Exploration of Sorafenib Influences on Gene Expression of Hepatocellular Carcinoma.

Huancheng Wang,Jia Liu

doi:10.3389/fgene.2020.577000

Abstract

PurposeThe aim of this study was to develop a comprehensive differential gene profile for hepatocellular carcinoma (HCC) patients treated with sorafenib.MethodsThe RNA sequencing data and miRNA sequencing data of 114 HCC patients treated with sorafenib only and 326 HCC control patients treated without any chemotherapeutic drugs were studied using differential expression, functional enrichment, and protein–protein interaction analysis.ResultsCompared with HCC patients without any chemotherapy drugs, the sorafenib-treated patients develop 66 differentially expressed genes (DEGs), including 12 upregulated genes and 54 downregulated genes. Additionally, three differentially expressed miRNAs (DEMs) also show specific expression pattern. With further analysis, five primary genes including HTR2C, TRH, AGTR2, MCHR2, and SLC6A2 as well as three miRNAs (hsa-miR-4445, hsa-miR-466, and hsa-miR-2114) have been suggested as the potential targets for sorafenib. The specific gene expression of five genes has been validated in clinical HCC patients by ELISA method. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses indicate several significantly enriched biological processes (BPs), cellular components (CCs), and molecular functions (MFs).ConclusionSince sorafenib is becoming increasingly important in HCC treatment clinically, this study will help us understand the potential targets and eliminate diverse existing side effects of it as well as explore several potential clinical biomarkers with comprehensive analysis of differential gene expression profile.

Highlights

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver, comprising 75–85% of cases of liver cancer (El-Serag, 2011)
We compared the mRNA expression of HCC patients treated only with sorafenib and HCC patients without any chemotherapy drugs based on the expression levels of all mRNAs
Compared with HCC patients without any chemotherapeutic drugs, patients treated with sorafenib alone displayed three differentially expressed miRNAs (DEMs), including two upregulated miRNAs and one downregulated miRNAs (Figures 1C,D)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver, comprising 75–85% of cases of liver cancer (El-Serag, 2011). The hepatitis B virus (HBV) and hepatitis C virus (HCV) are critical causes of viral hepatitis that lead to the development of HCC (Colquhoun, 2016). Known as Nexavar, the most popularly used chemotherapeutic agent to treat HCC recently, is an oral multikinase inhibitor that efficiently inhibits tumor cell proliferation and angiogenesis and promotes tumor cell apoptosis (Feng et al, 2019; Bertacco et al, 2020). It was demonstrated to be a unique target drug for HCC (Hu et al, 2019) It functions as a small multi-tyrosine kinase inhibitor that blocks Raf kinase, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) (Nagai et al, 2019). Some HCC patients are reported to develop drug resistance to sorafenib (Raoul et al, 2019)

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