癌基因C14ORF166驱动宫颈癌耐药以及转移的分子机制

Previously, we demonstrated that C14ORF166 was markedly upregulated in cervical cancer, and that overexpression of C14ORF166 is associated with pelvic lymph node metastasis and poor prognosis in uterine cervical cancer. Here we show that overexpression of C14ORF166 induced enhanced cervical cancer stem cell characters, promoted chemo-resistence and distant metastasis by activating JAK2/STAT3 and Wnt/β-catenin signaling pathway in vitro. Furthermore, C14ORF166 could increase the levels of JAK2, STAT3 phosphorylation and the mRNA levels of IL-10，IL-11 and MCL1. Therefore, in the present project, we aim to employ a series of experiments in both in vivo and in vitro systems to investigate the mechanism of JAK2/STAT3 and Wnt/β-catenin signaling pathway. Furthermore, this project would discuss the corelation between the expression of C14ORF166 and proteins related to the biological function of chemo-resistence and distant metastasis in clinical samples, which may provide new biomarkers and targets for the diagnosis and treatment of cervical cancer.

前期研究我们已证明，C14ORF166蛋白在宫颈癌中的表达显著上升，并且C14ORF166的表达水平与宫颈癌临床分期、盆腔淋巴结转移及不良预后密切相关（已发表)。预实验发现上调C14ORF166可以显著促进宫颈癌细胞自我更新能力，增强宫颈癌细胞转移和对化疗药物的抵抗能力。进一步研究发现C14ORF166能激活JAK2/STAT3及Wnt/β-catenin信号通路；并促进JAK2及Stat3磷酸化，增强其下游基因IL-10，IL-11及MCL1的转录水平。本项目将承上启下，以过表达和内源性沉默C14ORF166的宫颈癌细胞为模型，通过一系列细胞、分子生物学及动物实验探讨C14ORF166激活JAK2/STAT3及Wnt/β-catenin信号通路的具体分子机制；通过体内外系统，并进一步结合临床样本，验证C14ORF166驱动宫颈癌细胞耐药及转移的功能，为宫颈癌的诊治提供新的靶标。

前期研究我们已证明C14ORF166 蛋白在宫颈癌中的表达显著上升，并且可以促进淋巴结转移进而导致宫颈癌恶性进展（已发表）。本项目发现C14ORF166结合蛋白.NUSAP1和HN1在宫颈癌中表达上调并与患者不良预后密切相关。NUSAP1的高表达通过增强肿瘤干细胞特性和促进肿瘤的上皮间质转换的进程，促进肿瘤侵袭转移。HN1通过激活NF-κB通路促进淋巴管新生和淋巴结转移，进而导致宫颈癌恶性进展。这些研究为宫颈癌的临床预后和治疗提供了潜在靶标。