Kir2.1 interaction with Stk38 promotes invasion and metastasis of human gastric cancer by enhancing MEKK2-MEK1/2-ERK1/2 signaling

Potassium ion channels are emerging as pro-malignant factors involved in cancer progression. In this study, we found that invading human gastric cancer (GC) cells express high level of inwardly rectifying potassium channel 2.1 (Kir2.1). Silencing Kir2.1 markedly reduced the invasive and metastatic capabilities as well as the epithelial-mesenchymal transition (EMT) of GC cells. The pro-malignant nature of Kir2.1 in GC cells was independent of potassium permeation but relied on its interaction with serine/threonine-protein kinase 38 (Stk38) to inhibit ubiquitination and degradation of mitogen-activated protein kinase kinase kinase 2 (MEKK2). Degradation of MEKK2 was mediated by small mothers against decapentaplegic-specific E3 ubiquitin protein ligase 1 (Smurf1), which resulted in activation of the MEK1/2-ERK1/2-Snail pathway in GC cells. In human GC tissues, expression was high and positively correlated with invasion depth and metastatic status of the tumors as well as poor overall patient survival. Cox regression analysis identified Kir2.1 as an independent prognostic indicator for GC patients. Our results suggest that Kir2.1 is an important regulator of GC malignancy and acts as a novel prognostic marker and a therapeutic target for GC.

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