Serum Markers of Epithelial Mesenchymal Transition as Predictors of HCV-induced Liver Fibrosis, Cirrhosis and Hepatocellular Carcinoma

Mona M Zoheiry; Shaimaa Aa Hasan; Eman El-Ahwany; Faten M Nagy; Hoda Abu Taleb; Mona Nosseir; Mona Magdy; Safa Meshaal; Mohamed Darwish El-Talkawy; Inas Raafat

doi:10.19082/1626

Serum Markers of Epithelial Mesenchymal Transition as Predictors of HCV-induced Liver Fibrosis, Cirrhosis and Hepatocellular Carcinoma

Electron Physician. 2015 Dec 20;7(8):1626-37. doi: 10.19082/1626. eCollection 2015 Dec.

Authors

Affiliations

¹ Department of Immunology, Theodor Bilharz Research Institute, Faculty of Medicine, Cairo University, Giza, Egypt.
² Environmental Department, Theodor Bilharz Research Institute, Faculty of Medicine, Cairo University, Giza, Egypt.
³ Department of Pathology, Theodor Bilharz Research Institute, Faculty of Medicine, Cairo University, Giza, Egypt.
⁴ Department of Clinical Pathology, Faculty of Medicine, Cairo University, Giza, Egypt.
⁵ Department of Gastroenterology, Theodor Bilharz Research Institute, Faculty of Medicine, Cairo University, Giza, Egypt.

PMID: 26816590
PMCID: PMC4725417
DOI: 10.19082/1626

Abstract

Introduction: Hepatitis C virus (HCV) is a major cause of chronic liver disease in Egypt, leading to hepatic fibrosis, liver cirrhosis (LC), and hepatocellular carcinoma (HCC). Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM). Newly-recognized pathogenic mechanisms point to the epithelial-mesenchymal transition (EMT) of hepatocytes to matrix synthesizing (myo-) fibroblasts. Transforming growth factor-beta (TGF-β1), bone morphogenic protein (BMP)-7, and connective tissue growth factor (CTGF) are biomarkers reflecting the EMT process. YKL-40 is a glycoprotein member of ECM and plays a role in cancer cell proliferation. The purpose of this study was to determine the serum biomarkers of EMT and its impact on the fibrogenic process and tumorigenesis in HCV-genotype 4 patients.

Methods: In this case-control study that was conducted in 2013-2014, 97 HCV-infected patients were subjected to clinical examination, laboratory investigations, and liver biopsy. According to the histopathologic examination, they were classified to F0 (14 cases), F1 (17 cases), F2 (15 cases), F3 (18 cases), F4 (22 cases), and HCC (11 cases). Fifteen age- and gender-matched subjects were included as normal controls. Serum levels of TGF-β1, BMP-7, CTGF, YKL-40 were assessed, and the TGF-β1/BMP-7 ratios were calculated. The data were analyzed by plotting the receiver operating characteristic curve (ROC), Pearson product-moment correlation coefficient, and Spearman's rank correlation coefficient (Spearman's rho).

Results: Serum levels of TGF-β1, BMP-7, CTGF, and YKL-40 were significantly increased in all patient groups compared to controls (p < 0.001). LC exhibited the highest CTGF level and YKL-40 was highest in HCC. The TGF-β1/ BMP-7 ratios reflected the progression of EMT from CHC to LC, however, there was no significant difference between LC and HCC. TGF-β1/ BMP-7 ratio is considered to reflect positive correlation with CTGF in LC group (r = 0.629; p < 0.03) and YKL-40 in HCC group (r = 0.504; p < 0.04).

Conclusion: Increased TGF-β1/BMP-7 ratio and CTGF levels reflect the rate of EMT and provide information about fibrogenic activity. Also, this ratio, in association with YKL-40, can be used to predict malignant transformation in HCV-genotype 4 Egyptian patients.

Keywords: Bone Morphogenic Protein (BMP)-7; Connective Tissue Growth Factor (CTGF); Liver Fibrosis; Transforming Growth Factor-Beta (TGF-β); YKL-40.