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Snail knockdown reverses stemness and inhibits tumour growth in ovarian cancer.

ABSTRACT: To develop effective therapies for advanced high grade serous ovarian cancer (HGSOC), understanding mechanisms of recurrence and metastasis is necessary. In this study, we define the epithelial/mesenchymal status of cell lines that accurately model HGSOC, and evaluate the therapeutic potential of targeting Snai1 (Snail), a master regulator of the epithelial/mesenchymal transition (EMT) in vitro and in vivo. The ratio of Snail to E-cadherin (S/E index) at RNA and protein levels was correlated with mesenchymal morphology in four cell lines. The cell lines with high S/E index (OVCAR8 and COV318) showed more CSC-like, motile, and chemoresistant phenotypes than those with low S/E index (OVSAHO and Kuramochi). We tested the role of Snail in regulation of malignant phenotypes including stemness, cell motility, and chemotherapy resistance: shRNA-mediated knockdown of Snail reversed these malignant phenotypes. Interestingly, the expression of let-7 tumour suppressor miRNA was upregulated in Snail knockdown cells. Furthermore, knockdown of Snail decreased tumour burden in an orthotopic xenograft mouse model. We conclude that Snail is important in controlling HGSOC malignant phenotypes and suggest that the Snail/Let-7 axis may be an attractive target for HGSOC treatment.

SUBMITTER: Hojo N

PROVIDER: S-EPMC5992154 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Snail knockdown reverses stemness and inhibits tumour growth in ovarian cancer.

Hojo N N Huisken A L AL Wang H H Chirshev E E Kim N S NS Nguyen S M SM Campos H H Glackin C A CA Ioffe Y J YJ Unternaehrer J J JJ

Scientific reports 20180607 1

To develop effective therapies for advanced high grade serous ovarian cancer (HGSOC), understanding mechanisms of recurrence and metastasis is necessary. In this study, we define the epithelial/mesenchymal status of cell lines that accurately model HGSOC, and evaluate the therapeutic potential of targeting Snai1 (Snail), a master regulator of the epithelial/mesenchymal transition (EMT) in vitro and in vivo. The ratio of Snail to E-cadherin (S/E index) at RNA and protein levels was correlated wit ...[more]

PMID: 29880891

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Project description:ObjectiveSpondin-2 (SPON2) is highly expressed in a variety of tumors and has been associated with poor prognosis, but the relationship to triple-negative breast cancer (TNBC) is unclear. The aim of this study is to investigate the expression of SPON2 in TNBC and its function.MethodsImmunohistochemistry was used to detect the expression of the SPON2 protein in TNBC and in normal tissue adjacent to cancer and breast fibroadenoma. The GEO database GSE76275 dataset was used to study the expression of SPON2 mRNA in TNBC and non-TNBC. The expression of SPON2 mRNA was detected by qPCR in TNBC cells MDA-MB-231, non-TNBC breast cancer cells MCF-7, and normal breast cells MCF-10A. Kaplan Meier-Plotter database was used to analyze the relationship between SPON2 expression and TNBC prognosis. ShRNA lentivirus was used to knock down high expression of SPON2 in TNBC cells. The effects of knockdown of SPON2 expression on the proliferation, migration, invasion, apoptosis, and subcutaneous tumorigenic ability of TNBC cells in nude mice were analyzed using CCK8, clone formation assay, scratch assay, transwell migration assay, transwell invasion assay, Hoechst apoptosis assay, and tumorigenic ability in nude mice. Transcriptome sequencing of TNBC cells with knockdown SPON2 expression. In combination with the GEO database, GO and KEGG analyses were performed, and psychophysiological interaction Protein-Protein Interaction Networks (PPI) analysis was performed for transcriptome sequencing of the differentially expressed genes. The changes in the expression of PI3K-ATK pathway proteins after SPON2 knockdown were detected by Western blot.ResultsOur study shows that upregulation of SPON2 in TNBC is associated with poorer patient outcomes. Knockdown of SPON2 inhibited TNBC cell proliferation, clone formation, migration, invasion, and tumorigenic ability and promoted apoptosis. Knockdown of SPON2 up-regulated TNBC cell adhesion and down-regulated PI3K-ATK pathway, and PPI results showed that CCL2 was the key protein.ConclusionsSPON2 may be a valuable biomarker for the diagnosis and prognosis of TNBC and is a potential therapeutic target for TNBC.

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Snail knockdown reverses stemness and inhibits tumour growth in ovarian cancer.

Publications

Snail knockdown reverses stemness and inhibits tumour growth in ovarian cancer.

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