Leucine-rich repeats and immunoglobulin-like domains 3 suppresses hypoxia-induced vasculogenic mimicry in glioma by promoting the ubiquitination and degradation of Snail2

PURPOSE: Leucine-rich repeats and immunoglobulin-like domains 3 (LRIG3) functions as a tumor suppressor in glioma. Although our previous study demonstrated that LRIG3 inhibited angiogenesis via the PI3K/AKT/VEGFA pathway under normoxia, its impact on glioma vascularization under hypoxia remains elusive. Vasculogenic mimicry (VM), an alternative form of neovascularization, plays a pivotal role in glioma progression, particularly within hypoxic tumor microenvironments. This study aimed to investigate the effects of LRIG3 on hypoxia-induced VM in glioma and to elucidate the underlying molecular mechanisms. METHODS: The effects of LRIG3 on VM were evaluated in vitro using tube formation and 3D spheroid invasion assays. Histological analysis of intracranial xenografts and glioblastoma specimens was performed to assess LRIG3's impact on glioma vascularization in vivo. The underlying mechanisms were investigated using western blot, quantitative real-time PCR (qRT-PCR), and ubiquitination assays. RESULTS: LRIG3 expression was inversely correlated with VM density in the central hypoxic regions of both xenografts and glioblastoma specimens. Under hypoxia, LRIG3 overexpression inhibited the invasion and tube formation capacities of glioma cells, whereas its knockdown promoted these activities. Mechanistically, LRIG3 suppressed VM phenotypes by downregulating Snail2 at the post-translational level, rather than affecting VEGFA. LRIG3 promoted the ubiquitination of Snail2, leading to its proteasomal degradation and destabilization under hypoxia. CONCLUSIONS: LRIG3 inhibits hypoxia-induced VM in glioma by facilitating the proteasomal degradation of Snail2 via ubiquitination.