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

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.