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  2. MicroRNA-140 impedes DNA repair by targeting FEN1 and enhances chemotherapeutic response in breast cancer

MicroRNA-140 impedes DNA repair by targeting FEN1 and enhances chemotherapeutic response in breast cancer

  • Oncogene. 2020 Jan;39(1):234-247. doi: 10.1038/s41388-019-0986-0.
Xiao Lu 1 Rui Liu 1 Meina Wang 1 Alagamuthu Karthick Kumar 1 Feiyan Pan 1 Lingfeng He 1 Zhigang Hu 2 Zhigang Guo 3
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing, 210023, China.
  • 2 Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing, 210023, China. huzg_2000@126.com.
  • 3 Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing, 210023, China. guo@njnu.edu.cn.
Abstract

An increased DNA repair capacity is associated with drug resistance and limits the efficacy of chemotherapy in breast cancers. Flap Endonuclease 1 (FEN1) participates in various DNA repair pathways and contributes to Cancer progression and drug resistance in chemotherapy. Inhibition of FEN1 serves as a potent strategy for Cancer therapy. Here, we demonstrate that microRNA-140 (miR-140) inhibits FEN1 expression via directly binding to its 3' untranslated region, leading to impaired DNA repair and repressed breast Cancer progression. Overexpression of miR-140 sensitizes breast Cancer cells to chemotherapeutic agents and overcomes drug resistance in breast Cancer. Notably, ectopic expression of FEN1 abates the effects of miR-140 on DNA damage and the chemotherapy response in breast Cancer cells. Furthermore, the transcription factor/repressor Ying Yang 1 (YY1) directly binds to the miR-140 promoter and activates miR-140 expression, which is attenuated in doxorubicin resistance. Our results demonstrate that miR-140 acts as a tumor suppressor in breast Cancer by inhibiting FEN1 to repress DNA damage repair and reveal miR-140 to be a new anti-tumorigenesis factor for adjunctive breast Cancer therapy. This novel mechanism will enhance the treatment effect of chemotherapy in breast Cancer.

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