p53‐inducible gene 3 promotes cell migration and invasion by activating the FAK/Src pathway in lung adenocarcinoma

• Published in: Cancer science Vol. 109; no. 12; pp. 3783 - 3793
• Main Authors: Gu, Meng‐Meng, Gao, Dexuan, Yao, Ping‐An, Yu, Lan, Yang, Xiao‐Dong, Xing, Chun‐Gen, Zhou, Jundong, Shang, Zeng‐Fu, Li, Ming
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.12.2018; John Wiley and Sons Inc
• Subjects: A549 Cells; Adenocarcinoma; Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - metabolism; Adult; Aged; Animals; Apoptosis; Binding sites; Biomarkers; Cancer therapies; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Cell adhesion & migration; Cell Line, Tumor; Cell migration; Cell Movement; Clinical trials; Deoxyribonucleic acid; DNA; DNA damage; Female; Focal adhesion kinase; Focal Adhesion Kinase 1 - metabolism; Gene expression; Gene Expression Regulation, Neoplastic; Genomes; Growth factors; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; invasion; Kinases; Lung cancer; Lung carcinoma; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lymph nodes; Lymphatic Metastasis; Lymphatic system; Male; Metastases; Metastasis; Mice; Middle Aged; migration; Mutation; Neoplasm Invasiveness; Neoplasm Transplantation; Non-small cell lung carcinoma; non‐small cell lung cancer; Original; p53 Protein; p53‐inducible gene 3; Paxillin; Phosphorylation; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins pp60(c-src) - metabolism; Signal Transduction; Small cell lung carcinoma; Squamous cell carcinoma; Therapeutic applications; Tumors; Up-Regulation; United States > US; China; Japan; non-small cell lung cancer; migration; p53-inducible gene 3; invasion; focal adhesion kinase
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.13818

The p53‐inducible gene 3 (PIG3) is one of the p53‐induced genes at the onset of apoptosis, which plays an important role in cell apoptosis and DNA damage response. Our previous study reported an oncogenic role of PIG3 associated with tumor progression and metastasis in non‐small cell lung cancer (NSCLC). In this study, we further analyzed PIG3 mRNA expression in 504 lung adenocarcinoma (LUAD) and 501 lung squamous cell carcinoma (LUSC) tissues from The Cancer Genome Atlas database and we found that PIG3 expression was significantly higher in LUAD with lymph node metastasis than those without, while no difference was observed between samples with and without lymph node metastasis in LUSC. Gain and loss of function experiments were performed to confirm the metastatic role of PIG3 in vitro and to explore the mechanism involved in its oncogenic role in NSCLC metastasis. The results showed that PIG3 knockdown significantly inhibited the migration and invasion ability of NSCLC cells, and decreased paxillin, phospho‐focal adhesion kinase (FAK) and phospho‐Src kinase expression, while its overexpression resulted in the opposite effects. Blocking FAK with its inhibitor reverses PIG3 overexpression‐induced cell motility in NSCLC cells, indicating that PIG3 increased cell metastasis through the FAK/Src/paxillin pathway. Furthermore, PIG3 silencing sensitized NSCLC cells to FAK inhibitor. In conclusion, our data revealed a role for PIG3 in inducing LUAD metastasis, and its role as a new FAK regulator, suggesting that it could be considered as a novel prognostic biomarker or therapeutic target in the treatment of LUAD metastasis. Our data demonstrated that PIG3 might function as a FAK regulator in NSCLC and could serve as a novel prognostic biomarker or therapeutic target in the treatment of NSCLC metastasis. This evidence will further help scientists to understand NSCLC progression and to develop new therapeutic strategies.