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GABARAPL1 Inhibits EMT Signaling through SMAD-Tageted Negative Feedback.

ABSTRACT: The pathway of selective autophagy, leading to a targeted elimination of specific intracellular components, is mediated by the ATG8 proteins, and has been previously suggested to be involved in the regulation of the Epithelial-mesenchymal transition (EMT) during cancer's etiology. However, the molecular factors and steps of selective autophagy occurring during EMT remain unclear. We therefore analyzed a cohort of lung adenocarcinoma tumors using transcriptome analysis and immunohistochemistry, and found that the expression of ATG8 genes is correlated with that of EMT-related genes, and that GABARAPL1 protein levels are increased in EMT+ tumors compared to EMT- ones. Similarly, the induction of EMT in the A549 lung adenocarcinoma cell line using TGF-β/TNF-α led to a high increase in GABARAPL1 expression mediated by the EMT-related transcription factors of the SMAD family, whereas the other ATG8 genes were less modified. To determine the role of GABARAPL1 during EMT, we used the CRISPR/Cas9 technology in A549 and ACHN kidney adenocarcinoma cell lines to deplete GABARAPL1. We then observed that GABARAPL1 knockout induced EMT linked to a defect of GABARAPL1-mediated degradation of the SMAD proteins. These findings suggest that, during EMT, GABARAPL1 might intervene in an EMT-regulatory loop. Indeed, induction of EMT led to an increase in GABARAPL1 levels through the activation of the SMAD signaling pathway, and then GABARAPL1 induced the autophagy-selective degradation of SMAD proteins, leading to EMT inhibition.

SUBMITTER: Jacquet M

PROVIDER: S-EPMC8533302 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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GABARAPL1 Inhibits EMT Signaling through SMAD-Tageted Negative Feedback.

Jacquet Marine M Hervouet Eric E Baudu Timothée T Herfs Michaël M Parratte Chloé C Feugeas Jean-Paul JP Perez Valérie V Reynders Célia C Ancion Marie M Vigneron Marc M Baguet Aurélie A Guittaut Michaël M Fraichard Annick A Despouy Gilles G

Biology 20210924 10

The pathway of selective autophagy, leading to a targeted elimination of specific intracellular components, is mediated by the ATG8 proteins, and has been previously suggested to be involved in the regulation of the Epithelial-mesenchymal transition (EMT) during cancer's etiology. However, the molecular factors and steps of selective autophagy occurring during EMT remain unclear. We therefore analyzed a cohort of lung adenocarcinoma tumors using transcriptome analysis and immunohistochemistry, a ...[more]

PMID: 34681055

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Project description:BackgroundScavenger receptor class A member 3 (SCARA3) is decreased in prostate cancer and myeloma. However, functions of SCARA3 in various cancers remain unclear. In this study, we tried to evaluate the functional study of SCARA3 in lung cancer.MethodsThe expression level of SCARA3 in the TCGA-database, lung cancer tissue microarray and lung cancer cells and the prognosis of lung cancer patients were measured. Lung cancer tissue microarray was analyzed pathologically using immunohistochemistry, and quantitative analysis of SCARA3 in normal lung cells and lung cancer cells was analyzed using western blot analysis. Survival curves for lung cancer patients were prepared with the Kaplan-Meier method. Migration and invasion of SCARA3 overexpressed lung cancer cells were determined using a Transwell chamber system. Proliferation of lung cancer cells was determined based on cell viability assay using cell culture in vitro and a tumorigenicity model of BALB/C nude mouse in vivo.ResultsThe expression of SCARA3 was abnormally reduced in TCGA-database, lung tissue microarray, and various lung cancer cells. However, overexpression of SCARA3 reduced the proliferation of lung cancer. The ability of SCARA3 to inhibit cancer cell proliferation was maintained even in vivo using a mouse xenograft model. In addition, overexpression of SCARA3 reduced migration and invasion ability of lung cancer cells and induced decreases of EMT markers such as β-catenin, vimentin, and MMP9. We aimed to prove the role of SCARA3 in the treatment of Lung cancer, and shown that the expression level of SCARA3 is important in cancer treatment using cisplatin. The enhancement of the effect of cisplatin according to SCARA3 overexpression is via the AKT and JNK pathways.ConclusionsThis study confirmed an abnormal decrease in SCARA3 in lung cancer. Overexpression of SCARA3 potently inhibited tumors in lung cancer and induced apoptosis by increasing sensitivity of lung cancer to cisplatin. These results suggest that SCARA3 is a major biomarker of lung cancer and that the induction of SCARA3 overexpression can indicate an effective treatment.

Dataset Information

GABARAPL1 Inhibits EMT Signaling through SMAD-Tageted Negative Feedback.

Publications

GABARAPL1 Inhibits EMT Signaling through SMAD-Tageted Negative Feedback.

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