Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing, 210023, China.
Oncogene. 2020 Jan;39(1):234-247. doi: 10.1038/s41388-019-0986-0. Epub 2019 Aug 30.
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.
DNA 修复能力的增强与耐药性有关，并限制了化疗在乳腺癌中的疗效。核酸内切酶 1（FEN1）参与多种 DNA 修复途径，并促进癌症的进展和化疗耐药性。FEN1 的抑制作用是癌症治疗的一种有效策略。在这里，我们证明 microRNA-140（miR-140）通过直接与其 3'非翻译区结合来抑制 FEN1 的表达，导致 DNA 修复受损和乳腺癌进展受到抑制。miR-140 的过表达使乳腺癌细胞对化疗药物敏感，并克服乳腺癌的耐药性。值得注意的是，FEN1 的异位表达减弱了 miR-140 对乳腺癌细胞中 DNA 损伤和化疗反应的影响。此外，转录因子/抑制剂 Ying Yang 1（YY1）直接与 miR-140 启动子结合并激活 miR-140 的表达，而在阿霉素耐药时则减弱。我们的研究结果表明，miR-140 通过抑制 FEN1 抑制 DNA 损伤修复，在乳腺癌中发挥肿瘤抑制作用，并揭示 miR-140 是一种新的辅助乳腺癌治疗的抗肿瘤因子。这种新的机制将增强乳腺癌化疗的治疗效果。
