Oncogene. 2017 Mar;36(11):1585-1596. doi: 10.1038/onc.2016.328.

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

JiHoon Kang1,6, Wanyeon Kim2,3,6, Sungmin Lee1,6, DanAh Kwon1, Jahyun Chun1, Beomseok Son1, EunGi Kim1, Jae-Myung Lee4, HyeSook Youn5, and BuHyun Youn1,2

1Department of Integrated Biological Science, Pusan National University, Busan, 46241, Republic of Korea; 2Department of Biological Sciences, Pusan National University, Busan, 46241, Republic of Korea; 3Integrative Graduate Program of Ship and Offshore Plant Technology for Ocean Energy Resource, Pusan National University, Busan, 46241, Republic of Korea; 4Department of Naval Architecture and Ocean Engineering, Pusan National University, Busan, 46241, Republic of Korea; and 5Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, 05006, Republic of Korea

Correspondence: Professor BuHyun Youn, Department of Biological Sciences, Pusan National University, Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan, 46241, Republic of Korea. Tel: 82-51-510-2264; Fax: 82-51-581-2962; E-mail: bhyoun72@pusan.ac.kr

Professor HyeSook Youn, Department of Integrative Bioscience and Biotechnology, Sejong University, 209 Neungdong-ro, Gwangjin-gu, Seoul, 05006, Republic of Korea. Tel: 82-2-3408-3921; Fax: 82-2-3408-4334; E-mail: hsyoun@sejong.ac.kr

6These authors contributed equally to this work.

Running title: TFAP2C-mediated lung tumorigenesis

 

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 EGFR/KRAS mutation-driven lung tumorigenesis is well understood, the mechanism of EGFR/KRAS-independent signal activation remains elusive. Enhanced TFAP2C 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 miRNA-183 and simultaneously activated CDK6-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.

Keywords: TFAP2C, miRNA, cell cycle, lung tumorigenesis, EMT

 

Summary 

Lung cancer killed approximately 160,000 people in United States in 2015, which is more than the death rates of the next four most common cancers combined. An understanding of the molecular mechanism underlying lung tumorigenesis is critically required to guide the development of curative treatments and methods of diagnosing lung cancer at an early stage. Non-small-cell lung cancer (NSCLC) is an aggressive type of lung cancer and accounts for around 85% of lung cancers. Accumulations of and interplay between genetic and epigenetic alterations in oncogenes, tumor-suppressor genes, and other factors involved in developmental signaling pathways are considered the main causative factors of NSCLC tumorigenesis. Aberrant proliferation of NSCLC has frequently been associated with mutational activations of receptor tyrosine kinase (RTK) signaling and of genes encoding RTKs (ALK, EGFR, MET, and ROS1) or intracellular signaling proteins such as KRAS or its effectors A-, B-, or C-RAF, or PIK3CA, which encodes PI3-kinase-a.

We identified that TFAP2C expression is required for NSCLC cell proliferation, the expressions of miR-183 and miR-33a are regulated by TFAP2C, and miR-183 and miR-33a negatively regulate the expressions of AKAP12 and CDK6, respectively. Moreover, it was uncovered that TFAP2C-miR-183-AKAP12 and TFAP2C-miR-33a-CDK6 pathways regulate cell cycle progression by controlling the expression and nuclear localization of cyclin D1, and the inhibition of miR-183a and activation of miR-33a in NSCLC cells suppresses metastatic conversion.

Taken together, 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 miRNA-183 and simultaneously activated CDK6-mediated cyclin D1 activation by downregulating tumor-suppressive miRNA-33a. Our results reveal a novel mechanism of TFAP2c-mediated cell cycle activation signaling via the regulation of two-functionally opposed miRNAs in NSCLC.

 

 

Schematic diagram illustrated that increase of TFAP2C promotes tumorigenesis and malignant development.

TFAP2C-mediated increase of miR-183 expression and decrease of miR-33a regulate the level of AKAP12 and CDK6. Increase of cyclin D1 levels in cytoplasm by decrease of AKAP12 and increase of CDK6 results in CDK6–cyclin D1 complex formation and its subsequent translocation into the nucleus, promoting cell cycle progression, proliferation and EMT.