Hepatitis C Virus as risk factor for development of hepatocellular carcinoma in Egypt: II-Enhancement role of matrix metalloproteinases-2 in dissemination of HCC

Hepatitis C Virus as risk factor for development of hepatocellular carcinoma in Egypt: II-Enhancement role of matrix metalloproteinases-2 in dissemination of HCC

Laila H. El-Sayed1, Manal A. Nabil1, Salwa Nayer. M. A2, Saeid A. Oda3, Abdel Rahman M. A4 and Hossam M. Ghoneim1
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) infection is a major public health problem all over the world. Egypt has the highest prevalence of HCV worldwide (17-26%) with subsequent high morbidity from chronic liver disease, cirrhosis and hepatocellular carcinoma (HCC). Matrix metalloproteinase are proteolytic enzymes that play a role in the degradation of extracellular matrix (ECM) which is necessary for invasion and metastasis of tumor cells. The present work was designed to study the relationship between HCV infection and circulating MMP-2 level in chronic HCV patients (either without or with hepatic complication) and compared to that of non- HCV cirrhotic patients as well as healthy controls, in order to clarify the role of HCV in changing microenvironment and underlying mechanisms associated with dissemination of malignancy. The level of MMP-2 was estimated in sera collected at different stages of HCV infections as well as in ascetic fluids collected from those developing either HCC or cirrhosis. Statistical analysis of their results revealed that MMP-2 levels were significantly elevated in all patient groups as compared to healthy controls. The level of MMP-2 in HCV patients with HCC was significantly elevated when compared to other HCV patients. Meanwhile MMP-2 in ascetic fluids of cirrhotic patients were similar to that detected in their sera, while in HCC patients there were 2.4 times elevations in serum level of MMP-2 as compared to that in ascetic fluids. These results revealed that HCV infection is not only responsible for biochemical and hematological abnormalities recorded at chronic stages of infection but also creating a microenvironmental change by enhancing MMP-2 release, which effect on infected cell by obliging them to modify their phenotype in order to survive, thus increasing the invasion potential and facilitate tumor progression.

Keywords: Hepatitis C Virus, hepatocellular carcinoma, II-Enhancement, MMP-2 HCC

Free Full-text PDF

How to cite this article:
Laila H. El-Sayed, Manal A. Nabil, Salwa Nayer. M. A, Saeid A. Oda, Abdel Rahman M. A 4and Hossam M. Ghoneim.Hepatitis C Virus, hepatocellular carcinoma, II-Enhancement, matrix metalloproteinases-2 in dissemination of HCC. American Journal of Cancer Research and Reviews, 2017,1:2


