Sun Yaoqi, Yao Lin, Wang Chunyan, Xiong Bing, Guo Jing, Wang Lian, Zhu Jihui, Cheng Zhongping, Liu Shupeng
Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China.
Nanjing Medical University, Nanjing 211100, China.
J Oncol. 2022 Mar 31;2022:6406122. doi: 10.1155/2022/6406122. eCollection 2022.
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. Despite the initial resection and chemotherapeutic treatment, relapse is common, which leads to poor survival rates in patients. A primary cause of recurrence is the persistence of ovarian cancer stem cells (OCSCs) with high tumorigenicity and chemoresistance. To achieve a better therapeutic response in EOC relapse, the mechanisms underlying acquired chemoresistance associated with relapse-initiating OCSCs need to be studied. Transcriptomes of both chemosensitive primary and chemoresistant relapse EOC samples were obtained from ICGC OV-AU dataset for differential expression analysis. The upregulated genes were further studied using KEGG and GO analysis. Significantly increased expression of eighteen CSC-related genes was found in chemoresistant relapse EOC groups. Upregulation of the expression in four hub genes including WNT3A, SMAD3, KLF4, and PAX6 was verified in chemoresistant relapse samples via immunohistochemistry staining, which confirmed the existence and enrichment of OCSCs in chemoresistant relapse EOC. KEGG and GO enrichment analysis in microarray expression datasets of isolated OCSCs indicated that quiescent state, increased ability of drug efflux, and enhanced response to DNA damage may have caused the chemoresistance in relapse EOC patients. These findings demonstrated a correlation between OCSCs and acquired chemoresistance and illustrated potential underlying mechanisms of OCSC-initiated relapse in EOC patients. Meanwhile, the differentially expressed genes in OCSCs may serve as novel preventive or therapeutic targets against EOC recurrence in the future.
上皮性卵巢癌（EOC）是最致命的妇科恶性肿瘤。尽管进行了初始切除和化疗，但复发很常见，这导致患者生存率较低。复发的一个主要原因是具有高致瘤性和化疗抗性的卵巢癌干细胞（OCSCs）持续存在。为了在EOC复发中获得更好的治疗反应，需要研究与复发起始OCSCs相关的获得性化疗抗性的潜在机制。从ICGC OV-AU数据集中获取了化疗敏感的原发性和化疗抗性复发EOC样本的转录组，用于差异表达分析。使用KEGG和GO分析对上调基因进行了进一步研究。在化疗抗性复发EOC组中发现了18个与CSC相关的基因表达显著增加。通过免疫组织化学染色在化疗抗性复发样本中验证了包括WNT3A、SMAD3、KLF4和PAX6在内的四个枢纽基因的表达上调，这证实了化疗抗性复发EOC中OCSCs的存在和富集。对分离的OCSCs的微阵列表达数据集进行KEGG和GO富集分析表明，静止状态、药物外排能力增强以及对DNA损伤的反应增强可能导致了复发EOC患者的化疗抗性。这些发现证明了OCSCs与获得性化疗抗性之间的相关性，并阐明了EOC患者中OCSC引发复发的潜在机制。同时，OCSCs中差异表达的基因可能在未来成为针对EOC复发的新型预防或治疗靶点。
