STOML2 Promotes Colorectal Cancer Progression by Promoting Lipid Raft Formation and NF-κB Activation

Abstract

Abstract Background As one member of lipid raft proteins, STOML2 is up-regulated in several tumor types and participates in the tumor progression. We investigated the biological function and the underlying mechanism of STOML2 in colorectal cancer (CRC).Methods We used Real-time PCR and immunohistochemical analysis to access the levels of STOML2 in 7 CRC cell lines and 119 human paraffin-embedded CRC samples. Immunohistochemical analysis was performed to measure the expression of Ki67, CD31 and VEGFC in 50 human CRC samples. We determined the ability of STOML2 to activate NF-κB signaling using luciferase reporter assay, Real-time PCR and western blotting. The effects of STOML2 overexpression and knockdown with its specific short hairpin RNAs in CRC cell lines were detected using colony formation and tube formation assays. We analyzed development of CRC xenograft tumors in nude mice.Results STOML2 expression levels were increased in CRC cell lines and samples from CRC patients, compared with normal controls, and were associated with disease stage and survival outcomes. Overexpression of STOML2 in HCT116 and SW480 cell lines promoted proliferation and angiogenesis via promoting lipid raft formation and activating the NF-κB pathway. STOML2-induced angiogenesis effects could be greatly reversed by bevacizumab, a therapeutic monoclonal antibody against target with VEGF. Moreover, STOML2-overexpressing CRC cells formed larger tumors featured with more neovascularization in nude mice as compared to vector-control CRC cells. We identified STOML2 as independent prognostic factor in CRC.Conclusions The lipid raft protein STOML2 is up-regulated in CRC cell lines and tissues from patients and promotes CRC cell proliferation and angiogenesis in vitro and in vivo. STOML2 promotes lipid raft formation and activates the NF-κB signaling pathway in CRC cells. Our findings suggest that STOML2 functions as an oncoprotein and a prognostic factor in CRC, which might use to identify whether CRC patients may benefit from bevacizumab therapy.