Down-regulation Of Dicer1 Expression Leads To Platinum Resistance In Ovarian Cancer

?Objectives?The mortality rate of epithelial ovarian cancer ranks first in female reproductive system tumors.Most patients are diagnosed with advanced stage diseases at the time of treatment.Although most patients can be relieved after treatment of debulking surgery plus platinum-based chemotherapy,they will still face recurrence and relapse,which leads to a very poor prognosis.For years,the treatment of ovarian cancer has become a major dilemma for doctors.So it is urgent and necessary to explore new treatment methods.In this study,we investigate the relationship between the expression level of Dicer1,an important molecule for microRNA processing,and platinum resistance in ovarian cancer,to enrich the theory of ovarian cancer resistance,and to provide new ideas for the treatment of ovarian cancer.?Methods]?The main methods of this study are as follows: The data of 168 patients with epithelial ovarian cancer diagnosed by Tongji Hospital from 2005 to 2013 are selected.Firstly,analyze the patients' data to find whether there is the correlation between Dicer1 expression level(the expression level of Dicer1 was detected by immunohistochemistry)and drug resistance as well as prognosis,and to verify it in ovarian cancer cell lines.Secondly,analyze the mRNA level of Dicer1 according to the date of patients diagnosed with high-grade serous ovarian cancer from TNE CANCER GENOME ATLAS(TCGA)Database.Gene Set Enrichment Analysis is used to enrich genes associated with the expression of Dicer1.Thirdly,verify the results of gene enrichment analysis by the ways of RT-qPCR and Western Blot in Ovarian cancer cell.MicroRNAs associated with Dicer1 are obtained by intersecting of Dicer1 expression-related microRNAs in TCGA database and miRNA target gene prediction database;lastly,demonstrate that Dicer1 and the regulatory genes can lead to platinum resistance in ovarian cancer cell lines and in animals.?Results?(1)Analysis combined Dicer1 expression with platinum resistance showed that platinum resistance was significantly associated with low expression of Dicer1.Additionally,low expression of Dicer1 was significantly associated with progression-free survival(PFS)and overall survival(OS).The result of platinum resistance was also terrified in ovarian cancer cell line OVCAR3;(2)The genes involved in differential level of Dicer1 in epithelial ovarian cancer patients in TCGA data were significantly associated with mitochondrial function,such as oxidative phosphorylation which was also verified in OVCAR3 cells;(3)Low expression of Dicer1 resulted in increased expression of mitochondrial function-regulated gene PGC-1?.Mir148 b was picked out by TCGA database and recognized miRNA targeting prediction software to associated with Dicer1 and PGC-1?.(4)Finally,we showed that down-regulation of Dicer1 can lead to cisplatin resistance through PGC-1?In vitro and in vivo.?Conclusion? Down-regulation of Dicer1 reduces the production of mir148 b,resulting in up-regulation of PGC-1?expression and finally ovarian cancer resistance to cisplatin.This study reveals another mechanism of platinum resistance,and it is expected that new ovarian cancer treatment strategies will be proposed to improve patient outcomes.