The correlation and role analysis of COL4A1 and COL4A2 in hepatocarcinogenesis.

Yanli Liu,Jingqi Chen,Jiaye Zhang,Yan Chen,Hasan Sohel,Xinrong Ke,Yin-Xiong Li

doi:10.18632/aging.102610

Abstract

Liver fibrosis biomarker, Type IV collagen, may function as hepatocarcinogenesis niche. However, among the six isoforms, the isoforms providing tumor microenvironment and their regulatory network are still unclarified. Based on bioinformatics analysis of hundreds of HCC transcriptome datasets from public databases, we found that COL4A1/2 expressions were significantly correlated with hepatocarcinogenesis, progression, and prognosis. The expressions of COL4A1/2 were significantly upregulated in the preneoplastic and HCC tissues compared with normal tissues. Moreover, the overexpression of COL4A2 was highly correlated with shorter progression-free survival in HCC patients. Bioinformatics analysis also generates an interactive regulatory network in which COL4A1/2 directly binding to integrin alpha-2/beta-1 initiates a sequentially and complicated signaling transduction, to accelerate cell cycle and promote tumorigenesis. Among those pathways, the PI3K-Akt pathway is significantly enriched in cooperative mutations and correlation analysis. This suggests that the key activated signaling is PI3K-Akt pathway which severing as the centerline linked with other pathways (Wnt and MAPK signaling) and cell behaviors signaling (cell cycle control and cytoskeleton change). Switching extracellular matrix collagen isoform may establish pro-tumorigenic and metastatic niches. The findings of COL4A1/2 and related signaling networks are valuable to be further investigated that may provide druggable targets for HCC intervention.

Highlights

Hepatocellular carcinoma (HCC) is the most prevalent malignancy in the liver with a high incidence and mortality rate globally [1]
In the Mas Liver (GSE14323), COL4A1 was overexpressed in liver cirrhosis and HCC, while COL4A2 was higher expressed in liver cirrhosis and HCC versus normal tissues (Figure 1A and Supplementary Figure 1B)
The mRNA levels of both COL4A1 and COL4A2 were significantly increased in subgroups of HCC patients classified by ethnicity, gender, age, tumor grade, and disease stages compared to normal people (Figure 2A–2L)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most prevalent malignancy in the liver with a high incidence and mortality rate globally [1]. The understanding of the etiology and the molecular mechanisms of HCC leads to the development of drugs including sorafenib, regorafenib, nivolumab, and lenvatinib, which have been approved by the FDA in unresectable HCC treatment [7,8,9,10]. These drugs are not satisfying, due to the rapid drug resistance development and toxicities [9, 11,12,13]. There is an urgent need for further understanding of the pathological mechanism of HCC and developing combination therapies that target different signaling mechanisms to reduce the drug resistance of HCC treatment

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Conclusion