LINC00467 Mediates PARP Inhibitor Resistance in High-grade Serous Ovarian Cancer by Regulating miR-485-5p/RAD50 axis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA859672 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:To investigate the essential gene associated with PARP inhibitor response， we established PARP inhibitor resistance SKOV3 cell line and RNA-seq was performed to confirm the differentially expressed gene
2025-07-01 | GSE208356 | GEO
Project description:Immune checkpoint inhibitors (ICIs) have revolutionized treatment for several tumor indications without demonstrated benefit for ovarian cancer patients. To improve the therapeutic ratio of ICIs in ovarian cancer patients, several different clinical trials are testing combinations with poly (ADP-ribose) polymerase (PARP) inhibitors. Comparing the immunomodulatory effects of clinically advanced PARP inhibitors may help to identify the best partner to combine with ICIs. We examined the treatment effect of talazoparib (a PARP trapper) and veliparib (a solely PARP enzymatic inhibitor) in homologous recombination deficient (HRD) and homologous recombination proficient (HRP) high-grade serous tubo-ovarian carcinoma (HGSC) cell lines on immune-related gene expression. We discovered and validated that CXCL8, IL-6, and TNF gene expression were upregulated after talazoparib treatment in both OVCAR3 (HRD) and CAOV3 (HRP) HGSC cell lines. In contrast, veliparib treatment slightly elevated similar genes exclusively in a HRD HGSC cell line model. We expanded these studies to include olaparib, a PARP trapper less potent than talazoparib, and found effects specific to COV361 (BRCA1 mutant) and OVCAR8 (BRCA1 methylated) HGSC cells but not all HRD HGSC cell lines. Our studies also identified differences among PARP trappers versus veliparib on augmenting CXCL10 expression. Finally, we show that talazoparib modulates the CXCL10 response in cGAS-defective cell lines, independent of the cGAS-STING pathway. These mechanistic studies advance our understanding of how different PARP inhibitors affect the immune system in various genetic backgrounds.
2025-01-03 | GSE285827 | GEO
Project description:Ovarian high-grade serous carcinoma (HGSC) is the most common and lethal subtype of ovarian cancer with limited therapeutic options. In recent years, PARP inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Therapies disrupting the spliceosome alter cancer transcriptomes and have shown potential to improve PARP inhibitor response. Indisulam (E7070) has been identified as a molecular glue that brings splicing factor RBM39 and DCAF15 E3 ubiquitin ligase in close proximity. Exposure to indisulam induces RBM39 proteasomal degradation through DCAF15-mediated polyubiquitination and subsequent RNA splicing defects. In this study, we demonstrate that loss of RBM39 induces splicing errors in DNA damage repair genes in ovarian cancer, leading to increased sensitivity to PARP inhibitors such as olaparib. Indisulam synergized with olaparib in multiple in vitro models of ovarian cancer regardless of PARP inhibitor sensitivity and improved olaparib response in mice bearing PARP inhibitor-resistant tumors. DCAF15 expression, but not BRCA1/2 mutational status, was essential for the synergy between indisulam and olaparib, suggesting that the combination therapy may benefit patients irrespective of their BRCA1/2 status. These findings demonstrate that combining RBM39 degraders and PARP inhibitors is a promising therapeutic approach to improving PARP inhibitor response in ovarian HGSC
2023-01-22 | GSE223011 | GEO
