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CRISP3, a potential tumor suppressor, inhibits the progression of high-grade serous ovarian carcinoma by modulating the PI3K/AKT pathway

ABSTRACT: Background: Ovarian cancer (OC) remains the most common cause of gynecological cancer-related death, and about 70% of the deaths are from advanced high-grade serous ovarian cancer (HGSOC). Cysteine-rich secretory protein 3 (CRISP3) is related to various human diseases, however, the roles and mechanisms of CRISP3 in HGSOC remain unclear. Methods: The clinical significance of CRISP3 in patients with OC was analyzed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases. CRISP3 ex-pression in OC tissues was validated by RNA-sequencing (RNA-seq), quantitative PCR, and immuno-histochemistry. Furthermore, we explored the effect of CRISP3 expression modulation on the biological be-havior of HGSOC through CCK-8, EdU, and transwell assays in vitro and the differences of CRISP3 during the progression of HGSOC in vivo. We utilized RNA-seq, GSEA and Western blotting to detect CRISP3's regulatory mechanisms. Finally, we employed data from the IMvigor210 cohort and TCGA to assess the correlation of CRISP3 with clinical response to immunotherapy, and the landscape of immune cell infiltra-tion. Results: CRISP3 expression was markedly reduced in HGSOC. In vitro studies demonstrated that CRISP3 knockdown significantly enhanced proliferation, migration, and invasion of HGSOC cells, whereas its overexpression suppressed these malignant phenotypes. Moreover, CRISP3 expression was found to be downregulated during OC progression in vivo. Mechanistically, CRISP3 acted as a tumor suppressor through the PI3K/AKT signaling pathway to inhibit the progression and metastasis of HGSOC. Addition-ally, we observed an association between CRISP3 expression and CD8⁺ T cells, macrophages, neutrophil and Th1 cells infiltration. Conclusions: We demonstrate that CRISP3 suppresses tumorigenesis in HGSOC by regulating the PI3K/AKT pathway, and that its expression alterations correlate with disease progression, supporting its utility as a biomarker.

ORGANISM(S): Homo sapiens

PROVIDER: GSE316844 | GEO | 2026/03/04

REPOSITORIES: GEO

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Project description:Background: The preferred site of metastasis in ovarian cancer (OC) is the fat-rich omentum. The interaction between cancer cells and adipocytes induces transcriptomic changes driving an invasive and pro-metastatic phenotype. Here we studied the effects of the OC cell-adipocyte crosstalk by using direct co-culture with immortalized human visceral pre-adipocytes and OC cells. Methods: OVCAR5 or OVCAR8 OC cells expressing either GFP or RFP were co-cultured with matured immortalized visceral pre-adipocyte (VNPAD). After direct co-culture, OC cells were FACS-sorted and cell proliferation, invasiveness, resistance to cisplatin were assessed. RNA-sequencing determined transcriptomic changes induced by co-culture. Immunohistochemistry (IHC) and ELISA measured C3 expression in metastatic tumors and in malignant ascites. Results: Direct co-culture with VNPAD led to increased proliferation, invasiveness and resistance to cisplatin of OC cells compared to monoculture. RNA-sequencing revealed 205 differentially expressed genes (DEGs) common to both VNPAD co-cultured OVCAR5 and OVCAR8 cells and enriched pathways such as PI3K/AKT and complement activation. Co-culture induced lipid transfer into OC cells promoted upregulation of complement C3 and C5 units, as measured at mRNA and protein levels. C3 or C5 inhibition reverted the invasive phenotype of OC cells and C3 knockdown reduced tumor progression in a xenograft model. Increased C3 expression was detected in metastatic vs. primary ovarian tumors (p<0.0001) and increased C3 secretion was observed in ascites from women with BMI > 25 (p = 0.01). C3 upregulation in OC cells was driven through activation of stress response pathway regulated by ATF4. Conclusions: Co-culture of adipocytes and cancer cells drives an invasive and chemo-resistant phenotype. These changes are induced by transfer of lipids from adipocytes to cancer cells causing activation of the complement proteins C3, C5, and of the integrated stress response pathway.

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CRISP3, a potential tumor suppressor, inhibits the progression of high-grade serous ovarian carcinoma by modulating the PI3K/AKT pathway

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