Cytosolic TMEM88 Promotes Invasion and Metastasis in Lung Cancer Cells by Binding DVLS

Abstract

Transmembrane protein 88 (TMEM88) is a transmembrane protein that plays a crucial role in regulating human stem cell differentiation and embryonic development. However, its expression and clinicopathologic significance in human neoplasms is unclear. In this study, the expression and subcellular localizations of TMEM88 were assessed in 214 cases of non-small cell lung cancer (NSCLC). Notably, TMEM88 was highly expressed in the cytosol of $60% NSCLC specimens examined. Higher expression of cytosolic TMEM88 in NSCLC correlated significantly with poor differentiation, high TNM stage, lymph node metastasis, and inferior survival. In NSCLC cells displaying membrane-localized TMEM88, we observed an inhibition of canonical Wnt signaling due to interactions of TMEM88 with the Wnt pathway factor Dishevelled (DVLS). In contrast, NSCLC cells with cytosol-localized TMEM88 lacked effects on Wnt signaling. Cytosolic interactions of TMEM88 and DVLS increased the expression of phosphorylated, active forms of p38, GSK3b (Thr390), and Snail, thereby reducing the expression of the tight junction-associated proteins ZO-1 and occludin, effects associated with enhanced invasive and metastatic cell characters. Importantly, attenuating the expression of cytosolic TMEM88 reduced metastatic prowess in xenograft models. Overall, our findings show how mislocalization of TMEM88 to the cytosol in NSCLC cells ablates its Wnt pathway regulatory properties, thereby promoting invasion and metastasis by activating the p38-GSK3b-Snail signaling pathway. Cancer Res; 75(21); 4527-37. Ó2015 AACR.

Transmembrane protein 88 (TMEM88) promoter hypomethylation is associated with platinum resistance in ovarian cancer

“…While the mechanism linking TMEM88 and platinum resistance remains incompletely elucidated here, one potential link is TMEM88 mediated inhibition of Wnt signaling. Our data demonstrating inhibition of Wnt target genes by TMEM88 knock down in OC cells and inverse correlations between TMEM88 and c-Myc or β-catenin in the ovarian TCGA database are consistent with recent reports identifying TMEM88 as an inhibitor of Wnt pathway in lung and breast cancer cells [36, 37]. The C-terminal VWV (Val-Trp-Val) sequence of TMEM88 directly interacts with the PDZ domain of Dishevelled-1 (Dvl-1) in Xenopus embryos leading to inhibition of the canonical Wnt/β-catenin signaling [28].…”

Lasp2 enhances tumor invasion via facilitating phosphorylation of FAK and predicts poor overall survival of non‐small cell lung cancer patients

“…Moreover, our data revealed that Lasp2 promoted tumor invasion through upregulating Snail and downregulating Zo‐1. Either Snail or Zo‐1 was previously confirmed as EMT facilitator which was regulated by several signaling pathways including MAPK, PI3K‐AKT, and FAK, etc . In the present study, we found that overexpressing Lasp2 increased the phosphorylation of FAK in Tyr397 and Tyr925 but not AKT, ERK, and P38.…”

TIMM50 promotes tumor progression via ERK signaling and predicts poor prognosis of non‐small cell lung cancer patients

“…Our studies suggested that TIMM50 also promoted tumor proliferation and invasion in NSCLC cells via upregulating Cyclin D1 and Snail and downregulating E‐cadherin. During tumor progression, multiple signaling pathways, such as ERK, AKT, P38, and FAK, were involved in modulating the expression of Cyclin D1, Snail, and E‐cadherin . Using Western blotting analysis, we found that overexpression of TIMM50 was capable of upregulating the levels of phosphorylated ERK and P90RSK.…”