MicroRNA-140 Enhances Breast Cancer Chemotherapy By Targeting FEN1

Nowadays,the number of people with cancer is increased in the world.Cancer has seriously affected human health.As one of the three major diseases in the world,cancer has become the focus of current medical research due to its high pathogenicity and high lethality.The current study shows that in cancer cells were found to aggravate DNA damage.In order to deal with damage in the cell,there are many DNA damage repair systems,so the research of DNA damage repair system is particularly important.Base ExcisionRepair-Repair(BER)is a widespread repair system in cells.FEN1 is a key rate-limiting enzyme in BER system.FEN1 as a structure specific and metal endonuclease takes part in DNA replication and DNA damage repair.In the process of DNA replication,FEN1 can mature Okazaki fragments.FEN1 is involved in the long patch base excision repair in the process of base excision repair(BER).In addition,FEN1 also can maintain the stability of gene and telomere.Studies have shown that FEN1 is associated with the development of cancer.We found that FEN1 is highly expressed in different tumors and lowly expressed in normal cells.Inhibition FEN1 expression can slow cell growth and proliferation.Also,it can enhance the sensitivity to chemotherapeutic drugs.This suggested that targeting FEN1 can be a promising biotherapyMicroRNA(miRNA)is a group of small non-codingRNA(18-25 nucleotides length),can regulate biological processes by regulating its target genes.A miRNA can regulate a variety of downstream target genes,this feature of miRNA give it functional diversity.Due to the small molecular properties of miRNA,it is often used as a tumor therapy drug and targeted therapy for related tumors.Elevated 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 of chemotherapy.Inhibition of FEN1 serves as a potent strategy for cancer therapy.Here,we demonstrate that microRNA-140(miR-140)inhibited FEN1 expression via direct binding to its 3' untranslated region,leading to impaired DNA repair and repressing breast cancer progression.Overexpression of miR-140 sensitizes breast cancer cells to chemotherapeutic agents and overcomes drug resistance in breast cancer.Of note,ectopic expression of FEN1 could abate the effect of miR-140 on DNA damage and chemotherapy response in breast cancer cells.Furthermore,the transcription factor/repressor Ying Yang1(YY1)directly binds to the miR-140 promoter and activates miR-140 expression,which was attenuated in the doxorubicin resistance condition.Our results demonstrate that miR-140 acts as a tumor suppressor in breast cancer through inhibiting FEN1 to repress DNA damage repair and reveal miR-140 to be a new anti-tumorigenesis factor for adjunctive therapy of breast cancer.This novel mechanism would enhance the treatment effect of chemotherapy in breast cancer.