14-3-3σ通过抑制NF-κB信号通路抑制结肠癌

Colorectal cancer (CRC) is one of the major causes of cancer-related deaths in the world, and the incidence and mortality of CRC have increased rapidly in China in recent years. Uncontrolled growth and distant metastasis are hallmarks of CRC, but the mechanisms are poorly understood. It is very important to study the molecular mechanism of metastasis of colorectal cancer to explore the novel bio-markers for the precise diagnosis and individualized medication. 14-3-3σhas a unique structure unlike the other 14-3-3 family members and is the only 14-3-3 family member with tumor suppressor activity. 14-3-3σ is a direct transcription target of TP53, and it protects TP53 from MDM2-mediated polyubiquitination and proteasomal degradation. The tumor suppressor role of 14-3-3σ is increasingly clear. Inactivation of 14-3-3σ is an early event in tumorigenesis and facilitate the initiation and progression. However, the impact of 14-3-3σ on cancer is not unequivocal. Preliminary study showed that loss of 14-3-3σ enhanced NF-κB target genes expression at mRNA level in HCT116 cell and loss of 14-3-3σ enhanced NF-κB transactivation activity. Meanwhile, 14-3-3σcould interact with p65 and caused p65 nuclear export. Moreover, 14-3-3σ could inhibit the migration of HCT116. According to the preliminary results, 14-3-3σ may play great roles in the development of colorectal cancer. In this project, we will validate the relationship between expression of 14-3-3σ and prognosis of patients by expanding the number of samples. The effects of 14-3-3σ on proliferation and metastasis of colon cancer were studied in vitro and in vivo. Meanwhile, the dysregulation of 14-3-3σ and mechanisms of above function of 14-3-3σ were explored by experiments. Thus will provide a possible molecular biomarker for the diagnosis and treatment effect prediction, as well as personalized treatment of colorectal cancer as a scientific experimental evidence.

结直肠癌（Colorectal Cancer,CRC）是目前世界上癌症相关主要死亡因素之一，转移后预后较差。深入研究CRC发生发展中的关键分子机制对于其早期诊断及治疗具有重要意义。14-3-3σ是14-3-3家族成员唯一具有肿瘤抑制功能的成员,但其在结直肠癌中的作用却鲜有报道。申请人通过前期研究发现在CRC细胞中14-3-3σ能够负性调控NF-κB通路，抑制p65入核及抑制NF-κB的活化和反式激活，同时其可抑制CRC细胞的迁移能力。上述结果提示14-3-3σ在结直肠癌的发生和发展中可能发挥抑癌基因作用。本研究拟深入探索14-3-3σ在结肠癌中的功能及负调控NF-κB信号通路的靶点及具体作用机制，扩大样本分析14-3-3σ表达与预后的关系，为CRC的诊断，疗效测定，治疗提供可能的分子标志物和治疗靶点。

结直肠癌（CRC）患者诊断时大多已出现转移，有90%的结直肠癌死亡病例由肿瘤转移导致。但是目前只有极少数针对血管生成的靶向药物用于治疗转移性结肠癌，亟需寻找新的分子靶点。14-3-3σ是肿瘤抑制因子，但其对结直肠癌的影响鲜有报道。本研究发现发现14-3-3σ在CRC中低表达且与患者生存预后相关。14-3-3σ可以抑制乏氧诱导的肿瘤迁移、侵袭和体内转移，这是因为14-3-3σ抑制HIF-1α蛋白的表达。14-3-3σ可直接调控HIF-1α的蛋白稳定性及泛素化降解，抑制血管生成进而介抑制直肠癌的发生发展。机制研究发现HIF-1α是E3连接酶NEDD4L的作用底物。14-3-3σ可通过促进NEDD4L和HIF-1α的结合介导其泛素化和蛋白降解，抑制其活性。通过分析肿瘤组织中14-3-3σ和HIF-1α的表达量，我们还发现14-3-3σ和HIF-1α的联合表达对发现直肠癌病人预后具有一定的预测价值。因此，我们的这项研究为结直肠癌的治疗靶点的寻找提供了新思路，14-3-3σ有望成为治疗结直肠癌的分子靶点。