EGFR and E-cadherin coregulated genes mediate the growth and metastasis of gastric cancer cells by ceRNA networks
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PROVIDER: PRJNA924044 | ENA |
REPOSITORIES: ENA
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Project description:EGFR and E-cadherin are key genes closely related with gastric cancer. EGFR overexpression while E-cadherin deletion are characteristic partners in certain types of gastric cancer. Discovering their co-regulatory mechanisms will contribute to provide molecular basis and newer therapeutic strategy for this type of gastric cancer.In this study, E-cadherin overexpression and EGFR knockdown were performed in gastric cancer cells, and their effects on cell growth and metastasis were confirmed. Gene microarrays were used to analyze the changes of gene expression profile. A group of molecular targets co-regulated by EGFR and E-cadherin were found, including lncRNAs, circRNAs and mRNAs. Total 1204 DEGs are related to EGFR knockdown, while 3882 DEGs related to E-cadherin overexpression. Among their downregulated mRNAs, GLI2 and CEACAM6 were identical targets with most significance. Furthermore, 274 overlapping DEGs were screened as potential co-regulatory targets of EGFR and E-cadherin.With GLI2 and CEACAM6 as co-targets, we mapped two representative ceRNA networks to throw light on the co-regulation mechanism of EGFR and E-cadherin in regulating gastric cancer cells.
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Project description:Van Marck et al. (Cancer Research, 2005) published that overexpression of P-cadherin in a melanoma cell line promoted homo- and heterotypic cell-cell adhesion, induced an epitheloïd morphology, and impaired cancer cell invasion. Therefore, we wanted to compare the RNA expression profile between the empty vector control cells and the P-cadherin overexpression variant. This experiment could provide us with effector molecules of P-cadherin that mediate its anti-invasive function.
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Project description:The loss of E-cadherin causes dysfunction of the cell-cell junction machinery, which is an initial step in epithelial-to-mesenchymal transition (EMT), facilitating cancer cell invasion and the formation of metastases. A set of transcriptional repressors of E-cadherin (CDH1) gene expression, including Snail1, Snail2 and Zeb2 mediate E-cadherin down-regulation in breast cancer. However, the molecular mechanisms underlying the control of E-cadherin expression in breast cancer progression remain largely unknown. Here, by using global gene expression approaches, we uncover a novel function for Cdc42 GTPase-activating protein (CdGAP) in the regulation of expression of genes involved in EMT. We found that CdGAP used its proline-rich domain to form a functional complex with Zeb2 to mediate the repression of E-cadherin expression in ErbB2-transformed breast cancer cells. Conversely, knockdown of CdGAP expression led to a decrease of the transcriptional repressors Snail1 and Zeb2, and this correlated with an increase in E-cadherin levels, restoration of cell-cell junctions, and epithelial-like morphological changes. In vivo, loss of CdGAP in ErbB2-transformed breast cancer cells impaired tumor growth and suppressed metastasis to lungs. Finally, CdGAP was highly expressed in basal-type breast cancer cells, and its strong expression correlated with poor prognosis in breast cancer patients. Together, these data support a previously unknown nuclear function for CdGAP where it cooperates in a GAP-independent manner with transcriptional repressors to function as a critical modulator of breast cancer through repression of E-cadherin transcription. Targeting Zeb2-CdGAP interactions may represent novel therapeutic opportunities for breast cancer treatment.
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Project description:The loss of E-cadherin causes dysfunction of the cell-cell junction machinery, which is an initial step in epithelial-to-mesenchymal transition (EMT), facilitating cancer cell invasion and the formation of metastases. A set of transcriptional repressors of E-cadherin (CDH1) gene expression, including Snail1, Snail2 and Zeb2 mediate E-cadherin down-regulation in breast cancer. However, the molecular mechanisms underlying the control of E-cadherin expression in breast cancer progression remain largely unknown. Here, by using global gene expression approaches, we uncover a novel function for Cdc42 GTPase-activating protein (CdGAP) in the regulation of expression of genes involved in EMT. We found that CdGAP used its proline-rich domain to form a functional complex with Zeb2 to mediate the repression of E-cadherin expression in ErbB2-transformed breast cancer cells. Conversely, knockdown of CdGAP expression led to a decrease of the transcriptional repressors Snail1 and Zeb2, and this correlated with an increase in E-cadherin levels, restoration of cell-cell junctions, and epithelial-like morphological changes. In vivo, loss of CdGAP in ErbB2-transformed breast cancer cells impaired tumor growth and suppressed metastasis to lungs. Finally, CdGAP was highly expressed in basal-type breast cancer cells, and its strong expression correlated with poor prognosis in breast cancer patients. Together, these data support a previously unknown nuclear function for CdGAP where it cooperates in a GAP-independent manner with transcriptional repressors to function as a critical modulator of breast cancer through repression of E-cadherin transcription. Targeting Zeb2-CdGAP interactions may represent novel therapeutic opportunities for breast cancer treatment.
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