TMEM196 inhibits lung cancer metastasis by regulating the Wnt/β-catenin signaling pathway.

Abstract

The TMEM196 protein, which comprises four membrane-spanning domains, belongs to the TMEM protein family. TMEM196 was identified as a candidate tumor suppressor gene in lung cancer. However, its role and mechanism in lungcancer metastasis remain unclear. Here, we study the role of TMEM196 in tumor metastasis to further verify the function in lung cancer. In this study, we used qRT-PCR, western blot analysis and immunohistochemistry to examine the expression levels of TMEM196 and related proteins in lung cancer tissues and tumor cells. We utilized Transwell assays, xenograft nude mouse models, and TMEM196-/- mouse models to evaluate the effects of TMEM196 on tumor invasion and metastasis. Finally, we used bioinformatics analysis and dual-luciferase reporter gene assays to explore the molecular mechanism of TMEM196 as a tumor suppressor. We found that TMEM196 mRNA and protein expression levels were significantly decreased in lung cancer tissues and cells. Low expression of TMEM196 in clinical patients was associated with poor prognosis. TMEM196 strongly inhibited tumor metastasis and progression in vitro and in vivo. The primary lung tumors induced by tail vein-inoculated B16 cells in TMEM196-/- mice were significantly larger than those in TMEM196+/+ mice. Mechanistically, TMEM196 inhibited the Wnt signaling pathway and repressed β-catenin promoter transcription. TMEM196 silencing in lung cancer cells and mice resulted in significant upregulation of the expression of β-catenin and Wnt signaling pathway downstream target genes (MMP2 and MMP7). Decreasing β-catenin expression in TMEM196-silenced cancer cells attenuated the antimetastatic effect of TMEM196. Our results revealed that TMEM196 acts as a novel lung cancer metastasis suppressor via the Wnt/β-catenin signaling pathway.