Hepatitis C Virus as risk factor for development of hepatocellular carcinoma in Egypt: I- HCV promotes HCC progression by increasing cancer stem marker (CD133 and CD44) expression


Hepatitis C Virus as risk factor for development of hepatocellular carcinoma in Egypt: I- HCV promotes HCC progression by increasing cancer stem marker (CD133 and CD44) expression


Laila H. El-Sayed 1, Manal A. Nabil 1,  Salwa Nayer. M. A 2, Saeid A. Oda 3 , Abdel Rahman M. A 4and Hossam M. Ghoneim 1
1Departement of Immunology & Allergy-Medical Research Institute, Alexandria University
2Departement of Cancer Management & Research- Medical Research Institute, Alexandria University
3Departement of Internal Medicine-Medical Research Institute, Alexandria University
4Departementof Clinical Pathology- Alexandria Military Academy Hospital


American Journal of Cancer Research and Reviews

Hepatitis C virus (HCV) represents a major public health problem, affecting 3% of the world’s population. In majority of infected patients, HCV can effectively evade innate immunity resulting in chronic hepatitis, which can progress to cirrhosis and hepatocellular carcinoma (HCC). Similar to most solid tumors, HCCs are believed to contain poorly differentiated cancer stem cell-like cells (CSCs) that initiate tumorigenesis and confer resistance to chemotherapy. The present work attempted to study the mRNA expression of cancer stem cell markers (CD133 and CD44) in patients with chronic hepatitis C virus (reflecting the role of HCV) and their correlation with progression toward cirrhosis and HCC. Peripheral blood mononuclear cell (PBMC) prepared from chronic HCV patients (either with or without complications) were probed for mRNA expression of CD133 and CD44 by RT-PCR and compared to that of non-HCV cirrhotic patients as well as healthy control subjects. Our results showed that mRNA expression of CD133 was significantly elevated in all HCV patients either with or without complications but not in those with non-HCV cirrhosis, with maximal expression in patients without complications (HCV patients only). On the other hand, maximal CD44 mRNA expression was recorded in HCC patients. Taken together, these results suggests that, chronic HCV infection appear to predispose cells towards the path of acquiring cancer stem cell traits by inducing CD133 and CD44 expression and it prove the hypothesis that the viral interference with signaling network of normal stem cells leads to their transformation into CSCs.


Keywords: Hepatitis C Virus, hepatocellular carcinoma, Egypt, I- HCV, HCC, CD133, CD44

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How to cite this article:
Laila Hamdy El Sayed et al.,. Hepatitis C Virus as risk factor for development of hepatocellular carcinoma in Egypt: I- HCV promotes HCC progression by increasing cancer stem marker (CD133 and CD44) expression. American Journal of Cancer Research and Reviews, 2017,1:1


References:

