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TFAP2C promotes lung tumorigenesis and aggressiveness through miR-183- and miR-33a-mediated cell cycle regulation

Oncogene volume 36, pages 1585–1596 (2017)Cite this article

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Abstract

Non-small cell lung cancer (NSCLC) remains one of the leading causes of death worldwide, and thus new molecular targets need to be identified to improve treatment efficacy. Although epidermal growth factor receptor (EGFR)/KRAS mutation-driven lung tumorigenesis is well understood, the mechanism of EGFR/KRAS-independent signal activation remains elusive. Enhanced TFAP2C (transcription factor activating enhancer-binding protein 2C) expression is associated with poor prognosis in some types of cancer patients, but little is known of its relation with the pathogenesis of lung cancer. In the present study, we found that TFAP2C overexpression was associated with cell cycle activation and NSCLC cell tumorigenesis. Interestingly, TFAP2C blocked AKAP12-mediated cyclin D1 inhibition by inducing the overexpression of oncogenic microRNA (miRNA)-183 and simultaneously activated cyclin-dependent kinase 6-mediated cell cycle progression by downregulating tumor-suppressive miRNA-33a. In a mouse xenograft model, TFAP2C promoted lung tumorigenesis and disease aggressiveness via the miR-183 and miR-33a pathways. The study provides a mechanism of mitogenic and oncogenic signaling via two functionally opposed miRNAs and suggests that TFAP2C-induced cell cycle hyperactivation contributes to lung tumorigenesis.

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Acknowledgements

This work was supported by the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (2014R1A1A1A05002112 and 2013M2A2A7042502), the Ministry of Education (2013R1A1A2059832 to W Kim and 2014R1A1A2004061 to H Youn) and the Ministry of Science, ICT & Future Planning through GCRC-SOP (2011-0030013).

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  1. J Kang, W Kim and S Lee: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Integrated Biological Science, Pusan National University, Busan, Republic of Korea

    J Kang, S Lee, D Kwon, J Chun, B Son, E Kim & B Youn

  2. Department of Biological Sciences, Pusan National University, Busan, Republic of Korea

    W Kim & B Youn

  3. Integrative Graduate Program of Ship and Offshore Plant Technology for Ocean Energy Resource, Pusan National University, Busan, Republic of Korea

    W Kim

  4. Department of Naval Architecture and Ocean Engineering, Pusan National University, Busan, Republic of Korea

    J-M Lee

  5. Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, Republic of Korea

    H Youn

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Kang, J., Kim, W., Lee, S. et al. TFAP2C promotes lung tumorigenesis and aggressiveness through miR-183- and miR-33a-mediated cell cycle regulation. Oncogene 36, 1585–1596 (2017). https://doi.org/10.1038/onc.2016.328

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