GOLM1-induced Vascular Permeability and Angiogenesis in Hepatocellular Carcinoma through Modulation of Cancer...

Enhanced angiogenesis and impaired vascular integrity facilitate cancer metastasis. There is accumulating evidence that cancer-derived exosomes take a functional role in these processes. In our previous study, we revealed that Golgi Membrane protein 1 (GOLM1) can promote metastasis of Hepatocellular Carcinoma (HCC), and miRNAs can modulate angiogenesis and vascular permeability in HCC. The objective is to reveal that GOLM1 can promote HCC progression in an exosomal miRNA-dependent way.

Comprehensive bioinformatics analysis and experiments were conducted to associate GOLM1 expression with angiogenesis in HCC. The effect of hepatoma cell-derived exosomes on Human Umbilical Vein Endothelial Cells (HUVEC) was tested. Exosomal miRNA expression was profiled and validated in GOLM1-knockdown HCC cells. Targets of miR-4449 and miR-3651 were predicted with online tools and validated in vitro. Correlation between miR-4449/miR-3651 and microvascular invasion or recurrence in HCC was assessed.

GOLM1 correlated with angiogenesis in HCC. HCC cell-derived exosomes can be transferred to endothelial cells, and GOLM1 can regulate exosome-induced angiogenesis and vascular permeability. In vitro experiments showed that GOLM1 knockdown reduced exosomal abundance of miR-4449 and miR-3651, which target KEAP1 and ZO-1, respectively. Elevated miR-4449 and miR-3651 expression were correlated with microvascular invasion and recurrence in HCC patients.

We demonstrated that GOLM1 can promote HCC progression independent of its role in modulating EGFR/RTK cell-surface recycling, indicating that patients with high GOLM1 expression may benefit more from anti-angiogenic drugs and highlighting the potential of targeting miR-4449 and miR-3651 to prevent angiogenesis and vascular leakiness in HCC. However, in vivo studies are further needed to validate the effect of miR-4449 and miR-3651 inhibitors in compromising angiogenesis and vascular permeability. Besides, a larger validation cohort is indispensable for establishing the correlation between miR-4449/miR-3651 expression and microvascular invasion and tumor recurrence in HCC.

Our findings suggest that, under the control of GOLM1, HCC cell-derived exosomal miR-4449 and miR-3651 increase angiogenesis and vascular permeability by targeting KEAP1 and ZO-1, highlighting the potential of exosomal miRNAs as promising therapeutic targets for HCC.