HE4 Silence Combined with DDP in the Treatment of Ovarian Cancer, Especially Platinum-resistant Ovarian Cancer.

IF 2.5 4区医学 Q3 ONCOLOGY

Current cancer drug targets Pub Date : 2026-08-10 DOI:10.2174/0115680096428971260308193220

Yaxin Zuo, Ruiqin Wang, Yunshu Xu, Xiaodan Zhang, Chunhong Chen, Yanling Gong, Meixing Yan, Dan Hu

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引用次数: 0

Abstract

Introduction: Ovarian cancer (OC) is the most lethal gynecological malignancy. Human epididymis protein 4 (HE4) is a secreted glycoprotein serving as a clinical OC biomarker. This study aimed to employ RNAi technology to silence HE4 gene expression, combined with cisplatin (DDP), to explore the effects on the OVCAR-3 cell line and its cisplatin-resistant counterpart.

Methods: The cisplatin-resistant cell line OVCAR-3/DDP was established via stepwise dose escalation. RT-qPCR and Western blot were used to detect the expression of HE4, JAK2, STAT3, and ERK1/2 genes and proteins in HOSEpiC, OVCAR-3, and OVCAR-3/DDP. The effects of HE4 siRNA combined with cisplatin on the proliferation, migration, invasion, and apoptosis of OC cells were evaluated, and the effects on gene and protein expression in cells were detected.

Results: HE4 was significantly upregulated in OVCAR-3, especially in OVCAR-3/DDP. Knockdown of HE4 inhibited the proliferation, migration, and invasion of OC cells, promoted cell apoptosis, and increased the sensitivity of drug-resistant cells to DDP. The combined application of HE4 siRNA and DDP was more effective than single-drug treatment. Mechanistically, knockdown of HE4 reduced the mRNA levels of JAK2, STAT3, ERK1/2, and the phosphorylation levels of their proteins. suggesting involvement of these pathways. However, the synergy with cisplatin likely also involves constraining cancer cell plasticity, a key adaptive resistance mechanism.

Discussion: Platinum-resistant OC has limited treatment options, posing a major clinical challenge. HE4 siRNA, especially when combined with DDP, shows therapeutic potential for OC, particularly platinum-resistant OC-this is linked to the inhibition of JAK/STAT3 and ERK1/2 signaling after HE4 silencing. Future research should clarify pathway-related genes to deepen the understanding of HE4's mechanisms in OC. Additionally, optimizing the delivery strategy of HE4 siRNA remains a key focus for its clinical translation.

Conclusion: HE4 may regulate tumor progression and drug resistance by activating the JAK/STAT and MAPK pathways, holding promise as a new target for OC treatment. The combined application of HE4 siRNA and DDP may provide a new treatment option for OC.

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HE4沉默联合DDP治疗卵巢癌，特别是铂耐药卵巢癌

卵巢癌（OC）是最致命的妇科恶性肿瘤。人附睾蛋白4 （HE4）是一种分泌糖蛋白，可作为临床OC生物标志物。本研究旨在采用RNAi技术沉默HE4基因表达，联合顺铂（DDP），探讨对OVCAR-3细胞系及顺铂耐药细胞系的影响。方法：采用逐步剂量递增的方法建立顺铂耐药细胞系OVCAR-3/DDP。采用RT-qPCR和Western blot检测HOSEpiC、OVCAR-3和OVCAR-3/DDP中HE4、JAK2、STAT3、ERK1/2基因和蛋白的表达。观察HE4 siRNA联合顺铂对OC细胞增殖、迁移、侵袭和凋亡的影响，并检测对细胞中基因和蛋白表达的影响。结果：HE4在OVCAR-3中显著上调，尤其是在OVCAR-3/DDP中。下调HE4可抑制OC细胞的增殖、迁移和侵袭，促进细胞凋亡，增加耐药细胞对DDP的敏感性。HE4 siRNA与DDP联合应用比单药治疗更有效。从机制上讲，HE4的敲低降低了JAK2、STAT3、ERK1/2的mRNA水平及其蛋白的磷酸化水平。暗示了这些途径的参与。然而，与顺铂的协同作用可能还涉及限制癌细胞的可塑性，这是一个关键的适应性耐药机制。讨论：铂耐药OC的治疗选择有限，这是一个重大的临床挑战。HE4 siRNA，特别是与DDP联合时，显示出治疗OC的潜力，特别是铂耐药OC-这与HE4沉默后抑制JAK/STAT3和ERK1/2信号传导有关。未来的研究应明确通路相关基因，以加深对HE4在OC中的作用机制的理解。此外，优化HE4 siRNA的递送策略仍然是其临床翻译的关键焦点。结论：HE4可能通过激活JAK/STAT和MAPK通路调控肿瘤进展和耐药，有望成为OC治疗的新靶点。HE4 siRNA与DDP联合应用可能为OC的治疗提供新的选择。

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

Current cancer drug targets 医学-肿瘤学

CiteScore

5.40

自引率

0.00%

发文量

105

审稿时长

1 months

期刊介绍： Current Cancer Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular drug targets involved in cancer, e.g. disease specific proteins, receptors, enzymes and genes. Current Cancer Drug Targets publishes original research articles, letters, reviews / mini-reviews, drug clinical trial studies and guest edited thematic issues written by leaders in the field covering a range of current topics on drug targets involved in cancer. As the discovery, identification, characterization and validation of novel human drug targets for anti-cancer drug discovery continues to grow; this journal has become essential reading for all pharmaceutical scientists involved in drug discovery and development.