Abstract 5148: Plakophilin 3 and ovarian cancer progression: Functional transition from early expression to advanced-state regulation through RB and STAT3 pathways

Abstract Background: Ovarian cancer (OC) is a heterogeneous disease with a high mortality rate and poor prognosis, primarily due to late-stage diagnosis. The identification of reliable biomarkers is crucial for improving patient outcomes. Plakophilin 3 (PKP3) is often overexpressed in cancers, yet its role in OC remains poorly understood. Methods: We performed immunohistochemistry with tissue microarray, including normal (n=39), benign (n=66), borderline (n=44), and ovarian cancer (n=187), and analyzed clinical and survival rates according to the expression of PKP3. Either lacking or overexpressing PKP3 in immortalized normal cell and OC cell lines, we measured cell proliferation, cell cycle, and migration. Molecule change associated them checked western blot and qRT-PCR. Additionally, cellular localization of PKP3 in cancer cells was confirmed via cell fraction and immunofluorescence. Results: The expression levels of PKP3 in OC are higher than in normal and benign tissues; notably, PKP3 shows the highest expression in stage I compared to other stages. Analysis of overall and disease-free survival revealed that patients with high PKP3 expression had a better prognosis than those with low PKP3 expression. Overexpression of PKP3 in immortalized normal cell lines led to increased cell growth. The depletion of PKP3 in OC cells triggered G1 cell cycle arrest. This was achieved through the attenuation of retinoblastoma (RB) protein phosphorylation and suppression of E2F1 target gene expression, ultimately resulting in reduced cell growth. Although PKP3 depletion decreased OC cell growth, it paradoxically increased cell migration. This increase in migration was mediated by the activation of STAT3. Regulation of RB and STAT3 activation by PKP3 was confirmed to occur in the nucleus. We found that alteration of PKP3 expression in normal and OC ultimately regulates the progression of OC. Conclusion: PKP3 promotes the initiation of OC by driving cell growth, and in advanced stages, its reduced expression is associated with increased epithelial-mesenchymal transition (EMT), leading to a worse prognosis. This study suggests that PKP3 could serve as a biomarker for early diagnosis and that targeting the PKP3-STAT3 axis may offer new therapeutic opportunities for OC. Citation Format: Ha-Yeon Shin, JueYoung Kim, Jae-Hoon Kim. Plakophilin 3 and ovarian cancer progression: Functional transition from early expression to advanced-state regulation through RB and STAT3 pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5148.