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MiR-200b and miR-15b regulate chemotherapy-induced epithelial-mesenchymal transition in human tongue cancer cells by targeting BMI1

Oncogene volume 31, pages 432–445 (2012)Cite this article

Abstract

Chemotherapy has been reported to induce epithelial-mesenchymal transition (EMT) in tumor cells, which is a critical step in the process of metastasis leading to cancer spreading and treatment failure. However, the underlying mechanisms of chemotherapy-induced EMT remain unclear, and the involvement of microRNAs (miRNA) in this process is poorly understood. To address these questions, we established stable chemotherapy-resistant tongue squamous cell carcinoma (TSCC) cell lines CAL27-res and SCC25-res by exposing the parental CAL27 and SCC25 lines to escalating concentrations of cisplatin for 6 months. CAL27-res and SCC25-res cells displayed mesenchymal features with enhanced invasiveness and motility. MiRNA microarray illustrated that miR-200b and miR-15b were the most significantly downregulated microRNAs in CAL27-res cells. Ectopic expression of miR-200b and miR-15b with miRNA mimics effectively reversed the phenotype of EMT in CAL27-res and SCC25-res cells, and sensitized them to chemotherapy, but inhibition of miR-200b and miR-15b in the sensitive lines with anti-sense oligonucleotides induced EMT and conferred chemoresistance. Retrieving the expression of B lymphoma Mo-MLV insertion region 1 homolog (BMI1), a target for miR-200b and miR-15b, in the presence of the miRNA mimics by transfecting CAL27-res cells with pcDNA3.1–BMI1-carrying mutated seed sequences of miR-200b or miR-15b at its 3′-UTR recapitulated chemotherapy-induced EMT. In vivo, enforced miR-200b or miR-15b expression suppressed metastasis of TSCC xenografts established by CAL27-res cells. Clinically, reduced miR-200b or miR-15b expression was associated with chemotherapeutic resistance in TSCCs and poor patient survival. Our data suggest that reduced expression of miR-200b and miR-15b underscores the mechanisms of chemotherapy-induced EMT in TSCC, and may serve as therapeutic targets to reverse chemotherapy resistance in tongue cancers.

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Acknowledgements

This work was supported by Grants to JL from National Natural Science Foundation of China (81072225), Natural Science Foundation of Guangdong Province (10251008901000022, 9151008901000201) and Guangzhou Science and Technology Bureau (2008Z1-E201); and to ES from ‘973’ Program Projects (2010CB912800, 2011CB504203, 2009CB521706) from Ministry of Science and Technology of China, National Natural Science Foundation of China (30921140312, 30831160515, 30830110), and Natural Science Foundation of Guangdong Province (8251008901000011), Key Laboratory of malignant tumor gene regulation and target therapy of Guangdong Higher Education Institutes, Sun Yat-sen University (KLB09001), and to LL from National Natural Science Foundation of China (81072177).

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  1. L Sun and Y Yao: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

    L Sun, Y Yao, B Liu, L Lin, M Yang & E Song

  2. Department of Oral & Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

    Z Lin, W Zhang, W Chen, C Pan & J Li

  3. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Q Liu

  4. Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

    E Song

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Sun, L., Yao, Y., Liu, B. et al. MiR-200b and miR-15b regulate chemotherapy-induced epithelial-mesenchymal transition in human tongue cancer cells by targeting BMI1. Oncogene 31, 432–445 (2012). https://doi.org/10.1038/onc.2011.263

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