PDF(Pubmed)
Abstract：
The interferon stimulated gene 15 (ISG15), a ubiquitin like protein and its conjugates have been implicated in various human malignancies. However, its role in ovarian cancer progression and metastasis is largely unknown. In high grade serous ovarian cancer (HGSOC), ascites is the major contributor to peritoneal metastasis. In this study, we identified significantly elevated ISG15 protein expression in HGSOC patient ascites, ascites derived primary ovarian cancer cells (POCCs), POCC small extracellular vesicles (sEVs) as well as metastatic tissue. Our results demonstrates that ISG15 increases exocytosis in ascites-derived POCCs by decreasing the endosome-lysosomal fusion, indicating a key role in sEV secretion. Further, knockdown (KD) of ISG15 resulted in a significant decrease in vesicles secretion from HGSOC cells and in vivo mouse models, leading to reduced HGSOC cell migration and invasion. Furthermore, our pre-clinical mouse model studies revealed the influence of vesicular ISG15 on disease progression and metastasis. In addition, knockdown of ISG15 or using the ISG15 inhibitor, DAP5, in combination therapy with carboplatin showed to improve the platinum sensitivity in-vitro and reduce tumour burden in-vivo. We also found that ISG15 expression within sEV represents a promising prognostic marker for HGSOC patients. Our findings suggest that ISG15 is a potential therapeutic target for inhibiting progression and metastasis in HGSOC and that vesicular ISG15 expression could be a promising biomarker in the clinical management of ovarian cancer. Significance: High-grade serous ovarian cancer (HGSOC) has high morbidity and mortality rates, but its progression and metastasis are still poorly understood, and there is an urgent need for early detection and targeted therapies. Our study presents novel findings that implicate ISG15-mediated vesicular proteins in the advancement and spread of HGSOC. These results offer pre-clinical evidence of potential new molecular targets, prognostic markers and therapeutic strategies for HGSOC that could ultimately enhance patient survival.
摘要：
干扰素刺激基因15（ISG15），泛素样蛋白及其结合物与各种人类恶性肿瘤有关。然而,其在卵巢癌进展和转移中的作用尚不清楚。在高级别浆液性卵巢癌（HGSOC）中，腹水是腹膜转移的主要原因。在这项研究中,我们发现HGSOC患者腹水中ISG15蛋白表达显著升高，腹水来源的原发性卵巢癌细胞（POCC），POCC小细胞外囊泡(sEV)以及转移组织。我们的结果表明，ISG15通过减少内体-溶酶体融合来增加腹水衍生POCC的胞吐作用，表明在sEV分泌中起关键作用。Further,ISG15的敲低（KD）导致HGSOC细胞和体内小鼠模型的囊泡分泌显着减少，导致HGSOC细胞迁移和侵袭减少。此外，我们的临床前小鼠模型研究揭示了囊泡ISG15对疾病进展和转移的影响.此外,击倒ISG15或使用ISG15抑制剂，DAP5与卡铂的联合治疗显示出在体外提高铂敏感性并在体内降低肿瘤负荷。我们还发现sEV内的ISG15表达代表了HGSOC患者的有希望的预后标志物。我们的研究结果表明，ISG15是抑制HGSOC进展和转移的潜在治疗靶点，囊泡ISG15表达可能是卵巢癌临床治疗中一个有前途的生物标志物。意义：高级别浆液性卵巢癌（HGSOC）具有较高的发病率和死亡率，但是它的进展和转移仍然知之甚少，迫切需要早期发现和靶向治疗。我们的研究提出了新的发现，暗示ISG15介导的囊泡蛋白在HGSOC的发展和传播中。这些结果为潜在的新分子靶标提供了临床前证据，HGSOC的预后标志物和治疗策略可最终提高患者的生存率。
