Bin Cheng
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Affiliations: Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
Published online on: July 7, 2014 https://doi.org/10.3892/ijo.2014.2537
Pages: 1638-1648

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Abstract

Hepatitis B virus X protein (HBx) is implicated in the pathogenesis of hepatocellular carcinoma (HCC) via a network of signaling pathways. Notch pathway is a major member of the network. Notch signaling may generate opposing effect in different steps of carcinogenesis, depending on the tumor cell type and the status of other signaling pathways, such as Wnt signaling pathway. Our previous studies have shown that activated Notch1 signaling is required for HBx to promote proliferation and survival of human hepatic cell line L02. However, the exact mechanisms remain vague. Here, we used L02/HBx cell lines as a cell model to study the relationship between Notch and Wnt/β-catenin pathways in promoting proliferation. We observed that activated Notch1 and Wnt/β-catenin signaling pathways and L02 cell malignant transformation were induced by HBx. Inhibition of the Notch1 pathway decreased the activation of Wnt/β-catenin pathway and cell proliferation, while inhibition of the Wnt/β-catenin pathway impaired cell proliferation, but did not significantly affect Notch1 signaling pathway in L02/HBx cells. Furthermore, inhibition of the Wnt/β-catenin pathway overcame the inhibition effect of knockdown Notch1 on proliferation and survival in L02/HBx cells. Additionally, the activity of Wnt/β-catenin signaling appears to be consistent with Fzd10 expression. Therefore, we demonstrate that Wnt signaling is downstream of the Notch pathway in regulating proliferation of L02/HBx cells, and which may be related to Fzd10 instead of Fzd7. These data suggest a new model of HBx-related HCC via cooperation between Wnt and Notch pathways.

