Roles and Molecular Mechanisms of Biomarkers in Hepatocellular Carcinoma with Microvascular Invasion: A Review

Abstract

Hepatocellular carcinoma (HCC) being a leading cause of cancer-related death, has high associated mortality and recurrence rates. It has been of great necessity and urgency to find effective HCC diagnosis and treatment measures. Studies have shown that microvascular invasion (MVI) is an independent risk factor for poor prognosis after hepatectomy. The abnormal expression of biomacromolecules such as circ-RNAs, lncRNAs, STIP1, and PD-L1 in HCC patients is strongly correlated with MVI. Deregulation of several markers mentioned in this review affects the proliferation, invasion, metastasis, EMT, and anti-apoptotic processes of HCC cells through multiple complex mechanisms. Therefore, these biomarkers may have an important clinical role and serve as promising interventional targets for HCC. In this review, we provide a comprehensive overview on the functions and regulatory mechanisms of MVI-related biomarkers in HCC.

Keywords: Biomarkers; Hepatocellular carcinoma; Microvascular invasion; Molecular mechanism; Progress.

Fig. 1. Effect of biomarkers associated with MVI of HCC and their mechanisms.

Aberrantly expressed biomarkers in HCC with MVI can be involved in the process of cell proliferation and apoptosis, invasion and metastasis, angiogenesis, EMT, immune escape. BOP1, block of proliferation 1; EMT, epithelial-mesenchymal transition; FN1, fibronectin 1; FGF5, fibroblast growth factor 5; HCC, hepatocellular carcinoma; LncRNA MVIH, lncRNA associated with microvascular invasion; MAGL, monoacylglycerol lipase; MTDH, metadherin; MVI, microvascular invasion; PD-L1, programmed cell death-ligand 1; PIVKA-II, prothrombin induced by vitamin K absence II; STIP1, stress-induced phosphoprotein 1; STMN1, stathmin 1; USP7, ubiquitin-specific protease 7.

Fig. 2. Biological role of the biomarkers in the development of EMT.

E-cadherin is an epithelial marker, and N-cadherin, vimentin, Snail, nuclear β-catenin and MMP-9 are mesenchymal markers in EMT-related proteins. In the pathological process of HCC with MVI, several markers can induce EMT by increasing the expression of mesenchymal markers and reducing the expression of epithelial markers, thereby promoting the migration, invasion, and metastasis of HCC cells. BOP1, block of proliferation 1; DDR1, discoidin domain receptor 1; EMT, epithelial-mesenchymal transition; HCC, hepatocellular carcinoma; MAGL, monoacylglycerol lipase; MTDH, metadherin; MVI, microvascular invasion; PIVKA-II, prothrombin induced by vitamin K absence II; STIP1, stress-induced phosphoprotein 1; STMN1, stathmin 1.