MicroRNA-224 is implicated in lung cancer pathogenesis through targeting caspase-3 and caspase-7

// Ri Cui 1,4,* , Taewan Kim 2,* , Matteo Fassan 1,3 , Wei Meng 5 , Hui-Lung Sun 1 , Young-Jun Jeon 1 , Caterina Vicentini 6 , Esmerina Tili 1,7 , Yong Peng 8 , Aldo Scarpa 9 , Guang Liang 10 , Yong Kui Zhang 11 , Arnab Chakravarti 5 and Carlo M. Croce 1 1 Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA 2 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Department of Medicine (DIMED), University of Padua, Padua, Italy 4 Chemical Biology Research Center, School of Pharmaceutical Sciences, and Lung Cancer Research Center, The Zhoushan Hospital of Wenzhou Medical University , Wenzhou, Zhejiang, China 5 Department of Radiation Oncology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA 6 Applied Research on Cancer Network (ARC-NET) Research Centre, University of Verona, Verona, Italy 7 Department of Anesthesiology, Wexner Medical Center, The Ohio State University, Columbus, OH, USA 8 Division of Thoracic Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Collaborative Innovation Center of Biotherapy, Chengdu, China 9 Department of Pathology and Diagnostics, University of Verona, Verona, Italy 10 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China 11 Department of Cardio-Thoracic Surgery, Lung Cancer Research Center, Zhoushan Hospital of Wenzhou Medical University, Zhoushan, Zhejiang, China * These authors have contributed equally to this work Correspondence to: Carlo M. Croce, email: // Yong Peng, email: // Keywords : miR-224, lung cancer, caspase-3, caspase-7 Received : July 23, 2015 Accepted : August 08, 2015 Published : August 19, 2015 Abstract We recently reported that miR-224 was significantly up-regulated in non-small cell lung cancer (NSCLC) tissues, in particular in resected NSCLC metastasis. We further demonstrated that miR-224 functions as an oncogene in NSCLC by directly targeting TNFAIP1 and SMAD4. However, the biological functions of miR-224 in NSCLC are controversial and underlying mechanisms of miR-224 in the progression and metastasis of lung cancer remain to be further explored. Here we report that caspase3 (CASP3) and caspase7 (CASP7) are previously unidentified targets of miR-224 in NSCLC, and that miR-224 promotes lung cancer cells proliferation and migration in part by directly targeting CASP7 and down-regulating its expression. In addition, miR-224 attenuated TNF-α induced apoptosis by direct targeting of CASP3 resulting in reduction of cleaved PARP1 expression in lung cancer cells. Furthermore, the expression of miR-224 negatively correlates with the expression of CASP7 and CASP3 in tissue samples from patients with lung cancer. Finally, we found that activated NF-κB signaling is involved in the regulation of miR-224 expression in lung cancer. Our study provides new insight in understanding of oncogenic role of miR-224 in the lung cancer pathogenesis and suggests that NF-κB/miR-224/CASP3, 7 pathway could be a putative therapeutic target in lung cancer.