Dataset Information

AXL Mediates Esophageal Adenocarcinoma Cell Invasion through Regulation of Extracellular Acidification and Lysosome Trafficking.

ABSTRACT: Esophageal adenocarcinoma (EAC) is a highly aggressive malignancy that is characterized by resistance to chemotherapy and a poor clinical outcome. The overexpression of the receptor tyrosine kinase AXL is frequently associated with unfavorable prognosis in EAC. Although it is well documented that AXL mediates cancer cell invasion as a downstream effector of epithelial-to-mesenchymal transition, the precise molecular mechanism underlying this process is not completely understood. Herein, we demonstrate for the first time that AXL mediates cell invasion through the regulation of lysosomes peripheral distribution and cathepsin B secretion in EAC cell lines. Furthermore, we show that AXL-dependent peripheral distribution of lysosomes and cell invasion are mediated by extracellular acidification, which is potentiated by AXL-induced secretion of lactate through AKT-NF-?B-dependent MCT-1 regulation. Our novel mechanistic findings support future clinical studies to evaluate the therapeutic potential of the AXL inhibitor R428 (BGB324) in highly invasive EAC.

SUBMITTER: Maacha S

PROVIDER: S-EPMC6126204 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

AXL Mediates Esophageal Adenocarcinoma Cell Invasion through Regulation of Extracellular Acidification and Lysosome Trafficking.

Maacha Selma S Hong Jun J von Lersner Ariana A Zijlstra Andries A Belkhiri Abbes A

Neoplasia (New York, N.Y.) 20180903 10

Esophageal adenocarcinoma (EAC) is a highly aggressive malignancy that is characterized by resistance to chemotherapy and a poor clinical outcome. The overexpression of the receptor tyrosine kinase AXL is frequently associated with unfavorable prognosis in EAC. Although it is well documented that AXL mediates cancer cell invasion as a downstream effector of epithelial-to-mesenchymal transition, the precise molecular mechanism underlying this process is not completely understood. Herein, we demon ...[more]

PMID: 30189359

Similar Datasets

Project description:Esophageal cancer is a lethal malignancy worldwide. Previously, low expression of metastasis suppressor Nm23H1 and tight junction (TJ) protein claudin-1 (CLDN1) have been known to correlate with poor prognosis in esophageal squamous cell carcinoma (ESCC). However, the molecular interaction between them has not been clarified. In the present study, we first examined the expression of Nm23H1 and CLDN1 in 74 surgical ESCC samples by immunohistochemistry (IHC) to verify their clinicopathologic significance. The biologic effects of Nm23H1 gene silencing or overexpression in ESCC cell lines were then studied by migration and invasion studies, and its regulation on CLDN1 expression was also investigated by western blot analysis. Moreover, the expression of Nm23H1 and CLDN1 at the same invasion front of ESCC tumors was verified by immunofluorescence. The results showed a significantly positive correlation between the expression of Nm23H1 and CLDN1 (?=0.296, P=0.011) in surgical specimens, especially for the 34 tumors with lymph-node metastasis (?=0.455, P=0.007). In ESCC cell lines, silencing of Nm23H1 expression markedly enhanced cell invasiveness, accompanied by increased Akt phosphorylation and decreased CLDN1 expression. Conversely, Nm23H1-expressed transfectants exhibited reduced invasiveness, decreased Akt phosphorylation and correspondingly increased CLDN1 expression. Regain of CLDN1 expression in ESCC cells significantly suppressed invasiveness, but did not influence the Akt phosphorylation. Moreover, treating Nm23H1-depleted cells with the AKT inhibitor MK2206 recovered CLDN1 expression, and diminished the invasiveness of ESCC cells. Finally, decreased expressions of both CLDN1 and E-cadherin were observed at the invasive front of the Nm23H1-negative tumors. Overall, our current study documented that reduced Nm23H1 expression activates the AKT signaling pathway, results in diminished CLDN1 expression and potentiates invasiveness of ESCC cells. Enhancement of Nm23H1 expression, inhibition of the AKT signaling pathway, or combined, might be a potential treatment strategy in selective ESCC patients.

Dataset Information

AXL Mediates Esophageal Adenocarcinoma Cell Invasion through Regulation of Extracellular Acidification and Lysosome Trafficking.

Publications

AXL Mediates Esophageal Adenocarcinoma Cell Invasion through Regulation of Extracellular Acidification and Lysosome Trafficking.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets