TFAP2C-mediated upregulation of TGFBR1 promotes lung tumorigenesis and epithelial–mesenchymal transition

• Published in: Experimental & molecular medicine Vol. 48; no. 11; p. e273
• Main Authors: Kim, Wanyeon, Kim, EunGi, Lee, Sungmin, Kim, Daehoon, Chun, Jahyun, Park, Kang Hyun, Youn, HyeSook, Youn, BuHyun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2016; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/1; 13/109; 13/31; 13/51; 13/89; 14/34; 631/67/1612/1350; 64/60; 82/80; 96/63; Aged; Animals; Biomedical and Life Sciences; Biomedicine; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinogenesis - pathology; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; Medical Biochemistry; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Molecular Medicine; Original; original-article; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Receptors, Transforming Growth Factor beta - genetics; Receptors, Transforming Growth Factor beta - metabolism; Signal Transduction; Stem Cells; Transcription Factor AP-2 - genetics; Transcription Factor AP-2 - metabolism; Transcriptional Activation
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/emm.2016.125

TFAP2C (transcription factor-activating enhancer-binding protein 2C) expression has been positively correlated with poor prognosis in patients with certain types of cancer, but the mechanisms underlying TFAP2C-mediated tumorigenesis in non-small-cell lung cancer (NSCLC) are still unknown. We previously performed a microarray analysis to identify TFAP2C regulation genes, and TGFBR1 (transforming growth factor-β receptor type 1) was found to be upregulated by TFAP2C. We observed that TFAP2C or TGFBR1 overexpression led to oncogenic properties, such as cell viability, proliferation and cell cycle progression. TGFBR1 upregulation induced by TFAP2C also promoted cell motility and migration, leading to malignant development. We also found that PAK1 (p21 protein (Cdc42/Rac)-activated kinase 1) signaling was involved in TFAP2C/TGFBR1-induced tumorigenesis. These results were confirmed by an in vivo xenograft model and patient tissue samples. This study shows that TFAP2C promoted tumor progression by upregulation of TGFBR1 and consequent activation of PAK1 signaling. Lung cancer: Insights into mechanism of tumor formation The gene regulatory protein TFAP2C contributes to non-small cell lung cancer (NSCLC) by stimulating cell proliferation and motility. Although TFAP2C expression has previously been associated with cancer, little was known about how it contributes to tumor formation. BuHyun Youn at Pusan National University, Busan, and colleagues found that in NSCLC cell lines TFAP2C increases the levels of the cell surface receptor TGFBR1 and promotes cell survival and proliferation. They also showed that overexpression of this receptor leads to an increase in cell motility by activating the enzyme p21-activated kinase 1. High levels of TFACP2C and TGFBR1 are found in lung tissue of NSCLC patients and depletion of either in a mouse model of NSCLC reduces tumor size. Together, these findings highlight potential new drug targets for halting lung cancer progression.