Clinical Significance and Potential Mechanisms of ATP Binding Cassette Subfamily C Genes in Hepatocellular Carcinoma.

Xin Zhou,Xi-Wen Liao,Tian-Man Li,Chen-Lu Lan,Tao Peng,Zhong-Liu Wei,Guang-Zhi Zhu,Jun-Qi Liu,Jia-Mi Huang,Xin-Ping Ye

doi:10.3389/fgene.2022.805961

Abstract

The purpose of this investigation was to assess the diagnostic and prognostic significance of ATP binding cassette subfamily C (ABCC) genes in hepatocellular carcinoma (HCC). The Student t-test was used to compare the expression level of ABCCs between HCC and paraneoplastic tissues. Receiver operating characteristic curve (ROC) analysis was applied for diagnostic efficiency assessment. The Kaplan–Meier method and Cox proportional hazards model were respectively applied for survival analysis. Genes with prognostic significance were subsequently used to construct prognostic models. From the perspective of genome-wide enrichment analysis, the mechanisms of prognosis-related ABCC genes were attempted to be elaborated by gene set enrichment analysis (GSEA). It was observed in the TCGA database that ABCC1, ABCC4, ABCC5, and ABCC10 were significantly upregulated in tumor tissues, while ABCC6 and ABCC7 were downregulated in HCC tissues. Receiver operating characteristic analysis revealed that ABCC7 might be a potential diagnostic biomarker in HCC. ABCC1, ABCC4, ABCC5, and ABCC6 were significantly related to the prognosis of HCC in the TCGA database. The prognostic significance of ABCC1, ABCC4, ABCC5, and ABCC6 was also observed in the Guangxi cohort. In the Guangxi cohort, both polymerase chain reaction and IHC (immunohistochemical) assays demonstrated higher expression of ABCC1, ABCC4, and ABCC5 in HCC compared to liver tissues, while the opposite was true for ABCC6. GSEA analysis indicated that ABCC1 was associated with tumor differentiation, nod-like receptor signal pathway, and so forth. It also revealed that ABCC4 might play a role in HCC by regulating epithelial-mesenchymal transition, cytidine analog pathway, met pathway, and so forth. ABCC5 might be associated with the fatty acid metabolism and KRT19 in HCC. ABCC6 might impact the cell cycle in HCC by regulating E2F1 and myc. The relationship between ABCC genes and immune infiltration was explored, and ABCC1,4,5 were found to be positively associated with infiltration of multiple immune cells, while ABCC6 was found to be the opposite. In conclusion, ABCC1, ABCC4, ABCC5, and ABCC6 might be prognostic biomarkers in HCC. The prognostic models constructed with ABCC1, ABCC4, ABCC5, and ABCC6 had satisfactory efficacy.

Highlights

Hepatocellular carcinoma (HCC) generally followed cirrhosis given rise by metabolic disorder (Yang et al, 2019), chronic ethanol intake (Llovet et al, 2016), and hepatitis virus infection (Fujiwara et al, 2018)
Antibodies for ABCC1, ABCC4, FIGURE 1 | ABCC1, ABCC2, ABCC4, ABCC5, ABCC6, ABCC7, ABCC9, and ABCC10 were differently expressed between the HCC tissues and paraneoplastic tissues based on the RNA-seq data of the TCGA database: (A) ABCC1, (B) ABCC2, (C) ABCC4, (D) ABCC5, (E) ABCC6, (F) ABCC7, (G) ABCC9, and (H) ABCC10
They revealed that ABCC1, ABCC4, ABCC5, and ABCC10 were significantly upregulated in HCC tissues, while ABCC6 and ABCC7 were significantly downregulated in HCC tissues

Summary

Introduction

Hepatocellular carcinoma (HCC) generally followed cirrhosis given rise by metabolic disorder (Yang et al, 2019), chronic ethanol intake (Llovet et al, 2016), and hepatitis virus infection (Fujiwara et al, 2018). The leading metabolic risk factor for HCC is non-alcoholic fatty liver disease (NAFLD) (Zhang, 2018), which is mainly related to obesity and type 2 diabetes. It is acknowledged that hepatitis B virus (HBV) and hepatitis C virus (HCV) were the main infectious etiologies for cirrhosis and HCC. People in specific regions entailing relatively high exposure to Aflatoxin B1 were accompanied by high incidence and mortality of HCC (Long et al, 2008; Wogan et al, 2012; Zhang W et al, 2017). The multi-kinase inhibitor, is one of first-line drugs approved for the treatment of advanced HCC. It can improve survival, the long-term survival of HCC patients is limited due to the drug resistance. The discovery of new hub genes for developing HCC-targeted drugs and specific genes that improve and maintain drug susceptibility might be hopeful for advanced-stage HCC patients

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Results

Conclusion