长链非编码RNA lncZFPM2-AS1通过结合HNRNPC调控PD-L1促进卵巢透明细胞癌侵袭转移的机制研究

Ovarian clear cell carcinoma (OCCC), as a subtype of ovarian epithelial carcinoma, is characterized by advanced diagnosis, early recurrence and metastasis, and resistance to chemotherapy. Our previous study found that long non-coding RNA ZFPM2-AS1 was highly expressed specifically in OCCC, and the high expression of ZFPM2-AS1 could significantly promote the proliferation and invasion of OCCC cell lines. Recently, we predicted the existence of the binding domain between HNRNPC and ZFPM2-AS1. The preliminary mechanism study showed that the misadjusted ZFPM2-AS1 down-regulated the expression of HNRNPC and PD-L1 in OCCC cell lines. Meanwhile, we also found the high expression of PD-L1 is closely related to the recurrence and poor survival of OCCC patients. Therefore, we establish the hypothesis that ZFPM2-AS1 regulates the biological behavior of PD-L1 in OCCC cells by combining with HNRNPC. This study intends to verify the effect and key binding domain of ZFPM2-AS1 and HNRNPC, and to further clarify the regulatory effect of ZFPM2-AS1 on the expression and function of PD-L1, and the effect on the biological behavior of OCCC cells. This study can not only reveal the pathogenesis and development of OCCC, but also provide new therapeutic targets to OCCC.

卵巢透明细胞癌(OCCC)具有确诊晚、容易复发转移等恶性特征。我们前期研究发现长链非编码RNA lncZFPM2-AS1在OCCC中呈特异性高表达，并可促进OCCC细胞的增殖和侵袭。我们发现核不均一核糖核蛋白C(HNRNPC)与ZFPM2-AS1结合。初步的机制实验证实失调的ZFPM2-AS1可以下调肿瘤细胞中HNRNPC与程序性细胞死亡蛋白-1配体(PD-L1)的表达。且通过临床样本提示肿瘤组织中PD-L1呈高表达的OCCC患者预后更差。由此建立了ZFPM2-AS1通过结合HNRNPC上调PD-L1表达从而促进OCCC发生侵袭转移的假说。本课题拟首先验证ZFPM2-AS1与HNRNPC的直接作用和关键结合位点；进一步明确ZFPM2-AS1/HNRNPC对PD-L1表达和功能的调节作用以及对OCCC细胞的生物学行为的影响。本课题不仅能帮助揭示OCCC的发生发展机制，而且能为治疗提供新靶点。

卵巢透明细胞癌(OCCC)具有确诊晚、容易复发转移等恶性特征。我们研究发现长链非编码RNA lncZFPM2-AS1在OCCC中呈特异性高表达，并可促进OCCC细胞的增殖和侵袭。我们发现核不均一核糖核蛋白C(HNRNPC)与ZFPM2-AS1结合。初步的机制实验证实ZFPM2-AS1可能通过结合HNRNPC进而影响下游IL6/STAT3信号通路。且申请者前期文章也提示肿瘤组织中PD-L1呈高表达的OCCC患者预后更差。在此基础上，申请人还进行了拓展实验，即对宫颈癌放疗抵抗和敏感组织进行多组学测序，该出发点目前尚未见相关报道。综上所述，本课题探讨了OCCC中的内在调控网络及其促进肿瘤转移的作用机制，并明确其中关键分子与OCCC临床病理及预后的相关性，这对于更好地明确OCCC转移复发机制、寻找OCCC治疗的新靶点具有重要的理论意义和潜在临床转化价值。