Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide. Although chemotherapy is used as a palliative treatment, ultimately, nearly all patients develop drug resistance. Therefore, the cell-inherent DNA repair pathway must reverse the DNA-damaging effect of cytotoxic drugs that mediates therapeutic resistance to chemotherapy. RAD18, a DNA damage-activated E3 ubiquitin ligase, is known to play a critical role in DNA damage repair in cancer cells. Here, we show that RAD18 is highly expressed in human 5-fluorouracil (5-FU)-resistant cancer cells after 5-FU treatment. In addition, RAD18 increases in CRC cells could induce DNA damage repair, suggesting that RAD18 might be a possible target for overcoming drug resistance. Moreover, the expression of tumor suppressor microRNA-145 (miR-145) was negatively correlated with RAD18 expression in CRC tissues of 140 patients. Using luciferase reporters carrying the 3′-untranslated region of RAD18 combined with Western blotting, we identified RAD18 as a direct target of miR-145. Also of interest, suppression of RAD18 by miR-145 enhanced DNA damage in CRC cells after 5-FU treatment. Finally, the 5-FU-resistant cancer cells could be selectively ablated by treatment with miR-145. Taken together, these results suggest that miR-145 can act as an RAD18 inhibitor and contribute as an important factor in reversing drug resistance after chemotherapy.
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Acknowledgments
The authors thank Dr. Wen-Jun Wang for her support and assistance with the preparation of the manuscript.
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No potential conflicts of interest were disclosed.
Authors’ contributions
Wei-Dong Li conceived and designed the experiments. Ye Dong and Yan-Zhen Deng performed the experiments. Ye Dong and Yan-Zhen Deng analyzed the data. Ye Dong, Wen-Jun Wang, and Wei-Dong Li wrote the paper.
Grant support
This study was supported by grants from the National Natural Science Foundation of China (no. 81301939). The costs of publication of this article were defrayed in part by the payment of page charges.
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Rui-Lei Liu and Ye Dong contributed equally to this work.
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Liu, RL., Dong, Y., Deng, YZ. et al. Tumor suppressor miR-145 reverses drug resistance by directly targeting DNA damage-related gene RAD18 in colorectal cancer. Tumor Biol. 36, 5011–5019 (2015). https://doi.org/10.1007/s13277-015-3152-5
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DOI: https://doi.org/10.1007/s13277-015-3152-5