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GATA6 promotes epithelial-mesenchymal transition and metastasis through MUC1/?-catenin pathway in cholangiocarcinoma.

ABSTRACT: GATA6 acts as an oncogene or tumour suppressor in different cancers. Previously, we found that aberrant expression of GATA6 promoted metastasis in cholangiocarcinoma (CCA). However, the mechanism by which GATA6 promotes metastasis in CCA is unclear. In the present study, we aimed to investigate the role of GATA6 in CCA cell epithelial-mesenchymal transition (EMT). Our results showed that GATA6 expression was positively associated with N-cadherin and vimentin expression but negatively associated with E-cadherin expression in 91 CCA samples. GATA6 promoted EMT and metastasis in CCA cells in vitro and in vivo based on knockdown and overexpression analyses. ChIP-sequencing data revealed that MUC1 is a novel downstream target of GATA6. GATA6 upregulated MUC1 expression through binding to both the 1584 and 1456 GATA-motifs in the promoter region and enhancing its transcription by luciferase reporter assays and point-mutant assays. MUC1 expression was positively associated with N-cadherin and vimentin expression but negatively associated with E-cadherin expression in 91 CCA samples. In addition, MUC1 promoted EMT in CCA cells based on knockdown and overexpression analyses. Moreover, MUC1 knockdown significantly abrogated the GATA6-induced EMT in CCA cells, indicating that MUC1 promoted EMT through upregulating MUC1 in CCA cells. ?-Catenin is a putative transcriptional coactivator that regulates EMT in cancers. Our data showed that MUC1 expression was positively associated with nuclear ?-catenin expression in 91 CCA samples. MUC1 upregulated nuclear ?-catenin expression in CCA cells. Moreover, MUC1 bound to ?-catenin in CCA cells based on protein immunoprecipitation analyses. MUC1 knockdown significantly decreased the binding of MUC1 to ?-catenin, and thereby decreased nuclear ?-catenin protein levels in CCA cells, indicating that MUC1 bound to ?-catenin and increased its nuclear expression in CCA cells. Together, our results show that GATA6 promotes EMT through MUC1/?-catenin pathway in CCA, indicating potential implications for anti-metastatic therapy.

SUBMITTER: Deng X

PROVIDER: S-EPMC7567063 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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GATA6 promotes epithelial-mesenchymal transition and metastasis through MUC1/β-catenin pathway in cholangiocarcinoma.

Deng Xiang X Jiang Peng P Chen Jian J Li Jianwei J Li Dajiang D He Yu Y Jiang Yan Y Zhang Yujun Y Xu Shuangnian S Li Xi X Wang Shuguang S Tian Feng F

Cell death & disease 20201015 10

GATA6 acts as an oncogene or tumour suppressor in different cancers. Previously, we found that aberrant expression of GATA6 promoted metastasis in cholangiocarcinoma (CCA). However, the mechanism by which GATA6 promotes metastasis in CCA is unclear. In the present study, we aimed to investigate the role of GATA6 in CCA cell epithelial-mesenchymal transition (EMT). Our results showed that GATA6 expression was positively associated with N-cadherin and vimentin expression but negatively associated ...[more]

PMID: 33060563

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Project description:Osteosarcoma (OS) is a rare type of tumor and mostly occurs in children and adolescents. Approximately 10‑25% of patients with OS have lung metastases, and lung damage caused by lung metastasis is the main cause of mortality. Therefore, studying the growth and metastasis of OS is key in reducing OS mortality and improving prognosis. The expression of long non‑coding RNA (lncRNA) cancer susceptibility 15 (CASC15) in OS patients or OS cell lines were quantified by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The expression of vimentin, E‑cadherin, N‑cadherin, and cyclin D were detected by RT‑qPCR and western blotting. Mice were injected with OS cell lines via the tail vein to observe tumor formation in the lung. CCK‑8 and EdU assays were utilized to evaluate cell proliferation. Both Ttranswell assay and cell scratch test detected cell migration. The results revealed that lncRNA‑CASC15 was highly expressed in clinical samples and OS cells. In vitro verification experiments revealed that CASC15 promoted the growth of OS cells. Rescue experiments demonstrated that CASC15 affected the cell cycle by activating the Wnt/β‑catenin pathway, thereby promoting cell proliferation. Furthermore, the transfection dose test indicated that lentiviruses expressing various doses of CASC15‑overexpression (oe‑CASC15) altered the proliferation and migration status of OS cells. CASC15 promoted OS cell metastasis both in vivo and in vitro. The overexpression of CASC15 revealed that the occurrence of metastasis was also related to the Wnt/β‑catenin pathway. The western blotting results revealed that CASC15 could lead to β‑catenin entering the nucleus via the Wnt pathway to promote the epithelial‑mesenchymal transition (EMT) of OS cells. To sum up, CASC15 promoted the proliferation of OS cells in vitro and the growth of OS xenograft tumors in vivo. Moreover, CASC15 promoted the entry of β‑catenin into the nucleus, thus activating the Wnt pathway and subsequently promoting the EMT of OS cells.

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GATA6 promotes epithelial-mesenchymal transition and metastasis through MUC1/?-catenin pathway in cholangiocarcinoma.

Publications

GATA6 promotes epithelial-mesenchymal transition and metastasis through MUC1/β-catenin pathway in cholangiocarcinoma.

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