Acquisition of radioresistance in docetaxel-resistant human lung adenocarcinoma cells is linked with dysregulation of miR-451/c-Myc-survivin/rad-51 signaling

// Rui Wang 1,* , Dong-Qin Chen 1,* , Jia-Yuan Huang 1 , Kai Zhang 1 , Bing Feng 1 , Ban-Zhou Pan 1 , Jing Chen 1 , Wei De 2 , Long-Bang Chen 1 1 Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, China 2 Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 210002, China * Co-first authors Correspondence: Long-Bang Chen, email: // Keywords : lung adenocarcinoma, chemoresistance, radioresistance, miR-451, c-Myc, rad-51, survivin Received : May 26, 2014 Accepted : July 05, 2014 Published : July 07, 2014 Abstract Chemoresistant tumors usually fail to respond to radiotherapy. However, the mechanisms involved in chemo- and radiotherapy cross resistance are not fully understood. Previously, we have identified microRNA (miR)-451 as a tumor suppressor in lung adenocarcinoma (LAD). However, whether miR-451 plays critical roles in chemo- and radiotherapy cross resistance in LAD is unclear. Here, we established two docetaxel-resistant LAD cell models (SPC-A1/DTX and H1299/DTX), and showed that miR-451 was significantly downregulated in docetaxel-resistant LAD cells. Gain - and loss - of - function assays indicated that re-expression of miR-451 could reverse radioresistance of docetaxel-resistant LAD cells both in vitro and in vivo through promoting apoptosis and DNA double-strand breaks (DSBs). The proto-oncogene c-Myc was identified as a direct target of miR-451, and re-expression of miR-451 inhibited survivin and rad-51 expression by reducing the amount of c-Myc protein binding to their promoters. Silencing of c-Myc could phenocopy the effects of miR-451 upregulation, and restoration of c-Myc could partially rescue the effect of miR-451 upregulation on radiosensitivity of docetaxel-resistant LAD cells. Therefore, dysregulation of miR-451/c-Myc-survivin/rad-51 signaling is responsible for radioresistance of docetaxel-resistant LAD cells, and targeting it will be a potential strategy for reversing chemo- and radiotherapy cross resistance of LAD patients.