Project description:Estrogen is an important hormone that affects muscle development in female animals. Previous studies have shown that estrogen can protect muscle cells from apoptosis by inhibiting the MAPK signaling pathway. However, the molecular mechanisms by which estrogen-induced MAPK signaling regulates myoblast growth and development remain unclear. In this study, RNA-seq was performed on ovariectomized small-tailed Han (OR-STH) sheep and sham surgery small-tailed Han (STH) sheep to analyze the effects of estrogen on muscle growth and development in female animals. There were 8,721 differentially expressed circRNAs (DECs), 143 differentially expressed miRNAs (DEMs) and 2,238 differentially expressed mRNAs (DEGs) in the longissimus dorsi between the OR-STH and STH groups. Bioinformatics analysis revealed that the differentially expressed gene MAPK15 was significantly enriched in the MAPK signaling pathway, which is important for muscle development. Therefore, we constructed the ceRNA network circFAM171A1/oar-miR-485-5p/MAPK15 and explored its effect on muscle growth and development. The results of the molecular mechanism experiments indicated that circFAM171A1 can sponge oar-miR-485-5p to regulate MAPK15. The addition of the exogenous hormone estradiol (E2) to sheep myoblasts could induce circFAM171A1, regulate the expression of oar-miR-485-5p and MAPK15, and promote the proliferation of sheep myoblasts. The results showed that MAPK15 and circFAM171A1 significantly promoted the proliferation of myoblasts and inhibited the apoptosis of myoblasts in sheep, whereas oar-miR-485-5p inhibited the expression of MAPK15 and circFAM171A1, inhibited myoblast proliferation and promoted apoptosis. Furthermore, circFAM171A1 attenuated the inhibitory effect of oar-miR-485-5p on myoblasts. In summary, estrogen induced the expression of circFAM171A1 in sheep myoblasts, and circFAM171A1 can act as a sponge for oar-miR-485-5p to promote the expression of the target gene MAPK15 and ultimately regulate the proliferation of sheep myoblasts. This study provides new insights into the molecular mechanism of estrogen regulation of muscle growth and development in female animals.
2025-03-26 | GSE288804 | GEO
Project description:Characterization of a RAD51C-Silenced High Grade Serous Ovarian Cancer Model During PARP Inhibitor Resistance Development
| PRJNA693039 | ENA
Project description:Ovarian cancer is the most lethal gynecologic cancer. High-grade serous ovarian carcinoma (HGSOC) is the most common histologic subtype, accounting for three quarters of ovarian cancer. To clarify the changes of gene expression in serous ovarian cancer, we performed lncRNA and mRNA microarrays to identify differentially expressed lncRNAs and mRNAs in High-grade and Low-grade serous ovarian carcinoma compared with Normal fallopian tube.
2020-02-12 | GSE135886 | GEO
Project description:PARP inhibitors differentially regulate immune responses in distinct genetic backgrounds of high-grade serous tubo-ovarian carcinoma
| PRJNA1206162 | ENA
Project description:Low-grade serous ovarian carcinomas are typically Ras-pathway mutated, TP53 wild-type, have limited chromosomal aberration, and are frequently associated with borderline tumors. By contrast, high-grade serous ovarian carcinoma lack Ras-pathway mutations, are invariably TP53 mutated, show widespread genomic change, and are commonly BRCA-pathway disrupted. We sought to identify differences in genomic copy number changes between co-existing borderline and invasive components of serous carcinoma. Paired co-existing borderline and invasive tumor components of ovarian serous carcinoma were sampled and profiled from tumors from 7 patients
2014-10-01 | E-GEOD-57279 | biostudies-arrayexpress
Project description:In this study, we performed miRNA profiles analysis of high-grade serous ovarian carcinoma compared to normal fallopian tube fimbria using microarray (Exiqon, Denmark) to evaluate their potential role in the pathogenesis of uterine leiomyoma. miRNA profiling analysis of the 10 samples including 5 high-grade serous ovarian carcinomas and 5 normal fallopian tube fimbria.
2014-11-14 | E-GEOD-61485 | biostudies-arrayexpress
Project description:Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed. Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed. Gene expression analysis was performed on five serous borderline tumors with BRAF mutation and five serous borderline tumors without BRAF mutation randomly. RNA was extracted from microdissected tumor cells. Expression profiling was carried out with Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays
2011-03-04 | E-GEOD-27659 | biostudies-arrayexpress