SIRT4 is associated with microvascular infiltration, immune cell infiltration, and epithelial mesenchymal transition in hepatocellular carcinoma.

Abstract

Aims: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. In the present study, we evaluated SIRT4 expression levels in HCC specimens and investigated the relationships between SIRT4 expression levels, clinicopathological factors, and microvascular infiltration (MVI) in HCC.

Methods: The expression levels of SIRT4 in 108 HCC specimens were examined by immunohistochemical staining. MVI in HCC specimens was divided into three subtypes: M0, M1, and M2. Comprehensive bioinformatics analysis was carried out to demonstrate SIRT4's biological functions and expression-related prognostic value.

Results: The diffuse cytoplasmic expression pattern of SIRT4 was observed in all adjacent nonneoplastic liver tissues. The levels of SIRT4 were higher in HCC than in any other type of cancer and normal tissues. In addition, the expression levels of SIRT4 were significantly decreased in HCC tissues when MVI was M1 or M2 (P=0.003) but were not related to the overall clinical outcome. To explain MVI regulated by SIRT4, we also found that SIRT4 expression correlated with epithelial-mesenchymal transition (EMT) markers and CD4+ T/NK cells and downregulated cancer-associated fibroblast cells. Also, there was a significant relationship between MVI and degree of cell differentiation (P=0.003), tumor size (P<0.001), alpha fetoprotein (AFP) (P=0.001), alanine aminotransferase (ALT) (P=0.024), and γ-glutamyl transferase (γ-GT) (P=0.024). However, SIRT4 was not an independent prognostic marker of HCC.

Conclusions: Our results demonstrated an association between SIRT4 expression levels, MVI, immune cell infiltration, and potential biological functions, including EMT in the progression of HCC.