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Published on: August 2, 2024
HE4 Silence Combined with DDP in the Treatment of Ovarian Cancer, Especially Platinum-resistant Ovarian Cancer
Yaxin Zuo1, Ruiqin Wang2, Yunshu Xu3
1School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China.
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.
Insights
Silencing Human epididymis protein 4 (HE4) with siRNA, especially combined with cisplatin (DDP), effectively inhibits ovarian cancer (OC) progression and overcomes drug resistance. This approach targets key signaling pathways, offering a promising new therapeutic strategy for platinum-resistant OC.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Ovarian cancer (OC) is a leading cause of gynecological cancer mortality.
- Human epididymis protein 4 (HE4) is a biomarker for OC and is upregulated in resistant cell lines.
- Developing novel therapeutic strategies for platinum-resistant OC is crucial due to limited treatment options.
Purpose of the Study:
- To investigate the therapeutic potential of silencing HE4 gene expression using RNA interference (RNAi) in ovarian cancer.
- To evaluate the combined effects of HE4 silencing and cisplatin (DDP) treatment on ovarian cancer cells, including cisplatin-resistant models.
- To elucidate the molecular mechanisms underlying the observed effects, focusing on key signaling pathways.
Main Methods:
- Establishment of a cisplatin-resistant ovarian cancer cell line (OVCAR-3/DDP) through stepwise dose escalation.
- Quantitative real-time PCR (RT-qPCR) and Western blot analysis to assess HE4, JAK2, STAT3, and ERK1/2 expression at gene and protein levels.
- Assessment of cell proliferation, migration, invasion, and apoptosis following HE4 knockdown and/or cisplatin treatment.
Main Results:
- HE4 expression was significantly elevated in OVCAR-3 and OVCAR-3/DDP cells.
- HE4 knockdown suppressed ovarian cancer cell proliferation, migration, and invasion, while enhancing apoptosis.
- Combined HE4 siRNA and DDP treatment demonstrated superior efficacy compared to monotherapy, increasing sensitivity in drug-resistant cells.
- HE4 silencing reduced JAK2, STAT3, and ERK1/2 mRNA levels and protein phosphorylation, indicating pathway involvement.
Conclusions:
- HE4 siRNA, particularly in combination with cisplatin, exhibits significant therapeutic potential for ovarian cancer, especially platinum-resistant types.
- The observed therapeutic effects are linked to the inhibition of JAK/STAT3 and ERK1/2 signaling pathways following HE4 silencing.
- Further research is warranted to fully understand HE4's role and optimize siRNA delivery for clinical translation in ovarian cancer treatment.
