孤儿核受体NR2F6诱导卵巢癌化疗耐受的分子机制

Chemo-resistance is the most common reason of treatment failure in patients with ovarian cancer. In clinic, chemo-resistance directly affects the efficacy of treatment and survival of patients. Therefore, identifying key molecular factor in Chemo-resistance process would be of great value for early diagnosis and therapy. Recently, we have confirmed that NR2F6 is overexpressed in cervical cancer samples, which is correlated with pelvic lymph node metastasis and poor prognosis. Additionally, we found that NR2F6 enhances chemo-resistance and promotes the recurrence of ovarian cancer. Further, we carried in vivo and in vitro experiments, and the results showed that NR2F6 accelerates the characteristics of ovarian cancer stem cell and promotes the capacity of chemo-resistance to cisplatin. Further research shows that we found that NR2F6 activates NOTCH signaling and JAK2/STAT3 signaling, and the mRNA and protein level of the downstream molecules of NOTCH signaling and JAK2/STAT3 signaling upregulated. Moreover, in the current project, we will combine in vivo and in vitro experimental systems with data from clinical samples, in order to explore the multi-dimensional mechanisms of NR2F6 overexpression-induced ovarian cancer chemo-resistance and stem cell characters. Our work may help provide new molecular targets and diagnostic markers for the treatment and prognosis of ovarian cancer.

化疗耐受是导致卵巢癌患者治疗失败最主要的原因，直接影响卵巢癌的治疗效果及患者的生存预后。因此，寻找化疗耐受的关键调控因子对于卵巢癌的诊断,治疗及患者的预后具有重要的意义。我们前期研究发现：①NR2F6在卵巢癌化疗耐受的临床样本中表达明显上调;② NR2F6的高表达可以促进卵巢癌细胞对化疗药物顺铂的耐受;③NR2F6的高表达会增加卵巢癌细胞肿瘤内的干细胞特性。进一步研究显示NR2F6可以激活NOTCH及JAK2/STAT3信号通路，增强其下游基因的转录水平。这些结果提示NR2F6高表达在卵巢癌化疗耐受中发挥重要作用。但是，NR2F6的高表达导致卵巢癌化疗耐受的具体分子机制目前并不清楚。因此本研究将进一步深入探讨NR2F6促进卵巢癌耐药及肿瘤干细胞特性的分子机制，为卵巢癌的诊断、治疗和预后提供新的分子靶点。

肿瘤干细胞是肿瘤化疗耐受、复发及转移的最重要的原因之一。鉴定参与维持肿瘤干细胞特性的关键通路及分子，对揭示肿瘤恶性进展的机制并依此开发高效的预防及诊疗的潜在标志物及靶点至关重要。围绕该研究主线，本项目取得的主要研究成果包括：1. 核孤儿受体NR2F6在铂耐受的卵巢癌的临床样本中表达显著上调，并转录激活Notch3的表达，从而激活Notch3通路并上调下游Jagged1，N3ICD，Hes1等基因的表达，进而促进肿瘤细胞的干细胞特性，导致其对化疗产生耐受。2. 经典的wnt/beta-catenin信号通路在具有高转移潜能的肿瘤细胞中异常活化，我们发现NUSAP1能够促进RanBP2对TCF4的sumo化修饰作用，而sumo化的TCF4能够进一步激活下游SOX2，NANOG，OCT4等经典多能干性基因的转录并促进肿瘤细胞的自我更新能力，继而导致肿瘤细胞发生远处转移；我们还发现，相对于癌旁组织，HN1在肿瘤组织中表达显著上调，而且HN1所介导的NF-kB信号通路的异常激活，并上调下游MMP3，MMP9，VEGF-C基因的表达，进而引起肿瘤中的淋巴管新生和淋巴结转移，该研究工作揭示了肿瘤淋巴结转移新的分子机制，提示了可以通过干预HN1的表达或作用来治疗淋巴结转移性的恶性肿瘤。3. circ-ITGB6在耐药性的卵巢癌组织和细胞系中显著上调，circ-ITGB6能够作为“分子脚手架”，促进IGF2BP2对FGF9 mRNA的稳定作用，进而上调分泌因子FGF9的表达量和分泌，后者在组织中介导了M0型巨噬细胞向促肿瘤的M2型转化，继而发挥了重塑免疫微环境的作用并促进了卵巢癌细胞自身对于化疗的耐受度。以上的研究揭示了肿瘤干细胞介导肿瘤治疗抵抗和发生复发转移的分子机制，为后续恶性肿瘤的诊疗提供了新的思路或潜在靶点。项目资助发表第一/通讯作者论文4篇，培养研究生多名。