SOX6基因引起细胞衰老的机制研究

Our early data showed that SOX6 was a target gene of oncomiR-155, which could inhibit the transition of cell cycle from G0/G1 phase to S phase and suppress the proliferation of tumor through p14ARF-HDM2-p53 pathway. We recently found that SOX6 could induce the senescence of tumor cell, which might be an important factor of its role in suppressing tumor proliferation. Further, we found that SOX6-induced senescence could be mediated by p53 rather than p16-Rb pathway. Since we have proved that SOX6 activated p53 pathway by inhibiting the expression of c-MYC gene, indicating that c-Myc might be a key gene in the process of SOX6-induced cell senescence. Therefore, gene knock out/over expression methods will be used to investigate the role of TP53, RB and c-MYC genes in SOX6-induced cell senescence, and elucidate the molecular mechanism on the down-regulation of c-MYC gene expression mediated by SOX6. It will help us to improve our understanding on the function of SOX6 in tumorigenesis, and provide a novel potential target for cancer therapy through the investigation on its role in the regulation of cell senescence.

本室早期研究证实转录调控因子SOX6为oncomiR-155的靶基因，其可通过p14ARF-HDM2-p53通路阻止细胞周期从G0/G1期向S期过渡，并可显著抑制肿瘤细胞增殖。我们近期首次发现SOX6可诱导肿瘤细胞发生衰老，提示其可能是导致SOX6抑制肿瘤细胞增殖的主要因素。进一步研究发现SOX6可通过p53通路而不是p16-Rb通路引起细胞衰老。由于本室前期研究证实SOX6通过抑制c-MYC基因的表达来实现p53通路的激活，推测c-MYC基因可能是介导SOX6引起细胞衰老的关键基因。我们拟通过基因敲除/过表达等方法研究TP53、RB和c-MYC等衰老相关基因在SOX6介导细胞衰老中的作用，并深入探索SOX6调控c-MYC基因表达的分子机制。本研究将通过揭示SOX6基因引起细胞衰老的分子机制深入了解其在肿瘤发生中的作用，为通过诱导细胞衰老靶向治疗肿瘤提供理论基础和新的潜在靶点。

本课题组前期研究发现SOX6可通过抑制细胞周期从G1期向S期转换抑制宫颈癌细胞增殖，然而SOX6抑制宫颈癌细胞增殖的机制尚未阐明。我们首先分析发现SOX6在宫颈癌组织中低表达，并且可能与其基因表达缺失有关，支持SOX6为抑制宫颈癌细胞增殖的基因。进一步研究发现SOX6依赖其HMG结构域引起宫颈癌细胞发生自噬性衰老，进而抑制细胞增殖。此外，我们经过一系列实验最终证实SOX6通过与MAP4K4基因启动子区结合增强其转录活性并促进MAP4K4表达，进而通过激活ERK-JNK-P38-ATF2通路促进TGFβ2表达，从而通过TGFβ2-Smad-p53/p15-Rb信号通路引起细胞发生衰老。本研究首次揭示了SOX6通过引起宫颈癌细胞发生衰老抑制细胞增殖的机制，补充了p16-Rb非依赖的细胞衰老通路，并为抗肿瘤靶向药物的研制提供潜在靶点。