Dysregulated epidermal growth factor and tumor growth factor-beta receptor signaling through GFAP-ACTA2 protein interaction in liver fibrosis.

Sobia Hassan,Summayya Shawana,Hussain Shah,Zil-E- Zil-E-Rubab

doi:10.12669/pjms.36.4.1845

Abstract

Objective:Viral hepatitis is associated with high morbidity and mortality. Identification of biological pathways involved in hepatic fibrosis resulting from chronic hepatitis C are essential for better management of patients. Constructing the HCV-human protein interaction network through bioinformatics may enable us to discover diagnostic biological pathways. We investigated to identify dysregulated pathways and gene enrichment based on actin alpha 2 (ACTA2) and glial fibrillar acidic protein (GFAP) interaction network analysis in hepatic fibrosis.Methods:This is an in-silico study conducted at Ziauddin University from March,2019 to September 2019. Enrichment and protein–protein interaction (PPI) network analysis of the identified proteins: GFAP and ACTA2 along with their mapped gene data sets was performed using FunRich version 3.1.3.Results:Biological pathway grouping showed enrichment of proteins (85.7%) in signalling pathway by epidermal growth factor receptor (EGFR) and Tumor growth factor (TGF)-beta Receptor followed by signaling by PDGF, FGFR and NGF (71.4%) (p < 0.001). SRC, PRKACA, PRKCA and PRKCD were enriched in both EGFR and TGF-beta Signalling pathways.Conclusion:EGFR and TGF-beta signalling pathways were enriched in liver fibrosis. SRC, PRKACA, PRKCA and PRKCD were enriched and differentially expressed in both EGFR and TGF-beta signalling pathways

Highlights

Hepatic fibrosis is the basic damage resulting from chronic hepatitis C (CHC) which is one of the prime health challenges.[1]
Our study done in 2014 revealed strong association of glial fibrillar acidic protein (GFAP) with the gold standard immunohistochemical marker, actin alpha 2 (ACTA2) suggesting that GFAP could be a useful indicator of early hepatic stellate cells (HSCs) activation in CHC patients.[10]
The results of our study show that biologic pathways associated with GFAP and ACTA2 were signaled by Tumor growth factor (TGF) β receptor signaling which is consistent with the previous studies

Summary

Introduction

Hepatic fibrosis is the basic damage resulting from chronic hepatitis C (CHC) which is one of the prime health challenges.[1]. Pak J Med Sci May - June 2020 Vol 36 No 4 www.pjms.org.pk 782 and grades of CHC.[5] The expression of contractile filaments, Alpha smooth muscle actin (α SMA), was identified in stellate cells forming a basis of using smooth muscle actin as an immunohistochemical marker, which detects HSCs activation and a useful marker for early diagnosis of hepatic fibrosis.[6] In addition to ACTA2, studies have shown that there is augmented expression of Glial Fibrillary Acidic -GFAP-positive HSCs in early stages of hepatic fibrosis.[7] The GFAP gene encodes a class III intermediate filament protein expressed in astrocytes of the central nervous system and their transformation capacity is well conserved.[8] A study in rodents reported the expression of GFAP with an increased expression in the acute response to injury in the rat, and a decreased in the chronic one.[9] It is reported that GFAP could represent a more useful marker than Alpha smooth muscle actin (α-SMA) of early HSCs activation and may be an early indicator of hepatic fibrogenesis. The GFAP positive hepatic cells may be antecedents of the HSCs detected by ACTA2 or they may denote a diverse subpopulation.[11,12]

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Conclusion