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01-07-2010 | Translational Research and Biomarkers

Epithelial-Mesenchymal Transition Induced by Hepatitis C Virus Core Protein in Cholangiocarcinoma

Authors: Tianyu Li, PhD, Dajiang Li, PhD, Long Cheng, PhD, Hongye Wu, MM, Zhanfeng Gao, PhD, Zipei Liu, PhD, Weiwei Jiang, PhD, Ying Hong Gao, MM, Feng Tian, MM, Lijin Zhao, PhD, Shuguang Wang, PhD

Published in: Annals of Surgical Oncology | Issue 7/2010

Abstract

Background

Cholangiocarcinoma (CC) is associated with chronic hepatitis C virus (HCV) infection. We investigated the effect of hepatitis C virus core protein (HCVc) on epithelial-mesenchymal transition (EMT) in CC and tried to identify its target trigger.

Methods

First, we examined expression of HCVc and epithelial and mesenchymal markers in CC tissues. Then we transient-transfected HCVc gene into a CC cell line and examined expression of lysyl oxidase-like 2 (LOXL2) and epithelial and mesenchymal markers by quantitative real-time polymerase chain reaction (PCR) and Western blotting. Finally, LOXL2 gene silencing was shown in QBC939/HCVc cells by RNA interference (RNAi), and we further examined expression of epithelial and mesenchymal markers by quantitative real-time PCR and Western blotting.

Results

Through immunohistochemical staining, the present study showed that HCVc is significantly associated with CC invasion and metastasis. In vitro study showed that HCVc expression induces EMT in CC cell line QBC939, and a mechanism through LOXL2 pathway is suggested. Expression of HCVc was significantly correlated with greater migratory and invasive potential of CC cells.

Conclusions

These observations indicate that HCVc plays a critical role in promoting invasion and metastasis of CC cells.

Okuda K, Nakanuma Y, Miyazaki M. Cholangiocarcinoma: recent progress. Part 1: epidemiology and etiology. J Gastroenterol Hepatol. 2002;17:1049–55.CrossRefPubMed

Kobayashi M, Ikeda K, Saitoh S, Suzuki F, Tsubota A, Suzuki Y, et al. Incidence of primary cholangiocelluar carcinoma of the liver in Japanese patients with HCV-related cirrhosis. Cancer. 2000;88:2471–7.CrossRefPubMed

Sato Y, Kato J, Takimoto R, Takada K, Kawano Y, Miyanishi K, et al. Hepatitis C virus core protein promotes proliferation of human hepatoma cells through enhancement of transforming growth factor a expression via activation of nuclear factor-kB. Gut. 2006;55:1801–8.CrossRefPubMed

Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441:431–6.CrossRefPubMed

Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 2007;7:415–28.CrossRefPubMed

Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2:76–83.CrossRefPubMed

Kang Y, Massagué J. Epithelial-mesenchymal transitions: twist in development and metastasis. Cell. 2004;118:277–9.CrossRefPubMed

Huber MA, Azoitei N, Baumann B, Grünert S, Sommer A, Pehamberger H, et al. NF-kB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest. 2004;114:569–81.PubMed

Bachelder RE, Yoon SO, Franci C, de Herreros AG, Mercurio AM. Glycogen synthase kinase-3 is an endogenous inhibitor of Snail transcription: implications for the epithelial-mesenchymal transition. J Cell Biol. 2005;168:29–33.CrossRefPubMed

10.

Csiszar K. Lysyl oxidases: a novel multifunctional amine oxidase family. Prog Nucleic Acid Res Mol Biol. 2001;70:1–32.CrossRefPubMed

11.

Gao YH, Li TY, Gao ZF, Jiang WW, Wang SG. Expression of LOXL2 protein in cholangiocarcinoma tissuses and relation with EMT. Zhonghua Pu Tong Wai Ke Za Zhi. 2008;23:794–7.

12.

Richmond PJM, Karayiannakis AJ, Nagafuchi A, Kaisary AV, Pignatelli M. Aberrant E-cadherin and α-catenin expression in prostate cancer: correlation with patient survival. Cancer Res. 1997;57:3189–93.PubMed

13.

Nakajima S, Doi R, Toyoda E, Tsuji S, Wada M, Koizumi M, et al. N-cadherin expression and epithelial-mesenchymal transition in pancreatic carcinoma. Clin Cancer Res. 2004;10:4125–33.CrossRefPubMed

14.

Wang SG, Han BL, Duan HC, Chen YS, Peng ZM. Establishment of a cell line of extrahepatic bile duct carcinoma. Zhonghua Shi Yan Wai Ke Za Zhi. 1997;14:67–8.

15.

