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

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.

MiR-320a effectively suppresses lung adenocarcinoma cell proliferation and metastasis by regulating STAT3 signals

“…8,9 The present study investigated the roles of miR320a in the proliferation of lung cancer cells, and found that overexpression of miR-320a enhanced the apoptosis of lung adenocarcinoma cells induced by irradiation in vitro and in vivo. Moreover, miR-320a significantly inhibited lung adenocarcinoma cell proliferation and migration by directly regulating STAT3 signals, which was supported by zhao et al, who found that miR-320a plays a critical role in invasion and metastasis of colorectal cancer by regulating Rac1 gene.…”

“…Furthermore, miR-451 can promote radioresistance of cancer cell apoptosis by directly targeting c-Myc. 9 MiR-320a is reported to be deregulated in many malignancy types. Recent studies indicated miR-320a inhibited gastric cancer cell proliferation by downregulating FoxM1 10 and suppressed cancer metastasis by directly targeting metadherin.…”

Exosome-derived microRNAs contribute to prostate cancer chemoresistance

“…miR-451 in this study following qPCR validation demonstrated a significant change in exosome derived from chemoresistance PCa cells as compared to their parental cells. In contrast, miR-451 was downregulated in docetaxelresistant lung adenocarcinoma cells (22). However, miR-451 was upregulated in multidrug-resistant (MDR) human ovarian cancer cell line (A2780DX5) and human cervix carcinoma cell line (KB-3-1), compared with their parental lines.…”

The Emerging Role and Promise of Long Noncoding RNAs in Lung Cancer Treatment

“…MiR-145 and miR-224 are reported to confer the chemoresistance of lung adenocarcinoma cells to cisplatin (CDDP) via delaying the progression of the cell cycle from G1 to S phase [13,14]. In addition, miR-650 has been shown as a potential target for chemosensitizing lung adenocarcinoma cells to DTX and of interest, miR-451 play a role in both DTX or CDDP resistance and radioresistance [15,16]. These results clearly suggest that dysregulation of miRNAs is associated with the resistance of lung cancer to anti-cancer therapies have been reported.…”