DNA damage responsive microRNAs misexpressed in human cancer modulate therapy sensitivity

Abstract

The DNA damage response (DDR) is activated upon DNA damage and prevents accumulation of mutations and chromosomal rearrangements, both driving carcinogenesis. Tumor cells often have defects in the DDR, which in combination with continuous cell proliferation are exploited by genotoxic cancer therapies. Most cancers, overcome initial sensitivity and develop drug resistance, e.g. by modulation of the DDR. Not much is known, however, about DNA damage responsive microRNAs in cancer therapy resistance. Therefore, we mapped temporal microRNA expression changes in primary breast epithelial cells upon low and high dose exposure to the DNA damaging agents ionizing radiation and cisplatin. A third of all DDR microRNAs commonly regulated across all treatments was also misexpressed in breast cancer, indicating a DDR defect. We repeated this approach in primary lung epithelial cells and non-small cell lung cancer samples and found that more than 40% of all DDR microRNAs was deregulated in non-small cell lung cancer. Strikingly, the microRNA response upon genotoxic stress in primary breast and lung epithelial cells was markedly different, although the biological outcome of DNA damage signaling (cell death/senescence or survival) was similar. Several DDR microRNAs deregulated in cancer modulated sensitivity to anti-cancer agents. In addition we were able to distinguish between microRNAs that induced resistance by potentially inducing quiescence (miR-296-5p and miR-382) or enhancing DNA repair or increased DNA damage tolerance (miR-21). In conclusion, we provide evidence that DNA damage responsive microRNAs are frequently misexpressed in human cancer and can modulate chemotherapy sensitivity.

MiR-593 mediates curcumin-induced radiosensitization of nasopharyngeal carcinoma cells via MDR1

“…Certain miRNAs were reported to affect the radiosensitivity of cancer cells, such as let-7, miR-21, miR-101, miR-421, and miR-181a (30)(31)(32)(33)(34). In esophageal cancer (EC), miR-593 degrades polo-like kinase 1 (PLK1) mRNA by direct binding to the 3'-UTR of PLK1 mRNA and reduced proliferation of EC cells (17).…”

Programmed cell death 2 protein induces gastric cancer cell growth arrest at the early S phase of the cell cycle and apoptosis in a p53-dependent manner

“…There are four cell cycle checkpoints, i.e., the G 1 , G 2 /M, intra-S and replication checkpoints during DNA damage (20,21). If DNA damage is beyond repair, then the cells will commit to apoptosis through induction of apoptosis pathways (22). ATM kinase could transduce DNA damage signals to checkpoint proteins.…”

Non-coding RNAs: An emerging player in DNA damage response

“…Recent studies have shown that in addition to these protein-coding genes, a subset of non-coding RNAs is also required for cellular responses to DNA damage [11,12]. To coordinate non-coding RNA-mediated DDR, DNA damage can alter the expression levels of non-coding RNAs [6,[13][14][15].…”