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

IF 5 2区医学 Q2 Medicine

Translational Oncology Pub Date : 2025-08-13 DOI:10.1016/j.tranon.2025.102495

Ghassan M. Saed , Harvey Sharma , Jenna Dabaja , Asad Nawaz , Ayesha Alvero , Robert T. Morris , Asma Basha , Lucas Werner , Toshima Z. Parris , Khalil Helou

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引用次数: 0

Abstract

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.

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新的基因重排导致敏感和耐药卵巢癌中Hornerin的表达改变

hornerin （HRNR）是s100融合蛋白家族的一部分，与多种癌症的不良预后有关，尽管其机制尚不清楚。本研究旨在探讨HRNR在卵巢癌中的作用。方法对原发性卵巢癌患者进行蛋白质组学分析（n = 252）和RNA测序（n = 96），以评估HRNR在不同组织型中的表达、生存结果，并鉴定HRNR基因的遗传变异。我们还评估了化疗敏感和化疗耐药卵巢癌细胞系以及不同疾病阶段血清样本中的HRNR水平。结果：与高级别浆液性癌相比，透明细胞癌和黏液性卵巢癌的HRNR水平明显更高，表达升高与生存期缩短相关。此外，与早期患者相比，晚期患者血清中HRNR水平升高。我们在高级别浆液性癌患者的HRNR外显子3中发现了几个潜在的有害遗传变异，包括从外显子3到外显子1和2之间的900 bp片段的易位。化疗耐药卵巢癌细胞的HRNR水平高于化疗敏感细胞。使用siRNA沉默HRNR可显著增强对所有卵巢癌细胞的细胞毒作用。结论shrnr在卵巢癌中有重要作用，可能作为预后指标。此外，靶向HRNR表达可能提供治疗益处，特别是对于化疗耐药或特定HRNR遗传变异的患者，这突出了在卵巢癌管理中进一步研究的必要性。hornerin （HRNR）与多种癌症的不良预后有关，但其在卵巢癌中的作用尚未得到充分探讨。我们的研究表明，与高级别浆液性癌相比，HRNR在透明细胞癌和黏液性卵巢癌中的表达明显更高，与较短的生存期相关。晚期患者HRNR水平升高提示其作为预后指标的潜力。我们还发现了HRNR中有害的遗传变异，包括一种可能影响疾病进展的新型易位。靶向HRNR可以提高化疗效果，特别是对于HRNR基因变异的患者，将其定位为卵巢癌中有前景的生物标志物和治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Translational Oncology ONCOLOGY-

CiteScore

8.40

自引率

2.00%

发文量

314

审稿时长

54 days

期刊介绍： Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.