Introduction The inhibitor of PARP (PARPi) is one of the most concerned drugs recently. Since both PARPi and platinum act through DNA damage, we intend to find targets for overcoming PARPi resistance through the differences of gene expression between platinum-resistant and platinum-sensitive ovarian patients in TCGA.
Methods We divided ovarian cancer patients in TCGA into platinum-sensitive and platinum-resistant groups and conducted differential gene analysis on them. MTT assay was used to draw the drug concentration tolerance curve of ovarian cancer cells. The effect of PART1 on cell growth was detected by EdU and CCK8 assays. Western blot was used to detect the effect of PART1 on DNA damage repair pathway. The effect of PART1 on PARPi sensitivity in vivo was verified by subcutaneous tumor formation in nude mice . RNA-seq was conducted to analyse the changes of gene and pathways.
Results LncRNA PART1 was significantly down-regulated in platinum-resistant patients in TCGA. CCK8 assays indicated knockdown of PART1 could confer resistance of cisplatin and olaparib on ovarian cancer cells. Cell proliferation was restricted after PART1 knockdown. Western blot experiments showed that PART1 played a role by inactivating the DNA damage response pathway. Subcutaneous tumor formation experiments verified that PART1 can enhance the sensitivity of cells to olaparib and promote proliferation in vivo. The RNA-seq results showed that DNA damage response pathway was significantly activated by PART1 knockdown.
Conclusion/Implications LncRNA PART1 augments PARPi sensitivity in ovarian cancer by inactivating DNA damage response pathway.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.