1 Alter MJ. Epidemiology of hepatitis C virus infection. World J Gastroenterol 2007; 13: 2436-41.
2 Lindenbach BD, Rice CM. Flaviviridae: The viruses and their replication. Philadelphia, PA: Lippubcott Williams and Wilkins, 2001: 991–1041.
3 Sharma SD. Hepatitis C virus: Molecular biology and current therapeutic options. Indian J Med Res 2010; 13: 17-34.
4 Tarr AW, Urbanowicz RA, Ball JK. The role of humoral and innate immunity in hepatitis C virus infection. Viruses 2012; 4: 1-27.
5 Liu HM, Gale M. Hepatitis C Virus evasion from RIG-I dependent hepatic innate immunity. Gastroenterol Res Pract 2010; 9: 548390.
6 Buonaguro L, Petrizzo A, Tornesello ML, Buonaguro FM. Innate immunity and hepatitis C virus infection: A microarray’s view. Infectious Agents and Cancer 2012; 7: 7-15.
7 Golden-Mason L, Rosen HR. Natural killer cells: Multifaceted players with key roles in hepatitis C immunity. Immunol Rev 2013; 255: 68-81.
8 Dolganiuc A, Chang S, Kodys K, Mandrekar P, Bakis G, Cormier M, et al. Hepatitis C virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-alpha and plasmacytoid dendritic cell loss in chronic HCV infection. J Immunol 2006; 177: 6758-68.
9 Banerjee A, Ray RB, Ray R. Oncogenic potential of hepatitis C virus proteins. Viruses 2010; 2: 2108-33.
10 Bartosch B, Thimme R, Blum HE, Zoulim F. Hepatitis C virus-induced hepatocarcinogenesis. J. Hepatol 2009; 51: 810-20.
11 Seita J, Weissman IL. Hematopoietic Stem Cell: Self-renewal versus differentiation. Rev Syst Biol Med. 2010; 2(6): 640-53.
12 Warr MR, Pietras EM, Passegue E. Mechanisms controlling hematopoietic stem cell functions during normal hematopoiesis and hematological malignancies. Advanced review 2011; 145: 1-21.
13 Strijbos MH, Gratama JW, Kraan J, Lamers CH, den Bakker MA, Sleijfer S. Circulating endothelial cells in oncology: Pitfalls and promises. Br J Cancer 2008; 98: 1731-5.
14 Zhu Z, Hao X, Yan M. Cancer stem/progenitor cells are highly enriched in CD133+CD44+ population in hepatocellular carcinoma. Int J Cancer 2010; 126: 2067-78.
15 Hou Y, Zou Q, Ge R, Shen F, Wang Y. The critical role of CD133+CD44+/high tumor cells in hematogenous metastasis of liver cancers. Cell Research 2012; 22: 259-72.
16 Mak AB, Kittanakom S, Stewart JM, Gingras AC, Mazitschek R, Moffat J, et al. Regulation of CD133 by HDAC6 promotes β-catenin signaling to suppress cancer cell differentiation. Cell Reports 2012; 2: 951-63.
17 Mima K, Okabe H, Ishimoto T, Hayashi H, Nakagawa S, Kuroki H, et al. CD44s regulates the TGF-beta- mediated mesenchymal phenotype and is associated with poor prognosis in patients with hepatocellular carcinoma. Cancer Res 2012; 72(13): 3414-23.
18 Okabe H, Ishimoto T, Mima K. CD44s signals the acquisition of the mesenchymal phenotype required for anchorage-independent cell survival in hepatocellular carcinoma. British Journal of Cancer 2014; 110 (4): 958-66.
19 Boyum A. Isolation of leukocytes from human blood. Scond J Clin Invest 1986; 21: 9-29.
20 Bahnassy A, Omran D, El-Bastawisy A, Fawzy A, Shetta M, Hussein N, et al. Circulating tumor and cancer stem cells in hepatitis C virus associated liver disease. World J Gastroenterol 2014; 20(48): 18240-8.
21 Romano M, Pirozzi G, Gringeri E, Boetto R, Zavan B, Cillo U, et al. Expression of cancer stem cell biomarkers as a tool for a correct therapeutic approach to hepatocellular carcinoma. Oncoscience 2015; 2 (5): 443-57.
22 Ma S, Lee TK, Zheng BJ, Chan KW, Guan XY. CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene 2008; 27:1749-58.
23 Sasaki A, Kamiyama T, Yokoo H, Nakanishi K, Kubota K, Haga H, et al. Cytoplasmic expression of CD133 is an important risk factor for overall survival in hepatocellular carcinoma. Oncology Reports 2010; 24: 537-46.
24 Chan AW, Tong JH, Chan SL, Lai PB, To KF. Expression of stemness markers (CD133 and EpCAM) in prognostication of hepatocellular carcinoma. Histopathology 2014; 64: 935-50.
25 Zhong C, Wu JD, Fang MM, Pu LY. Clinicopathological significance and prognostic value of the expression of the cancer stem cell marker CD133 in hepatocellular carcinoma: A meta-analysis. Tumor Biology 2015; 4: 6-18.
26 Ali N, Allam H, May R, Sureban SM, Bronze MS, Bader T, et al. Hepatitis C virus-induced cancer stem cell-like signatures in cell culture and murine tumor xenografts. J Virol 2011; 85(23): 12292-303.
27 Park CY, Choi SH, Kang SM, Ahn BY, Kim H, Jung G, et al. Nonstructural 5A protein activates b-catenin signaling cascades: Implication of hepatitis C virus-induced liver pathogenesis. J Hepatol 2009; 51: 853-64.
28 Liu J, Ding X, Tang J, Cao Y, Hu P, Zhou F, et al. Enhancement of canonical Wnt/ β -catenin signaling activity by HCV core protein promotes cell growth of hepatocellular carcinoma cells. PLoS ONE 2011; 6: 27496-500.
29 Ding G, Liu HD, Huang Q, Liang HX, Ding ZH, Huang G, et al. HDAC6 promotes hepatocellular carcinoma progression by inhibiting P53 transcriptional activity. FEBS Letters 2013; 587: 880-6.
30 Kanno K, Kanno S, Nitta H, Uesugi N, Sugai T. Overexpression of histone deacetylase 6 contributes to accelerated migration and invasion activity of hepatocellular carcinoma cells. Oncol. Rep 2012; 28: 867-73.
31 Lingala S, Cui YY, Chen X, Ruebner BH, Qian XF, Zern MA, et al. Immunohistochemical staining of cancer stem cell markers in hepatocellular carcinoma. Exp Mol Pathol 2010; 89(1): 27-35.
32 Oliva J. The identification of stem cells in human liver diseases and hepatocellular carcinoma. Exp Mol Pathol 2010; 3: 1003-21.
33 Hu S, Wu X, Zhou B, Xu Z, Qin J, Lu H, et al. IMP3 combined with CD44s, a novel predictor for prognosis of patients with hepatocellular carcinoma. J Cancer Res Clin Oncol 2014; 140: 883-93.
34 Niu ZS, Niu XJ, Wang M. Management of hepatocellular carcinoma: Predictive value of immunohistochemical markers for postoperative survival. World J Hepatol 2015; 7(1): 7-27.
35 Abe T, Fukuhara T, Wen X, Ninomiya A, Moriishi K, Maehara Y, et al. CD44 participates in IP-10 induction in cells in which hepatitis C virus RNA is replicating, through an interaction with toll-like receptor 2 and hyaluronan. J Virol 2012; 86: 6159-70.
36 Andre R, Racine RR, Hennig MJ, Lokeshwar VB. The role of CD44 in disease pathophysiology and targeted treatment. Front Immunol 2015; 6: 182-90.
37 Iqbal J, McRae S, Mai T, Banaudha K, Sarkar-Dutta M, Waris G. Role of hepatitis C virus induced osteopontin in epithelial to mesenchymal transition, migration and invasion of hepatocytes. PLOS ONE 2014; 9: 1-16.
38 Hernandez-Gea V, Friedman SL. Pathogenesis of liver fibrosis. Annu Rev Pathol 2011; 6: 425-56.
39 Bigarella CL, Liang R, Ghaffari S. Stem cells and the impact of ROS signaling. Development 2014; 141: 4206-18.
40 Khalifa KA, Alkilani AA, Ismail H, Soliman MA. Evaluation of some biochemical markers as prognostic factors in malignant lymphoma. Journal of the Egyptian Nat. Cancer Inst 2008; 20 (1): 47-54.