# CRISP3, a Potential Tumor Suppressor, Inhibits the Progression of High-Grade Serous Ovarian Carcinoma by Modulating the PI3K/AKT Pathway

## TL;DR

CRISP3 is a tumor suppressor that inhibits high-grade serous ovarian cancer by regulating the PI3K/AKT pathway and is linked to immune cell infiltration.

## Contribution

This study identifies CRISP3 as a novel tumor suppressor in HGSOC and reveals its role in modulating the PI3K/AKT pathway and immune cell infiltration.

## Key findings

- CRISP3 expression is reduced in HGSOC and its knockdown increases cancer cell proliferation and invasion.
- CRISP3 acts as a tumor suppressor by modulating the PI3K/AKT pathway.
- CRISP3 expression correlates with immune cell infiltration, including CD8+ T cells and macrophages.

## Abstract

Background: Ovarian cancer (OC) remains the most common cause of gynecological cancer-related death, and about 70% of these 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 expression in OC tissues was validated by RNA-sequencing (RNA-seq), quantitative PCR, and immunohistochemistry. Furthermore, we explored the effect of CRISP3 expression modulation on the biological behavior of HGSOC through CCK-8, EdU, and Transwell assays in vitro, and the differences in 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 infiltration. 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. Additionally, we observed an association between CRISP3 expression and CD8+ T cell, macrophage, neutrophil and Th1 cell infiltration. Conclusions: We demonstrate that CRISP3 suppresses tumorigenesis in HGSOC by regulating the PI3K/AKT pathway, and that alterations in its expression correlate with disease progression, supporting its utility as a biomarker.