CBX8在食管鳞状细胞癌转移过程中的功能、机制及其临床意义

The poor clinical outcome and prognosis of esophageal squamous cell carcinoma (ESCC) is mainly attributed to its highly invasive and metastatic nature. Recent researches are focused on the molecular mechanism under its initiation and progression, as well as the identification of new therapeutic targets. Plycomb group (PcG) proteins are involved in epigenetic gene silencing via modifying the chromatins, and CBX proteins are important partners of this group. Previously, we found that CBX8 repressed cell migration，invasion and EMT in ESCC cell line. In vitro assay indicate that the repression of cell migraton and invasion by CBX8 may be due to the inhibition of the transcription of Snail. In this study, we aim to explore the role of CBX8 in ESCC and clear that the molecular mechanism may be through regulating the transcription of Snail, and to elucidate the expression and clinical significance of CBX8 and Snail in ESCC tissues. We propose a new mechanism that CBX8 inhibits the cell migration, invasion and cancer metastasis of ESCC through regulating the expression of Snail gene. Our study may provide evidence and new therapeutic targets for the comprehensive treatment of ESCC.

食管鳞状细胞癌（简称食管鳞癌，ESCC）因常伴随转移而预后很差，其转移的分子机制及新的治疗靶点是目前的研究热点。多梳基因家族蛋白（PcG）是通过染色质重塑进行基因表观遗传调控的一类蛋白，CBX家族蛋白是其重要组成部分。我们前期研究显示：在HKESC1细胞中过表达CBX8，可抑制其侵袭能力，反之，在TE-1细胞中敲低CBX8，增加其迁移和侵袭能力，并且CBX8抑制其表皮-间质转化（EMT）。初步的机制研究表明，CBX8可能通过负性调控Snail，从而抑制TE-1细胞的迁移、和侵袭转移。本项目拟用ESCC多个细胞系进行沉默或过表达CBX8，在细胞水平和动物模型中研究CBX8在ESCC转移的作用及其机制；同时收集ESCC病人的临床标本，探讨CBX8/Snail通路在ESCC的临床预后和治疗方面的意义。这种CBX8/Snail通路调控ESCC转移的新机制，可能为ESCC的综合治疗提供新的依据和靶点

食管鳞状细胞癌转移常常是影响预后的重要因子， 也是肿瘤治疗后进展的主要原因之一。本研究报道了CBX8作为一个抑癌基因在食管鳞状细胞癌中发挥抑制肿瘤转移的功能。其具体机制是CBX8蛋白通过直接结合Snail启动子并抑制其转录活性，致使Snail基因的表达处于一个沉默的状态，而Snail作为EMT的关键因子势必引起下游分子，像E-cadherin、N-cadherin、Fibronectin以及Vimentin表达的改变，最终导致间质表型的产生促进肿瘤的转移。这是首次在ESCC中证明CBX8对EMT过程也具有调节功能，并且其功能依赖于Snail的表达。虽然在早期病人中CBX8可能是促进细胞增殖的作用，但是对于肿瘤进展的病人中CBX8发挥的抑制转移的功能可能更加重要，如何提高CBX8的表达水平可能对于病人的治疗起到更加重要的作用。