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1	Block TM, Mehta AS, Fimmel CJ and Jordan R: Molecular viral oncology of hepatocellular carcinoma. Oncogene. 22:5093–5107. 2003. View Article : Google Scholar : PubMed/NCBI
2	Martin-Vilchez S, Lara-Pezzi E, Trapero-Marugan M, Moreno-Otero R and Sanz-Cameno P: The molecular and pathophysiological implications of hepatitis B X antigen in chronic hepatitis B virus infection. Rev Med Virol. 21:315–329. 2011.PubMed/NCBI
3	Diao J, Garces R and Richardson CD: X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis. Cytokine Growth Factor Rev. 12:189–205. 2001. View Article : Google Scholar : PubMed/NCBI
4	Wang F, Zhou H, Xia X, Sun Q, Wang Y and Cheng B: Activated Notch signaling is required for hepatitis B virus X protein to promote proliferation and survival of human hepatic cells. Cancer Lett. 298:64–73. 2010. View Article : Google Scholar : PubMed/NCBI
5	Wang F, Zhou H, Yang Y, Xia X, Sun Q, Luo J and Cheng B: Hepatitis B virus X protein promotes the growth of hepatocellular carcinoma by modulation of the Notch signaling pathway. Oncol Rep. 27:1170–1176. 2012.PubMed/NCBI
6	Luo J, Zhou H, Wang F, Xia X, Sun Q, Wang R and Cheng B: The hepatitis B virus X protein downregulates NF-κB signaling pathways through decreasing the Notch signaling pathway in HBx-transformed L02 cells. Int J Oncol. 42:1636–1643. 2013.PubMed/NCBI
7	Wang F, Xia X, Wang J, Sun Q, Luo J and Cheng B: Notch1 signaling contributes to the oncogenic effect of HBx on human hepatic cells. Biotechnol Lett. 35:29–37. 2013. View Article : Google Scholar : PubMed/NCBI
8	Sun Q, Wang R, Wang Y, Luo J, Wang P and Cheng B: Notch1 is a potential therapeutic target for the treatment of human hepatitis B virus X protein-associated hepatocellular carcinoma. Oncol Rep. 31:933–939. 2014.PubMed/NCBI
9	Kopan R and Ilagan MX: The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 137:216–233. 2009. View Article : Google Scholar : PubMed/NCBI
10	Kopan R: Notch signaling. Cold Spring Harb Perspect Biol. 4:pii: a011213. 2012. View Article : Google Scholar
11	Kalaitzidis D and Armstrong SA: Cancer: the flipside of Notch. Nature. 473:159–160. 2011. View Article : Google Scholar : PubMed/NCBI
12	Ranganathan P, Weaver KL and Capobianco AJ: Notch signalling in solid tumours: a little bit of everything but not all the time. Nat Rev Cancer. 11:338–351. 2011. View Article : Google Scholar : PubMed/NCBI
13	Giovannini C, Gramantieri L, Chieco P, et al: Selective ablation of Notch3 in HCC enhances doxorubicin’s death promoting effect by a p53 dependent mechanism. J Hepatol. 50:969–979. 2009.PubMed/NCBI
14	Villanueva A, Alsinet C, Yanger K, et al: Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice. Gastroenterology. 143:1660–1669. e16672012. View Article : Google Scholar : PubMed/NCBI
15	Qi R, An H, Yu Y, et al: Notch1 signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis. Cancer Res. 63:8323–8329. 2003.PubMed/NCBI
16	Wang C, Qi R, Li N, et al: Notch1 signaling sensitizes tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human hepatocellular carcinoma cells by inhibiting Akt/Hdm2- mediated p53 degradation and up-regulating p53-dependent DR5 expression. J Biol Chem. 284:16183–16190. 2009. View Article : Google Scholar
17	Viatour P, Ehmer U, Saddic LA, et al: Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway. J Exp Med. 208:1963–1976. 2011. View Article : Google Scholar : PubMed/NCBI
18	Zimmerman ZF, Moon RT and Chien AJ: Targeting Wnt pathways in disease. Cold Spring Harb Perspect Biol. 4:pii: a008086. 2012. View Article : Google Scholar
19	Zhou J, Cheng P, Youn JI, Cotter MJ and Gabrilovich DI: Notch and wingless signaling cooperate in regulation of dendritic cell differentiation. Immunity. 30:845–859. 2009. View Article : Google Scholar : PubMed/NCBI
20	Camps J, Pitt JJ, Emons G, et al: Genetic amplification of the NOTCH modulator LNX2 upregulates the WNT/beta-catenin pathway in colorectal cancer. Cancer Res. 73:2003–2013. 2013. View Article : Google Scholar : PubMed/NCBI
21	Li C, Zhang Y, Lu Y, Cui Z, Yu M, Zhang S and Xue X: Evidence of the cross talk between Wnt and Notch signaling pathways in non-small-cell lung cancer (NSCLC): Notch3-siRNA weakens the effect of LiCl on the cell cycle of NSCLC cell lines. J Cancer Res Clin Oncol. 137:771–778. 2011. View Article : Google Scholar : PubMed/NCBI
22	Liao C, Zhao M, Song H, Uchida K, Yokoyama KK and Li T: Identification of the gene for a novel liver-related putative tumor suppressor at a high-frequency loss of heterozygosity region of chromosome 8p23 in human hepatocellular carcinoma. Hepatology. 32:721–727. 2000. View Article : Google Scholar
23	Cheng B, Zheng Y, Guo X, Wang Y and Liu C: Hepatitis B viral X protein alters the biological features and expressions of DNA repair enzymes in LO2 cells. Liver Int. 30:319–326. 2010. View Article : Google Scholar : PubMed/NCBI
24	Ueno K, Hirata H, Hinoda Y and Dahiya R: Frizzled homolog proteins, microRNAs and Wnt signaling in cancer. Int J Cancer. 132:1731–1740. 2013. View Article : Google Scholar : PubMed/NCBI
25	Terasaki H, Saitoh T, Shiokawa K and Katoh M: Frizzled-10, up-regulated in primary colorectal cancer, is a positive regulator of the WNT - beta-catenin - TCF signaling pathway. Int J Mol Med. 9:107–112. 2002.PubMed/NCBI
26	Nagayama S, Yamada E, Kohno Y, et al: Inverse correlation of the up-regulation of FZD10 expression and the activation of beta-catenin in synchronous colorectal tumors. Cancer Sci. 100:405–412. 2009. View Article : Google Scholar : PubMed/NCBI
27	Gugger M, White R, Song S, Waser B, Cescato R, Riviere P and Reubi JC: GPR87 is an overexpressed G-protein coupled receptor in squamous cell carcinoma of the lung. Dis Markers. 24:41–50. 2008. View Article : Google Scholar : PubMed/NCBI
28	Nagayama S, Fukukawa C, Katagiri T, et al: Therapeutic potential of antibodies against FZD 10, a cell-surface protein, for synovial sarcomas. Oncogene. 24:6201–6212. 2005. View Article : Google Scholar : PubMed/NCBI
29	Fukukawa C, Hanaoka H, Nagayama S, et al: Radioimmunotherapy of human synovial sarcoma using a monoclonal antibody against FZD10. Cancer Sci. 99:432–440. 2008. View Article : Google Scholar : PubMed/NCBI
30	Merle P, de la Monte S, Kim M, et al: Functional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma. Gastroenterology. 127:1110–1122. 2004. View Article : Google Scholar : PubMed/NCBI
31	Bengochea A, de Souza MM, Lefrancois L, et al: Common dysregulation of Wnt/Frizzled receptor elements in human hepatocellular carcinoma. Br J Cancer. 99:143–150. 2008. View Article : Google Scholar : PubMed/NCBI
32	Merle P, Kim M, Herrmann M, et al: Oncogenic role of the frizzled-7/beta-catenin pathway in hepatocellular carcinoma. J Hepatol. 43:854–862. 2005. View Article : Google Scholar : PubMed/NCBI
33	King TD, Zhang W, Suto MJ and Li Y: Frizzled7 as an emerging target for cancer therapy. Cell Signal. 24:846–851. 2012. View Article : Google Scholar : PubMed/NCBI
34	Nambotin SB, Lefrancois L, Sainsily X, et al: Pharmacological inhibition of Frizzled-7 displays anti-tumor properties in hepatocellular carcinoma. J Hepatol. 54:288–299. 2011. View Article : Google Scholar : PubMed/NCBI
35	Hsieh A, Kim HS, Lim SO, Yu DY and Jung G: Hepatitis B viral X protein interacts with tumor suppressor adenomatous polyposis coli to activate Wnt/beta-catenin signaling. Cancer Lett. 300:162–172. 2011. View Article : Google Scholar : PubMed/NCBI
36	Cha MY, Kim CM, Park YM and Ryu WS: Hepatitis B virus X protein is essential for the activation of Wnt/beta-catenin signaling in hepatoma cells. Hepatology. 39:1683–1693. 2004. View Article : Google Scholar : PubMed/NCBI