Oncotarget

Research Papers:

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, Dong-Qin Chen, Jia-Yuan Huang, Kai Zhang, Bing Feng, Ban-Zhou Pan, Jing Chen, Wei De and Long-Bang Chen _

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Oncotarget. 2014; 5:6113-6129. https://doi.org/10.18632/oncotarget.2176

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Abstract

Rui Wang1,*, Dong-Qin Chen1,*, Jia-Yuan Huang1, Kai Zhang1, Bing Feng1, Ban-Zhou Pan1, Jing Chen1, Wei De2 , Long-Bang Chen1

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.


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