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[Low expression of lncRNA-GAS5 promotes epithelial-mesenchymal transition of breast cancer cells in vitro].

ABSTRACT: OBJECTIVE:To investigate the role of long non-coding RNA growth arrest-specific transcript 5 (lncRNA-GAS5) in breast cancer progression and epithelial-mesenchymal transition (EMT) of the cancer cells. METHODS:Real-time quantitative PCR (qRT-PCR) was used to detect the expression of lncRNA-GAS5 in 37 pairs of breast cancer and adjacent non-tumor tissues and in parental MCF-7 cells and paclitaxel-resistant MCF-7 (MCF-7/PR) cells, and the correlation of lncRNA-GAS5 expression with the clinical stage and lymph node metastasis of breast cancer was investigated. The expressions of the genes related with cell cycle and EMT at both the mRNA and protein levels were detected using qRT-PCR, Western blotting and immunohistochemistry. The changes in the biological behaviors and morphology of breast cancer cells with either lncRNA-GAS5 knockdown or overexpression were observed. Nude mouse models were established bearing breast cancer xenografts derived from MCF-7/PR cells or MCF-7/PR cells over-expressing lncRNA-GAS5, and the inhibitory effect of paclitaxel on tumor growth was evaluated. RESULTS:The transcriptional levels of lncRNA-GAS5 were significantly lower in breast cancer tissues than in the adjacent non-tumor tissues (P<0.05), and decreased lncRNA-GAS5 expression was significantly correlated with TNM stage and lymph node metastasis of breast cancer (P<0.05). lncRNA-GAS5 expression was also significantly lowered in paclitaxel-resistant breast cancer cells and showed a positive correlation with P21 expression and a negative correlation with CDK6. MCF-7 cells during EMT presented with a lowered expression of lncRNA-GAS5, whereas lncRNA-GAS5 over-expression strongly suppressed MCF-7/PR cell migration and invasion, and increased the susceptibility of the cells to paclitaxel. In the tumor-bearing nude mouse models, lncRNA-GAS5 overexpression in the tumor cells obviously enhanced the inhibitory effect of paclitaxel on tumor growth and lung metastasis by reversing the EMT marker proteins. CONCLUSION:A decreased expression of lncRNA-GAS5 promotes lung metastasis of breast cancer by inducing EMT, suggesting the potential of lncRNA-GAS5 as a therapeutic target in breast cancer.

SUBMITTER: Ding YX

PROVIDER: S-EPMC6779650 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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[Low expression of lncRNA-GAS5 promotes epithelial-mesenchymal transition of breast cancer cells in vitro].

Ding Yong-Xing YX Duan Ke-Cai KC Chen Su-Lian SL

Nan fang yi ke da xue xue bao = Journal of Southern Medical University 20171101 11

<h4>Objective</h4>To investigate the role of long non-coding RNA growth arrest-specific transcript 5 (lncRNA-GAS5) in breast cancer progression and epithelial-mesenchymal transition (EMT) of the cancer cells.<h4>Methods</h4>Real-time quantitative PCR (qRT-PCR) was used to detect the expression of lncRNA-GAS5 in 37 pairs of breast cancer and adjacent non-tumor tissues and in parental MCF-7 cells and paclitaxel-resistant MCF-7 (MCF-7/PR) cells, and the correlation of lncRNA-GAS5 expression with th ...[more]

PMID: 29180320

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Project description:BackgroundTrastuzumab resistance followed by metastasis is a major obstacle for improving the clinical outcome of patients with advanced human epidermal growth factor receptor 2-positive (HER-2+) breast cancer. While long non-coding RNAs (lncRNAs) can modulate cell behavior, the contribution of these RNAs in trastuzumab resistance and metastasis of HER-2+ breast cancer is not well known. In this study, we sought to identify the regulatory role of lncRNA in trastuzumab resistance and accompanied Epithelial-mesenchymal Transition (EMT) process in advanced HER-2+ breast cancer.MethodsTrastuzumab-resistant SKBR-3-TR and BT474-TR cell lines were established by grafting SKBR-3 and BT474 cells into mouse models and subjected to trastuzumab treatment. LncRNA microarray followed by quantitative reverse transcription PCR (qRT-PCR) was carried out to verify the differentially expressed lncRNAs. Western blotting, bioinformatics analysis, immunofluorescence assay and immunoprecipitation assays (ChIP and RIP) were performed to identify the involvement and functional interactions between H3K27 acetylation and terminal differentiation-induced non-coding RNA (TINCR) or between TINCR and its downstream genes including miR-125b, HER-2 and Snail-1. In addition, a series of in vitro and in vivo assays were performed to assess the functions of TINCR.ResultsAn increase in both, IC50 value of trastuzumab and EMT was observed in the established trastuzumab-resistant cell lines. The expression level of TINCR was significantly increased in trastuzumab-resistant cells when compared with sensitive cells. Knockdown of TINCR reversed the trastuzumab resistance and the acquired EMT in these cells. TINCR was detected in the cytoplasm of breast cancer cells and could sponge miR-125b, thereby releasing HER-2 and inducing trastuzumab resistance. In addition, Snail-1 was found to be the target gene of miR-125b and overexpression of Snail-1 could reverse the suppressed migration, invasion, and EMT caused by TINCR silencing. The upregulation of TINCR in breast cancer was attributed to the CREB-binding protein (CBP)-mediated H3K27 acetylation at the promoter region of TINCR. Clinically, HER-2+ breast cancer patients with high TINCR expression levels were associated with poor response to trastuzumab therapy and shorter survival time.ConclusionTINCR could promote trastuzumab resistance and the accompanied EMT process in breast cancer. Therefore, TINCR might be a potential indicator for prognosis and a therapeutic target to enhance the clinical efficacy of trastuzumab treatment.

Dataset Information

[Low expression of lncRNA-GAS5 promotes epithelial-mesenchymal transition of breast cancer cells in vitro].

Publications

[Low expression of lncRNA-GAS5 promotes epithelial-mesenchymal transition of breast cancer cells in vitro].

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