TM6SF1 suppresses the progression of lung adenocarcinoma and M2 macrophage polarization by inactivating the PI3K/AKT/mTOR pathway

Objectives: There is increasing evidence of TM6SF1 low expression in lung adenocarcinoma (LUAD), but the function and mechanisms of TM6SF1 remain unclear. Thence, we plan to explore the specific role of TM6SF1 in LUAD and associated mechanisms. Methods: qRT-PCR could detect TM6SF1 mRNA. Immunohistochemistry staining was used for detection of MMP-2, TM6SF1, Ki67, MMP-9, and CD163 proteins. E-cadherin, Vimentin, N-cadherin, p-PI3K, PI3K, p-AKT, AKT, mTOR, p-mTOR, and marker proteins of M2 macrophages (CD206, CD163, ARG1, and Fizz1) were evaluated using western blot. Via utilization of CCK-8, colony formation and transwell assays, cell viability, proliferation, migration and invasion were assessed, respectively. Furthermore, we injected A549 cells into mice’ right flank for establishing a mouse xenograft model. Results: Down-regulation of TM6SF1 expression was observed in LUAD cells and tissues and TM6SF1 expression was positively associated with survival percent of LUAD patients. TM6SF1 overexpression repressed cell viability, proliferation, invasion, migration, EMT, and polarization of M2 macrophages in LUAD cells, along with tumor growth in xenograft mice. In addition, TM6SF1 up-regulation resulted in decreasing p-PI3K, p-AKT, PI3K, AKT, mTOR, and p-mTOR levels. TM6SF1-caused suppression of proliferation, migration, invasion, EMT as well as M2 macrophage polarization was reversed through the PI3K activator in LUAD cells. Conclusions: TM6SF1 inactivated the PI3K/AKT/mTOR pathway for dimpairing LUAD malignancy and polarization of M2 macrophages.