LRRC1 Promotes Angiogenesis Through Regulating AKT/GSK3β/β-Catenin/VEGFA Signaling Pathway in Hepatocellular Carcinoma

Tumor angiogenesis plays a crucial role in the progression of hepatocellular carcinoma (HCC), serving as a key process for metastasis and invasion. Leucine-rich repeat-containing 1 (LRRC1) has been reported to be abnormally upregulated in HCC. Nevertheless, the specific mechanism through which LRRC1 affects HCC is poorly understood. In our study, analysis of public datasets reveals a positive correlation between LRRC1 and VEGFA, which drives us to hypothesize the linkage between LRRC1 and tumor angiogenesis. Herein, we aimed to explore the role of LRRC1 in HCC angiogenesis and the involved mechanisms. In vitro, LRRC1 overexpression significantly increased the mRNA, protein, and secretory levels of VEGFA and promoted tumor-induced migration, invasion, and tube formation of HUVECs. Conversely, these effects were suppressed by the knockdown of LRRC1. In vivo, LRRC1 promoted the formation of new blood vessels in the chick embryo chorioallantois membrane, together with tumor growth and angiogenesis in xenograft mice. Further mechanism studies showed that LRRC1 enhances PDK1 stability by promoting its deubiquitination via USP7, thereby increasing AKT1 phosphorylation levels and activating the AKT/GSK3β/β-catenin/VEGFA signaling pathway, ultimately accelerating tumor angiogenesis in HCC. These findings demonstrated a novel role of LRRC1 in tumor angiogenesis, opening up new avenues for future research and treatment development.