1. Liver Cancer Fact Sheet. Lyon: IARC; International Agency for Research on Cancer. Globocan 2012.
2. Bartosch B, Thimme R, Blum HE, Zoulim F. Hepatitis C virus-induced hepatocarcinogenesis. J. Hepatol 2009; 51: 810-20.
3. Moradpour DF, Penin, C. M. Rice. Replication of hepatitis C virus. Nat. Rev. Microbiol 2007; 5: 453-463.
4. Von HT, Yoon JC, Alter H, Rice CM, Rehermann B, Balfe P, et al. Hepatitis C virus continuously escapes from neutralizing antibody and T-cell responses during chronic infection in vivo. Gastroenterology 2007; 132: 667-78.
5. Levrero M. Viral hepatitis and liver cancer: The case of hepatitis C. Oncogene 2006; 25: 3834-47.
6. Banerjee A, Ray RB, Ray R. Oncogenic potential of hepatitis C virus proteins. Viruses 2010; 2: 2108-33.
7. Yadav L, Puri N, Rastogi V, Satpute P, Ahmad R, Kaur G. Matrix metalloproteinases and cancer – roles in threat and therapy. Asian Pac J Cancer Prev 2014; 15 (3): 1085-91.
8. Gialeli C, Theocharis AD, Karamanos NK. Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS Journal 2011; 278: 16–27.
9. Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: Regulators of the tumor microenvironment. Cell 2010; 141: 52–67.
10. Radisky ES, Radisky DC. Matrix metalloproteinase induced epithelial-mesenchymal transition in breast cancer. Journal of Mammary Gland Biology and Neoplasia 2010; 15 (2): 201-12.
11. Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: Structure, Function and Biochemistry. Circulation Research 2003; 92: 827-39.
12. Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in development and disease. Nat. Rev. Mol. Cell Biol. 2014; 15: 786–801.
13. Krstic J, Santibanez JF. Transforming growth factor-beta and matrix metalloproteinases: Functional interactions in tumor stroma-infiltrating myeloid cells. The Scientific World Journal 2014; 10:115-29.
14. Abdelazim IA, Abu faza ML, Al kadi M. Immunoexpression of matrix metalloproteinase-2 (MMP-2) in epithelial ovarian cancers. Asian Pacific Journal of Reproduction 2013; 2(2); 136-41.
15. Zhao XI, Sun T, Che N, Sun D, Zhao N, Gu Q, et al. Promotion of hepatocellular carcinoma metastasis through matrix metalloproteinase activation by epithelial-mesenchymal transition regulator Twist1. J. Cell. Mol. Med. 2011; 15 (3): 691-700.
16. Xiang ZL, Zeng ZC, Fan J, Tang ZY, Zeng HY, Gao DM. Gene expression profiling of fixed tissues identified hypoxia-inducible factor-1alpha, VEGF, and matrix metalloproteinase-2 as biomarkers of lymph node metastasis in hepatocellular carcinoma. Clin Cancer Res 2011; 17(16): 5463-72.
17. Xiang ZL, Zeng ZC, Tang ZY, Fan J, Sun HC, Tan YS. Expression of cytokeratin 19 and matrix metalloproteinase 2 predicts lymph node metastasis in hepatocellular carcinoma. Mol Biol Rep 2011; 38: 3531-9.
18. Li Y, Zhang Q, Luo Z, Kang L, Qu J, Liu W, et al. Hepatitis C Virus activates Bcl-2 and MMP-2 expression through multiple cellular signaling pathways. J Virol 2012; 86: 12531-43.
19. Losikoff PT, Self AA, Gregory SH. Dendritic cells, regulatory T cells and the pathogenesis of chronic hepatitis C. Virulence 2012; 3: 610-20.
20. Smigielski J, Piskorz L, Talar-Wojnarowska R, Malecka-Panas E, Jablonski S, Brocki M . The estimation of metaloproteinases and their inhibitors blood levels in patients with pancreatic tumors. World J Surg Oncol 2013; 11: 137-44.
21. Wieland SF, Chisari FV. Stealth and Cunning: Hepatitis B and Hepatitis C Viruses. J Virol 2005; 79: 9369-80.
22. Kuyvenhoven JP, van Hoek B, Blom E, van Duijn W, Hanemaaijer R, Verheijen JH, et al. Assessment of the clinical significance of serum matrix metalloproteinases MMP-2 and MMP-9 in patients with various chronic liver diseases and hepatocellular carcinoma. Thromb Haemost. 2003; 89(4): 718-25.
23. Macías J, Mira J, Gilabert I, Neukam K, Roldán C, Viloria M, et al. Combined use of aspartate aminotransferase, platelet count and matrix metalloproteinase 2 measurements to predict liver fibrosis in HIV/hepatitis C virus-coinfected patients. HIV Med 2011; 12(1): 14-21.
24. Akca G, Tuncbilek S, SepiciDincel A. Association between matrix metalloproteinase (MMP)-2, MMP-9 and total antioxidant status of patients with asymptomatic hepatitis C virus infection. Letters in Applied Microbiology 2013; 57: 436-42.
25. El-Gindy I, El-Rahman AT, El-Alim MA, Zakj SS. Diagnostic potential of serum matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 as non invasive markers of hepatic fibrosis with HCV related chronic liver disease. Egypt J Immunol 2003; 10: 27-35.
26. Giannelli G, Bergamini C, Marinosci F, Fransvea E, Quaranta M, Lupo L, et al. Clinical role of MMP-2/TIMP-2 imbalance in hepatocellular carcinoma. Int J Cancer 2002; 97(4): 425-31.
27. Murawaki Y, Yamada S, Ikuta Y, Kawasaki H. Clinical usefulness of serum matrix metalloproteinase-2 concentration in patients with chronic viral liver disease. J Hepatol 1999; 30(6): 1090-8.
28. Boeker KH, Haberkorn CI, Michels D, Flemming P, Manns MP, Lichtinghagen R. Diagnostic potential of circulating TIMP-1 and MMP-2 as markers of liver fibrosis in patients with chronic hepa¬titis C. Clin Chim Acta 2002; 316: 71-81.
29. Sumer S, Demir NA, Kölgelier S, Inkaya AC, Arpaci A, Demir LS, et al. The clinical significance of serum apoptotic cytokeratin 18 neoepitope M30 (CK-18 M30) and matrix metalloproteinase 2 (MMP-2) levels in chronic hepatitis B atients with cirrhosis. Hepat Mon 2013; 13(6): 1-6.
30. Ishii Y, Nakasato Y, Kobayashi S, Yamazaki Y, Aoki T. A study on angiogenesis-related matrix metalloproteinase networks in primary hepatocellular carcinoma. J. Exp. Clin. Cancer Res 2003; 22: 461-71.
31. Ljumovic D, Diamantis I, Alegakis AK, Kouroumalis EA. Differential expression of matrix metalloproteinases in viral and non-viral chronic liver diseases. Clin. Chim. Acta 2004; 349: 203-11.
32. Prystupa A, Boguszewska-Czubara A, Bojarska-Junak A, Toruń-Jurkowska A, Roliński J, Załuska W. Activity of MMP-2, MMP-8 and MMP-9 in serum as a marker of progression of alcoholic liver disease in people from Lublin Region, eastern Poland. Annals of Agricultural and Environmental Medicine 2015; 22: 325-8.
33. Noh S, Jung M, Kim TS, Park CH, Lim SJ, Chung HC, et al. MMP-2 as a putative biomarker for carcinomatosis in gastric cancer. Hepato-Gastroenterology 2011; 58: 2015-9.
34. Noh S, Jung M, Lee HY, Wang B, Cho J, Kim TS, et al. Body fluid MMP-2 as a putative biomarker in metastatic breast cancer. Oncology Letters 2012; 3: 699-703.
35. Manenti L, Paganoni P, Floriani I, Torri W, Buda A, Taraboletti G, et al. Expression level of vascular endothelial growth factor, matrix metalloproteinase 2 & 9 and tissue inhibitor of metalloproteinases 1 & 2 in plasma of patients with ovarian carcinoma. Eur. J. Cancer 2003; 39: 1948-56.
36. Giavazzi R, Garofalo A, Ferri C, Lucchini V, Bone E A, Chiari S, et al. A synthetic inhibitor of matrix metalloproteinases, potentiates the antitumor activity of cisplatin in ovarian carcinoma xenografts. Clin. Cancer Res 1998; 4: 985-92.
37. Belotti D, Paganoni P, Manenti L, Garofalo A, Marchini S, Taraboletti G, et al. Matrix metalloproteinases (MMP9 and MMP2) induce the release of vascular endothelial growth factor (VEGF) by ovarian carcinoma cells: Implications for ascites formation. Cancer Research 2003; 63: 5224-9