Identification and Validation of TYMS as a Potential Biomarker for Risk of Metastasis Development in Hepatocellular Carcinoma.

Shuai Li,Deshi Dong,Jingyuan Zhao,Linlin Lv

doi:10.3389/fonc.2021.762821

Abstract

Metastasis is the major cause of hepatocellular carcinoma (HCC) mortality. Unfortunately, there are few reports on effective biomarkers for HCC metastasis. This study aimed to discover potential key genes of HCC, which could provide new insights for HCC metastasis. GEO (Gene Expression Omnibus) microarray and TCGA (The Cancer Genome Atlas) datasets were integrated to screen for candidate genes involved in HCC metastasis. Differentially expressed genes (DEGs) were screened, and then we performed enrichment analysis of Gene Ontology (GO), together with Kyoto Encyclopedia of Genes and Genomes (KEGG). A protein-protein interaction network was then built and analyzed utilizing STRING and Cytoscape, followed by the identification of 10 hub genes by cytoHubba. Four genes were associated with survival, their prognostic value was verified by prognostic signature analysis. Thymidylate synthase (TYMS) gene was identified as significant HCC metastasis-associated genes after mRNA expression validation and IHC analysis. TYMS silencing in HCC cells remarkedly inhibited growth and invasion. Finally, we found TYMS silencing dramatically decrease DNA synthesis and extracellular matrix (ECM) degradation, resulting in the inhibition of HCC metastasis, indicating TYMS had close associations with HCC development. These findings provided new insights into HCC metastasis and identified candidate gene prognosis signatures for HCC metastasis.

Highlights

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related deaths in the world [1]
With Gene Ontology (GO) function analysis, we discovered that the Differentially expressed genes (DEGs) are mostly enriched in the biological process of regulation of aging, regulation of phosphatidylinositol 3−kinase signaling (Figure 2A)
The results demonstrated four genes CCNA2 (Cyclin-A2), MSH2 (MutS homolog 2), TOP2A (Topoisomerase 2-alpha) and Thymidylate synthase (TYMS) were significantly positively correlated to patient outcomes, IGF2 was negatively correlated to patient outcomes (Figure 3C)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related deaths in the world [1]. The 5-year overall survival remains relatively poor, because of the difficulty associated with the early diagnosis and metastasis [2]. Metastasis is responsible for as much as 90% of most cancer-related deaths [3]. The multistep process of invasion and metastasis has been schematized as a sequence of discrete steps, often termed the invasion-metastasis cascade [4]. The acquisitions of extensive invasion potencies by cancer cells are key components in the metastatic cascade.

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