Project description:<p>BRCA1 mutations are a hallmark of hereditary ovarian cancer, strongly linked to deficiencies in homologous recombination (HR) DNA repair and impaired DNA replication fork protection. However, its roles in cancer progression beyond maintaining genomic integrity remain poorly understood. Through metabolomics approaches, we found BRCA1-deficiency strikingly increased choline metabolism. Loss of BRCA1 promotes choline uptake through upregulating choline transporter-like protein 4 (CTL4). BRCA1 directly binds and recruits EZH2-mediated H3K27Me3 deposition to CTL4 promoter. CTL4 was therefore overexpressed in ovarian cancer tissues with BRCA1 mutations. Furthermore, BRCA1-deficiency significantly promotes ovarian cancer invasion, while inhibition of CTL4 reverses the high metastatic potential of BRCA1-deficient ovarian cancer cells, suggesting the functionality and specificity of CTL4 as a therapeutic target. Additionally, we discovered that phosphocholine, the choline metabolite increased by CTL4 overexpression, interacted with and stabilized the epithelial-to-mesenchymal transition inducer FAM3C in BRCA1-deficient ovarian cancer cells. Importantly, we identified a potent CTL4 inhibitor, DT-13, which significantly reduces choline metabolism and effectively suppresses metastasis in BRCA1-deficient ovarian cancers. Therefore, our study uncovers a mechanism underlying metastasis in BRCA1-deficient cancers and identifies CTL4 as a therapeutic target for metastatic ovarian cancer patients with BRCA1 mutations.</p>
2026-05-15 | MTBLS12245 | MetaboLights
Project description:HRD analysis of the ovarian cancer
Project description:Ovarian cancer is a global problem, is typically diagnosed at a late stage and has no effective screening strategy. Platinum-based chemotherapy or Poly(ADP-ribose) polymerase inhibitors (PARPis) treatment are most frequently applied for ovarian cancer patients who are inoperable and in the advanced stage. The recognition of homologous recombination deficiency (HRD) as a biomarker to predict the effect of Platinum-based or PARPis treatment. WGS and WES can detect tumor HRD status but have several disadvantages which restrict their clinical application. My choice HRD CDx and Foundation Focus CDx are approved by FDA for HRD detection, however, whether they are applicable to the Chinese population or not is unknown. In this study, we created an SNP-based Tg-NGS panel to fill in gaps in Chinese patients’ HRD screening. Our results showed that the panel is cost and time-saving compared with WGS, but equivalent with SNP microarray on CNV and HRD detection. In summary, this newly developed kit is promising in clinical application to guide ovarian cancer and even other cancer types therapy.
Project description:We have sequenced miRNA libraries from human embryonic, neural and foetal mesenchymal stem cells. We report that the majority of miRNA genes encode mature isomers that vary in size by one or more bases at the 3’ and/or 5’ end of the miRNA. Northern blotting for individual miRNAs showed that the proportions of isomiRs expressed by a single miRNA gene often differ between cell and tissue types. IsomiRs were readily co-immunoprecipitated with Argonaute proteins in vivo and were active in luciferase assays, indicating that they are functional. Bioinformatics analysis predicts substantial differences in targeting between miRNAs with minor 5’ differences and in support of this we report that a 5’ isomiR-9-1 gained the ability to inhibit the expression of DNMT3B and NCAM2 but lost the ability to inhibit CDH1 in vitro. This result was confirmed by the use of isomiR-specific sponges. Our analysis of the miRGator database indicates that a small percentage of human miRNA genes express isomiRs as the dominant transcript in certain cell types and analysis of miRBase shows that 5’ isomiRs have replaced canonical miRNAs many times during evolution. This strongly indicates that isomiRs are of functional importance and have contributed to the evolution of miRNA genes
Project description:Homologous-recombination deficiency (HRD) is closely related to PARPi benefit in ovarian cancer (OC). The capacity of BRCA1 promoter methylation to predict prognosis and HRD status remains unclear. We aimed to correlate BRCA1 promoter methylation levels in patients with high-grade OC to HRD status and clinical behavior to assess its clinical relevance.