Zvaifler NJ. Relevance of the stroma and epithelial-mesenchymal transition (EMT) for the rheumatic diseases. Arthritis Res Ther. 2006;8:210.CrossRefPubMed

16.

Pantel K, Brakenhoff RH. Dissecting the metastatic cascade. Nat Rev Cancer. 2004;4:448–56.CrossRefPubMed

17.

Lan M, Kojima T, Osanai M, Chiba H, Sawada N. Oncogenic Raf-1 regulates epithelial to mesenchymal transition via distinct signal transduction pathways in an immortalized mouse hepatic cell line. Carcinogenesis. 2004;25:2385–95.CrossRefPubMed

18.

Gotzmann J, Huber H, Thallinger C, Wolschek M, Jansen B, Schulte-Hermann R, et al. Hepatocytes convert to a fibroblastoid phenotype through the cooperation of TGF-beta1 and Ha-Ras: steps towards invasiveness. J Cell Sci. 2002;115:1189–202.PubMed

19.

Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–54.CrossRefPubMed

20.

Perumal V, Wang J, Thuluvath P, Choti M, Torbenson M. Hepatitis C and hepatitis B nucleic acids are present in intrahepatic cholangiocarcinomas from the United States. Hum Pathol. 2006;37:1211–6.CrossRefPubMed

21.

Lu H, Ye MQ, Thung SN, Dash S, Gerber MA. Detection of hepatitis C virus RNA sequences in cholangiocarcinomas in Chinese and American patients. Chin Med J (Engl). 2000;113:1138–41.

22.

Yin F, Chen B. Detection of hepatitis C virus RNA sequences in hepatic portal cholangiocarcinoma tissue by reverse transcription polymerase chain reaction. Chin Med J (Engl). 1998;111:1068–70.

23.

Liu XF, Zou SQ, Qiu FZ. Pathogenesis of cholangiocarcinoma in the porta hepatis and infection of hepatitis virus. Hepatobiliary Pancreat Dis Int. 2003;2:285–9.PubMed

24.

Chen Rf, Li ZH, Chen JS, Zou SQ. Hepatitis C virus core protein modulating proliferation and apoptosis of hilar cholangiocarcinoma tissues. Zhonghua Shi Yan Wai Ke Za Zhi. 2002;19:510–1.

25.

Grimstad IA. Direct evidence that cancer cell locomotion contributes importantly to invasion. Exp Cell Res. 1987;173:515–3.CrossRefPubMed

26.

Peinado H, Del Carmen Iglesias-de la Cruz M, Olmeda D, Csiszar K, Fong KS, Vega S, et al. A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression. EMBO J. 2005;19:3446–58.CrossRef

27.

Peinado H, Moreno-Bueno G, Hardisson D, Pérez-Gómez E, Santos V, Mendiola M, et al. Lysyl oxidase-like 2 as a new poor prognosis marker of squamous cell carcinomas. Cancer Res. 2008;68:4541–50.CrossRefPubMed

28.

Hohenester E, Sasaki T, Timpl R. Crystal structure of a scavenger receptor cysteine-rich domain sheds light on an ancient superfamily. Nat Struct Biol. 1999;6:228–32.CrossRefPubMed

29.

Scarselli E, Ansuini H, Cerino R, Roccasecca RM, Acali S, Filocamo G, et al. The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus. EMBO J. 2002;21:5017–25.CrossRefPubMed

30.

Barth H, Schnober EK, Neumann-Haefelin C, Thumann C, Zeisel MB, Diepolder HM, et al. Scavenger receptor class B is required for hepatitis C virus uptake and cross-presentation by human dendritic cells. J Virol. 2008;82:3466–79.CrossRefPubMed

31.

Jia ZS, Du DW, Lei YF, Wei X, Yin W, Ma L, et al. Scavenger receptor class B type I mediates cell entry of hepatitis C virus. J Int Med Res. 2008;36:1319–25.PubMed

Title: Epithelial-Mesenchymal Transition Induced by Hepatitis C Virus Core Protein in Cholangiocarcinoma
Authors: Tianyu Li, PhD
Dajiang Li, PhD
Long Cheng, PhD
Hongye Wu, MM
Zhanfeng Gao, PhD
Zipei Liu, PhD
Weiwei Jiang, PhD
Ying Hong Gao, MM
Feng Tian, MM
Lijin Zhao, PhD
Shuguang Wang, PhD
Publication date: 01-07-2010
Publisher: Springer-Verlag
Published in: Annals of Surgical Oncology / Issue 7/2010
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-010-0925-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Epithelial-Mesenchymal Transition Induced by Hepatitis C Virus Core Protein in Cholangiocarcinoma

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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