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Kir2.1 Interaction with Stk38 Promotes Invasion and Metastasis of Human Gastric Cancer by Enhancing MEKK2-MEK1/2-ERK1/2 Signaling

Cancer research (Chicago, Ill.), 2018-06, Vol.78 (11), p.3041-3053 [Peer Reviewed Journal]

2018 American Association for Cancer Research. ;Copyright American Association for Cancer Research, Inc. Jun 1, 2018 ;ISSN: 0008-5472 ;EISSN: 1538-7445 ;DOI: 10.1158/0008-5472.CAN-17-3776 ;PMID: 29549164

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Title:
Kir2.1 Interaction with Stk38 Promotes Invasion and Metastasis of Human Gastric Cancer by Enhancing MEKK2-MEK1/2-ERK1/2 Signaling
Author: Ji, Cheng-Dong ; Wang, Yan-Xia ; Xiang, Dong-Fang ; Liu, Qiang ; Zhou, Zhi-Hua ; Qian, Feng ; Yang, Lang ; Ren, Yong ; Cui, Wei ; Xu, Sen-Lin ; Zhao, Xi-Long ; Zhang, Xia ; Wang, Yan ; Zhang, Peng ; Wang, Ji-Ming ; Cui, You-Hong ; Bian, Xiu-Wu
Subjects: Animals ; Cell Line, Tumor ; Epithelial-Mesenchymal Transition - genetics ; Extracellular signal-regulated kinase ; Gastric cancer ; Humans ; Invasiveness ; Kinases ; Malignancy ; MAP kinase ; MAP Kinase Kinase 1 - genetics ; MAP Kinase Kinase 2 - genetics ; MAP Kinase Kinase Kinase 2 ; MAP Kinase Kinase Kinases - genetics ; MAP Kinase Signaling System - genetics ; Mesenchyme ; Metastases ; Metastasis ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Potassium ; Potassium channels ; Potassium channels (inwardly-rectifying) ; Potassium Channels, Inwardly Rectifying - genetics ; Prognosis ; Protein kinase ; Protein-Serine-Threonine Kinases - genetics ; Proteins ; Regression analysis ; Signal transduction ; Signal Transduction - genetics ; Stomach cancer ; Stomach Neoplasms - genetics ; Stomach Neoplasms - pathology ; Therapeutic applications ; Threonine ; Tumors ; Ubiquitin ; Ubiquitin-protein ligase ; Ubiquitin-Protein Ligases - genetics ; Ubiquitination ; Ubiquitination - genetics
Is Part Of: Cancer research (Chicago, Ill.), 2018-06, Vol.78 (11), p.3041-3053
Description: Potassium ion channels are emerging as promalignant factors involved in cancer progression. In this study, we found that invading human gastric cancer cells express high levels 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 gastric cancer cells. The promalignant nature of Kir2.1 in gastric cancer 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 gastric cancer cells. In human gastric cancer 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 patients with gastric cancer. Our results suggest that Kir2.1 is an important regulator of gastric cancer malignancy and acts as a novel prognostic marker and a therapeutic target for gastric cancer. Kir2.1 contributes to invasion and metastasis by a noncanonical ion permeation-independent signaling pathway and may act as a novel prognostic marker and therapeutic target for gastric cancer. .
Publisher: United States: American Association for Cancer Research, Inc
Language: English
Identifier: ISSN: 0008-5472
EISSN: 1538-7445
DOI: 10.1158/0008-5472.CAN-17-3776
PMID: 29549164
Source: MEDLINE
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Kir2.1 Interaction with Stk38 Promotes Invasion and Metastasis of Human Gastric Cancer by Enhancing MEKK2-MEK1/2-ERK1/2 Signaling

2018 American Association for Cancer Research. ;Copyright American Association for Cancer Research, Inc. Jun 1, 2018 ;ISSN: 0008-5472 ;EISSN: 1538-7445 ;DOI: 10.1158/0008-5472.CAN-17-3776 ;PMID: 29549164

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