转录因子ZXDC促进宫颈癌淋巴结转移的机制研究

Cervical cancer is one of the most common malignancies that threaten the health of women worldwide. Lymph node metastasis is the most important reason leading to poor prognosis in advanced cervical cancer. Earlier, we have demonstrated that upregulation of oncogene TBLR1 promotes cervical lymph node metastasis [Br J Cancer. IF=6.176. Corresponding author]. Recently, we sequenced the transcriptome of TBLR1-expressing stable cell lines and found that the expression of zinc finger transcription factor ZXDC was significantly up-regulated and related to cervical lymph node metastasis. Furthermore, we verified low expression of ZXDC inhibited invasiveness and anoikis resistance of tumor cells, while decreased lymphangiogenesis and lymph node metastasis. Meanwhile, upregulation of ZXDC by TBLR1 in cervical cancer further activated TGF-β, Akt and NF-κB pathways. However, the specific molecular mechanism remains to be elucidated. Here, we intends to explore the mechanism of ZXDC in promoting lymph node metastasis of cervical cancer by using the modern research techniques of cell biology, molecular biology and laboratory zoology, and aims to provide effective new targets for clinical diagnosis and treatment for patients with advanced cervical cancer.

宫颈癌是严重威胁女性生命健康的恶性肿瘤之一，而淋巴结转移是导致晚期宫颈癌患者预后不良的最主要因素。前期，我们已发表文章证明癌基因TBLR1表达上调促进宫颈癌淋巴结转移【Br J Cancer. IF=6.176. 通讯作者】。近期，我们对TBLR1稳定高表达的细胞系进行转录组测序，发现锌指转录因子ZXDC的表达显著上调，并且与宫颈癌淋巴结转移密切相关。进一步，我们还发现：ZXDC低表达能抑制肿瘤细胞侵袭及抵抗失巢凋亡，并抑制淋巴管新生和淋巴结转移；同时ZXDC的低表达可进一步抑制TGF-β、Akt、NF-κB信号通路的激活。然而，具体的分子机制还有待阐明。本项目将结合前期研究基础，拟采用细胞生物学、分子生物学、实验动物学等现代研究技术，深入探讨ZXDC促进宫颈癌淋巴结转移的详细分子机制，为晚期宫颈癌患者的临床诊断治疗提供有效的新靶点。

宫颈癌是女性最常见的恶性肿瘤之一。课题组前期发现宫颈癌中TBLR1 高表达的宫颈癌细胞的侵袭迁移能力明显增强，在 TBLR1 高表达组中转录因子 ZXDC 的表达水平上调显著。基于以上前期基础，本研究通过一系列体内外实验揭示了ZXDC可以促进宫颈癌的转移，其通过上调IGF2BP3的表达来激活RhoA/ROCK通路，促进细胞骨架重排，从而促进宫颈癌细胞的迁移，最终促进宫颈癌的进展。此外，课题组着手于宫颈癌，利用公共数据库，进行生物信息学分析，从而建立用于判断预后的免疫相关模型，其结果提示高风险组的患者具有更差的总体生存。基于此点，纳入肾移植后的患者临床队列，将其与免疫正常的患者做对比，结果显示肾移植后的患者其感染HPV16的风险更高，HPV多重感染的风险也较高。本研究基于宫颈癌转移，引出对宫颈癌转移机制的探究，同时以转移为出发点，构建宫颈癌的预后模型，并且以本中心的临床数据为导向，全面对宫颈癌的发生发展过程进行深入地探究。