Novel gene rearrangement leads to altered expression of Hornerin in sensitive and chemoresistant ovarian cancer.

BACKGROUND: Hornerin (HRNR) is part of the S100-fused protein family and has been linked to poorer prognosis in various cancers, though the mechanisms remain unclear. This study aimed to explore the role of HRNR in ovarian cancer. METHODS: We conducted proteomic analysis (n = 252) and RNA sequencing (n = 96) on primary ovarian carcinomas to evaluate HRNR expression across different histotypes, survival outcomes, and to identify genetic variants in the HRNR gene. We also assessed HRNR levels in both chemosensitive and chemoresistant ovarian cancer cell lines, as well as in serum samples at different disease stages. RESULTS: Our findings revealed that HRNR levels were significantly higher in clear cell and mucinous ovarian carcinomas compared to high-grade serous carcinomas, with elevated expression associated with shorter survival. Additionally, HRNR levels increased in sera from late-stage patients compared to those in early stages. We identified several potentially harmful genetic variants in exon 3 of HRNR in patients with high-grade serous carcinoma, including a translocation of a 900 bp fragment from exon 3 to a region between exons 1 and 2. Chemoresistant ovarian cancer cells exhibited higher HRNR levels than chemosensitive cells. Silencing HRNR using siRNA markedly enhanced the cytotoxic effects on all tested ovarian cancer cells. CONCLUSIONS: HRNR plays a significant role in ovarian cancer with potential to serve as a prognostic marker. Additionally, targeting HRNR expression may offer therapeutic benefits, particularly for patients with chemoresistance or specific HRNR genetic variants, highlighting the need for further investigation in the management of ovarian cancer. SIGNIFICANCE: Hornerin (HRNR) is linked to poor prognosis in various cancers, but its role in ovarian cancer has been underexplored. Our study shows that HRNR expression is significantly higher in clear cell and mucinous ovarian carcinomas compared to high-grade serous carcinomas, correlating with shorter survival. Elevated HRNR levels in late-stage patients suggest its potential as a prognostic marker. We also identified harmful genetic variants in HRNR, including a novel translocation, which may affect disease progression. Targeting HRNR could enhance chemotherapy effectiveness, particularly for patients with HRNR genetic variants, positioning it as a promising biomarker and therapeutic target in ovarian cancer.