Molecular Mechanisms Of Transgelin2 And MiR - 200a In Breast Cancer Metastasis

Background:Emerging evidences has shown Transgelin is a tumor suppressor whose function has been ascribed in cancer metastasis. The function of Transgelin2, the homology of Transgelin, has not yet well determined. Our former study has shown Transgelin2was lower expression in MDA-MB-231HM cells, the role of Transgelin2in breast cancer metastasis still remains unclear.Experimental Design:Given that TAGLN2expression is reverse correlation with the metastatic phenotype, we overexpressed and knockdown Transgelin2in the cell lines to elucidate its role in breast cancer metastasis. Since knockdown Trasgelin2expression promotes the MDA-MB-231invasion, we then discover proteins interaction with Transgelin2via co-immuneprecipitation and LC/MS and find the pathway Transgelin2involved in. Luciferase assays, cell proliferation assay, flow cytometry, and mouse xenograft were performed to identify the pathway of Transgelin2and the mechanism implicated in breast cancer metastasis. At last, we compared the expression of Transgelin2in clinical samples obtained from patients with breast cancer with and without lymph node metastasis.Results:Knockdown Transgelin2promotes MDA-MB-231invasion. We identified PRDX1interaction with Transgelin2, and knockdown Transgelin2cause ROS elevated, mitochondrion redistributing and NF-κB activation lead to metastatic associated gene transcription. NF-κB downstream target genes CXCR4, MMP1, MMP2expression were increased. In Transgelin2knockdown group NF-κB activity is2.2times than control group. And Transglin2knockdown also enhanced the lung metastasis in mouse mode (P<0.001). In the lymph node negative panel, Transgelin2was8fold higher than the group with lymph node metastasis.Conclusions:Transgelin2is a tumor suppressor. Loss of Transgelin2transactivated NF-κB via interrupting PRDX1function and mitochondrion redistributing to promote breast cancer metastasis. Background:Emerging evidence suggests molecular and phenotypic association between treatment resistance and epithelial-mesenchymal transition (EMT) in cancer. Although the molecular events of miR-200family that cause EMT are becoming well defined, the role of miR-200family in therapy resistance remains unclear.Experimental Design:miR-200family expression was analyzed in gemcitabine resistance cells and radiation resistance cells. Since miR-200a is only consistently overexpressed in treatment resistance cells, we then compared the expression of miR-200a in samples obtained from patients with breast cancer who received preoperative chemotherapy followed by surgery and samples from patients who had directly surgery by real-time reverse transcriptase PCR. Luciferase assays, cell proliferation assay, colony formation, and mouse xenograft were performed to identify the targets of miR-200a and the mechanism implicated in treatment resistance. Survival analysis was used to evaluate the prognosis value of miR-200a.Results:Only miR-200a was consistent overexpressed in both treatment resistance cell lines. In the neoadjuvant panel, miR-200a was3.3fold higher than the group with direct surgery (P=0.037). We identified YAP1and TP53INP1as new targets of miR-200a. We demonstrated that miR-200a promoted treatment resistance through attenuating the p73induced apoptosis. miR-200a also enhanced the lung metastasis (P=0.015) via evasion of anoikis and miR200a signature was associated with disease-free survival(P=0.041).Conclusions:Upregulated miR-200a enhances treatment resistance and evasion of anoikis via target the YAP1and TP53INP1in treatment resistance cell lines modes and in tumor samples from chemoresistance patients.