F13B regulates angiogenesis and tumor progression in hepatocellular carcinoma via the HIF-1α/VEGF pathway

Abstract

Hepatocellular carcinoma (HCC) is a highly aggressive malignant tumor with a poor prognosis. This research aimed to investigate the role of F13B in HCC and its underlying mechanisms. Through comprehensive bioinformatics analysis of the GSE120123 and The Cancer Genome Atlas (TCGA)-Liver hepatocellular carcinoma (LIHC) datasets, we identified 220 overlapping prognosis-related genes. Eight key genes, including the previously unreported CCDC170 and F13B in HCC, were identified through Least Absolute Shrinkage and Selection Operator (LASSO)-Cox regression analysis. F13B emerged as a significant prognostic factor in HCC, warranting further investigation in subsequent analyses. In vitro experiments showed that F13B expression was notably reduced in HCC cell lines and tissues, particularly in Huh-7 and SMMC-7721 cells. Overexpression of F13B inhibited cell invasion, migration, and proliferation, while its knockdown produced the opposite effect. A lactate dehydrogenase (LDH) activity assay in human umbilical vein endothelial cells (HUVECs) demonstrated that F13B overexpression reduced vascular endothelial growth factor (VEGF)-induced cytotoxicity, whereas knockdown increased it. Further analysis revealed that F13B negatively regulates VEGFA expression, affecting HUVEC proliferation. In HUVECs, F13B overexpression reversed VEGF-induced upregulation of key angiogenesis markers, including phospho-VEGF receptor 2 (p-VEGFR2), matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), as well as AKT/mTOR signaling proteins, phospho-Akt (p-AKT), and phospho-mTOR (p-mTOR). Additionally, F13B negatively regulated VEGFA and hypoxia-inducible factor 1 A (HIF1A) under hypoxic conditions, counteracting the hypoxia-induced increase in cell viability. These findings suggest that F13B regulates angiogenesis through the HIF-1α/VEGF pathway and plays a crucial role in HCC progression. Our results highlight the potential of F13B as a therapeutic target in HCC, providing novel insights into the molecular mechanisms of HCC and its prognostic significance.