title: Oncogenic miR-137 contributes to cisplatin resistance via repressing CASP3 in lung adenocarcinoma.
abstract: Although targeted therapy can prolong the survival of non-small cell lung cancer (NSCLC) patients with EGFR mutations, chemotherapy still is the choice for patients with wild-type EGFR or failure in targeted therapy. However, most of the patients will eventually develop chemoresistance. Our previous study showed that miR-137 is a risky microRNA and is associated with poor prognosis in NSCLC patients. Here we investigated the role of miR-137 in cisplatin resistance in lung adenocarcinoma patients. Our data indicated that miR-137 overexpression increases the survival of lung cancer cells exposed to cisplatin and decreases cisplatin-induced apoptosis. Through computational prediction and microarray, we identified caspase-3 (CASP3) as a potential target of miR-137. Luciferase reporter and site-directed mutagenesis assays demonstrated that miR-137 downregulates CASP3 through binding to its 3'-UTR. Moreover, the endogenous CASP3 can be modulated by overexpressing or silencing miR-137 in lung adenocarcinoma cell lines regardless of EGFR status. Suppression of CASP3 by miR-137 provides cancer cells with anti-apoptotic ability, leading to cisplatin resistance. Immunohistochemistry results revealed an inverse correlation between miR-137 and CASP3 expressions in lung adenocarcinoma patients. Together, our data provide a new chemoresistance mechanism in lung adenocarcinoma and a possible target to control chemoresistance in lung adenocarcinoma patients.
authors.affiliation: Institute of Biomedical Sciences, National Chung-Hsing UniversityTaichung, Taiwan; Center of Genomic Medicine, National Taiwan UniversityTaipei, Taiwan.
authors.forename: Te-Jen
authors.initials: TJ
authors.lastname: Su
authors.affiliation: Department of Clinical Pathology, Taipei Institute of Pathology Taiwan.
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Ku
authors.affiliation: Institute of Statistical Science, Academia Sinica Taipei, Taiwan.
authors.forename: Hsuan-Yu
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Institute of Statistical Science, Academia Sinica Taipei, Taiwan.
authors.forename: Yi-Chiung
authors.initials: YC
authors.lastname: Hsu
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University Taipei, Taiwan.
authors.forename: Qi-Sheng
authors.initials: QS
authors.lastname: Hong
authors.affiliation: Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital Taichung, Taiwan.
authors.forename: Gee-Chen
authors.initials: GC
authors.lastname: Chang
authors.affiliation: Center of Genomic Medicine, National Taiwan UniversityTaipei, Taiwan; Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan UniversityTaipei, Taiwan.
authors.forename: Sung-Liang
authors.initials: SL
authors.lastname: Yu
authors.affiliation: Institute of Biomedical Sciences, National Chung-Hsing UniversityTaichung, Taiwan; Agricultural Biotechnology Center, National Chung Hsing UniversityTaichung, Taiwan; Rong Hsing Research Center for Translational Medicine, National Chung Hsing UniversityTaichung, Taiwan.
authors.forename: Jeremy Jw
authors.initials: JJ
authors.lastname: Chen
keywords: caspase 3; chemoresistance; cisplatin; lung adenocarcinoma; miR-137