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Tumor Biology

, Volume 36, Issue 7, pp 5011–5019 | Cite as

Tumor suppressor miR-145 reverses drug resistance by directly targeting DNA damage-related gene RAD18 in colorectal cancer

  • Rui-Lei Liu
  • Ye Dong
  • Yan-Zhen Deng
  • Wen-Jun Wang
  • Wei-Dong Li
Research Article

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.

Keywords

miR-145 Colorectal cancer DNA damage Drug resistance RAD18 

Notes

Acknowledgments

The authors thank Dr. Wen-Jun Wang for her support and assistance with the preparation of the manuscript.

Conflicts of Interest

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.

Supplementary material

13277_2015_3152_MOESM1_ESM.doc (34 kb)
Supplementary Methods (DOC 33 kb)
13277_2015_3152_MOESM2_ESM.xls (18 kb)
Table S1 (XLS 17 kb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Rui-Lei Liu
    • 1
  • Ye Dong
    • 1
  • Yan-Zhen Deng
    • 1
  • Wen-Jun Wang
    • 2
  • Wei-Dong Li
    • 1
  1. 1.Department of the First MedicineCancer Hospital of Guangzhou Medical CollegeGuangzhouChina
  2. 2.State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory DiseaseThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina

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