COLGALT2 is overexpressed in ovarian cancer and interacts with PLOD3.
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ABSTRACT:
SUBMITTER: Guo T
PROVIDER: S-EPMC7989968 | biostudies-literature | 2021 Mar
REPOSITORIES: biostudies-literature
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COLGALT2 is overexpressed in ovarian cancer and interacts with PLOD3.
Guo Ting T Li Bin B Kang Yu Y Gu Chao C Fang Fang F Chen Xiuying X Liu Xiaocheng X Lu Guo G Feng Chenchen C Xu Congjian C
Clinical and translational medicine 20210301 3
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Project description:BackgroundMetastasis, the leading cause of cancer-related death in patients diagnosed with ovarian cancer (OC), is a complex process that involves multiple biological effects. With the continuous development of sequencing technology, single-cell sequence has emerged as a promising strategy to understand the pathogenesis of ovarian cancer.MethodsThrough integrating 10 × single-cell data from 12 samples, we developed a single-cell map of primary and metastatic OC. By copy-number variations analysis, pseudotime analysis, enrichment analysis, and cell-cell communication analysis, we explored the heterogeneity among OC cells. We performed differential expression analysis and high dimensional weighted gene co-expression network analysis to identify the hub genes of C4. The effects of RAB13 on OC cell lines were validated in vitro.ResultsWe discovered a cell subcluster, referred to as C4, that is closely associated with metastasis and poor prognosis in OC. This subcluster correlated with an epithelial-mesenchymal transition (EMT) and angiogenesis signature and RAB13 was identified as the key marker of it. Downregulation of RAB13 resulted in a reduction of OC cells migration and invasion. Additionally, we predicted several potential drugs that might inhibit RAB13.ConclusionsOur study has identified a cell subcluster that is closely linked to metastasis in OC, and we have also identified RAB13 as its hub gene that has great potential to become a new therapeutic target for OC.
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Project description:Optimal debulking followed by chemotherapy is the standard treatment of managing late-stage ovarian cancer, but chemoresistance is still a major problem. In this study, we compared expression profiles of primary tumor tissue from five long-term (>8 years) and five short-term (<2 years) ovarian cancer survivors and identified clusterin as one of the genes that were significantly up-regulated in short-term survivors. We then evaluated the prognostic significance of clusterin and its possible correlation with chemoresistance in ovarian cancer by immunohistostaining of clusterin in 62 tumor samples from patients with stage III, high-grade serous ovarian cancer. After adjusting for debulking status and age, Cox regression analyses showed that high levels of clusterin expression correlate with poor survival (hazard ratio, 1.07; 95% confidence interval, 1.002-1.443; P = .04). We also investigated clusterin in paclitaxel resistance by modulating the endogenous clusterin expression in ovarian cancer cells and treating the cells with purified clusterin. Results indicate that high-clusterin-expressing ovarian cancer cells are more resistant to paclitaxel. Moreover, exposing ovarian cancer cells to exogenous clusterin increases cells' resistance to paclitaxel. Finally, using size exclusion chromatography and fluorescently labeled paclitaxel, we demonstrated that clusterin binds to paclitaxel. In summary, our findings suggest that high levels of clusterin expression increase paclitaxel resistance in ovarian cancer cells by physically binding to paclitaxel, which may prevent paclitaxel from interacting with microtubules to induce apoptosis. Thus, clusterin is a potential therapeutic target for enhancing chemoresponsiveness in patients with a high-level clusterin expression.
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2012-09-19 | E-GEOD-26055 | biostudies-arrayexpress
Project description:IntroductionExosomal microRNA (miRNA) as a mediator of intercellular communication plays an essential part in tumor-relevant angiogenesis. Therapy against angiogenesis has been demonstrated to have a remarkable antitumor efficacy in various malignancies, but not as expected in ovarian cancer.MethodsExosomes were isolated by ultracentrifugation. Exosomal miRNA sequencing and gene function experiments were used to identify the differential expressed miRNAs in exosomes and their mRNA targets. SKOV3 cell line that stably overexpressed miR-92b-3p was constructed by lentivirus. In vitro, angiogenesis was analyzed by tube formation assay and migration assay. The angiogenic and antitumor effects in vivo were assessed in zebrafish and nude mouse models. Combination index was calculated to assess the synergetic inhibition of angiogenesis between miR-92b-3p and Apatinib. Peptides were conjugated with exosomal membranes to obtain engineered exosomes.ResultsOvarian cancer cell-derived exosomes facilitated the angiogenesis and migration capability of vascular endothelial cells in vitro and in vivo. The expression of miR-92b-3p was much lower in ovarian cancer cell-derived exosomes than that in immortalized ovarian epithelial cell-derived exosomes. The exosomal miR-92b-3p modulated tumor-associated angiogenesis via targeting SOX4. Besides, Peptide-engineered exosomes with overexpressed miR-92b-3p showed the stronger abilities of anti-angiogenesis and antitumor than parental exosomes, whether alone or combined with Apatinib.ConclusionsOur findings demonstrate the effect and mechanism of exosomal miR-92b-3p from ovarian cancer cells on tumor-associated angiogenesis and the potential of artificially generated exosomes with overexpressed miR-92b-3p to be used as anti-angiogenic agent, which may provide a new approach for anti-angiogenic therapy of ovarian cancer.
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