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

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.