Abstract
Metastatic relapse of primary lung cancer leads to therapeutic resistance and unfavorable clinical prognosis; therefore, identification of key molecules associated with metastatic conversion has significant clinical implications. We previously identified a link between early brain metastasis of lung adenocarcinoma and amplification of the α-smooth muscle actin (ACTA2) gene. The aim of present study was to investigate the prognostic and functional significance of ACTA2 expression in cancer cells for the metastatic potential of lung adenocarcinomas. ACTA2 expression was analyzed in tumor cells from 263 patients with primary lung adenocarcinomas by immunohistochemistry, and was correlated with clinicopathologic parameters. The expression of ACTA2 in human lung adenocarcinoma cells was modulated with short hairpin RNAs (shRNA) and siRNAs specifically targeting ACTA2. The patients with lung adenocarcinomas with high ACTA2 expression in tumor cells showed significantly enhanced distant metastasis and unfavorable prognosis. ACTA2 downregulation remarkably impaired in vitro migration, invasion, clonogenicity, and transendothelial penetration of lung adenocarcinoma cells without affecting proliferation. Consistent with the in vitro results, depletion of ACTA2 in human lung adenocarcinoma PC14PE6 cells significantly reduced their metastatic potential without altering their tumorigenic potential. Expression of c-MET and FAK in lung adenocarcinoma cells was also reduced by ACTA2-targeting siRNAs and shRNAs, and was accompanied by a loss of mesenchymal characteristics. These findings indicate that ACTA2 regulates c-MET and FAK expression in lung adenocarcinoma cells, which positively and selectively influence metastatic potential. Therefore, ACTA2 could be a promising prognostic biomarker and/or therapeutic target for metastatic lung adenocarcinoma.
Highlights
Lung cancer is the most common cancer worldwide with the highest mortality rate [1]
Consistent with the in vitro results, depletion of ACTA2 in human lung adenocarcinoma PC14PE6 cells significantly reduced their metastatic potential without altering their tumorigenic potential
Expression of c-MET and Focal adhesion kinase (FAK) in lung adenocarcinoma cells was reduced by ACTA2-targeting siRNAs and short hairpin RNAs (shRNA), and was accompanied by a loss of mesenchymal characteristics
Summary
Lung cancer is the most common cancer worldwide with the highest mortality rate [1]. The identification of therapeutic targets in non–small cell lung cancer (NSCLC), such as EGF receptor (EGFR)-activating mutations, has enabled the development of effective targeted therapies for advanced NSCLC [2]. The 5-year survival rate for NSCLC remains 15% across all stages of the disease. These unfavorable clinical outcomes originate from its high invasive and metastatic potential [3, 4]. Lung adenocarcinoma is known to establish distant macrometastases in various organs, within months of diagnosis [5]. Current targeted therapeutics have limited efficacy for the treatment of distant metastases in lung adenocarcinoma
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