TFAP2C promotes lung tumorigenesis and aggressiveness through miR-183- and miR-33a-mediated cell cycle regulation.
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.
Department of Integrated Biological Science, Pusan National University, Busan, Republic of Korea.
J
J
Kang
Department of Biological Sciences, Pusan National University, Busan, Republic of Korea.|Integrative Graduate Program of Ship and Offshore Plant Technology for Ocean Energy Resource, Pusan National University, Busan, Republic of Korea.
W
W
Kim
Department of Integrated Biological Science, Pusan National University, Busan, Republic of Korea.
S
S
Lee
Department of Integrated Biological Science, Pusan National University, Busan, Republic of Korea.
D
D
Kwon
Department of Integrated Biological Science, Pusan National University, Busan, Republic of Korea.
J
J
Chun
Department of Integrated Biological Science, Pusan National University, Busan, Republic of Korea.
B
B
Son
Department of Integrated Biological Science, Pusan National University, Busan, Republic of Korea.
E
E
Kim
Department of Naval Architecture and Ocean Engineering, Pusan National University, Busan, Republic of Korea.
J-M
JM
Lee
Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, Republic of Korea.
H
H
Youn
Department of Integrated Biological Science, Pusan National University, Busan, Republic of Korea.|Department of Biological Sciences, Pusan National University, Busan, Republic of Korea.
B
B
Youn
D054758:A Kinase Anchor Proteins / Q000235:genetics; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D015398:Signal Transduction; D050656:Transcription Factor AP-2 / Q000235:genetics* / Q000378:metabolism
D054758:A Kinase Anchor Proteins; C491162:AKAP12 protein, human; D018797:Cell Cycle Proteins; C533449:MIRN183 microRNA, human; C550416:MIRN33a microRNA, human; D035683:MicroRNAs; C493679:TFAP2C protein, human; D050656:Transcription Factor AP-2; D051361:Cyclin-Dependent Kinase 6