TRIM31调节直肠癌放疗敏感性相关性的研究

Rectal cancer is one of the common cancers with increasing incidence. Neoadjuvant concurrent chemoradiotherapy has been practiced effectively in several randomized clinical Phase III trials and has been proven to be the standard care of locally advanced rectal cancer. However, not all patients will be benefit from neoadjuvant chemoradiotherapy. Thus, identifying the potential molecule markers that may affect chemoradio-sensitivity is important. Investigating the mechanism of chemoradio-resistance in rectal cancer will help improve the outcome and optimize treatment modalities in personalized treatment of rectal cancert. In our preliminary study, we analyzed the whole genome expression in both chemoradiotherapy response and non-response patients that underwent neoadjuvant chemoradiotherapy, screened and validated some of the chemoradiosensitivity related genes. We found that the expression of TRIM31 in the response group was much lower than that in the non-response group,suggesting that TRIM31 may play a critical role in the regulation of chemoradio-sensitivity. However, study about the relationship of TRIM31 and radiosensitivity has not been reported. In this project, we will apply rectal cancer cell lines with different radiosensitivity and animal models to further study the effects of TRIM31 on regulating radiosensitivity of rectal cancer in vitro and in vivo through over-expression and RNA interfering techniques. Meanwhile, we will correlate TRIM31 with pathological features and follow up data to evaluate its impact on prognosis of rectal cancer patients treated with neoadjuvant chemoradiotherapy. We expect the potential role of TRIM31 may be provided as a novel molecular marker in personalized chemoradiotherapy and brings long-term benefits for rectal cancer patients.

直肠癌是恶性程度较高且发病率逐年上升的肿瘤。随机临床研究显示新辅助放化疗能够显著提高直肠癌的疗效，但并非所有患者均对放化疗敏感。因此寻找影响直肠癌放化疗敏感性的分子标记物，并研究其作用机制，有助于优化治疗模式进行直肠癌的个体化治疗，提高疗效。我们在前期工作中采用全基因表达谱芯片对直肠癌新辅助治疗敏感组和不敏感组进行比较分析，发现TRIM31基因在敏感组中表达水平明显低于不敏感组。但TRIM31改变是否影响直肠癌放射敏感性，目前还未见国内外相关研究报道。在已有的大量前期工作基础上，本项目将在放射敏感性不同的肠癌细胞系和动物模型中，通过过表达和干扰TRIM31基因水平，从分子、细胞及动物水平进行深入研究,明确TRIM31与直肠癌放射敏感性的关系，探索其作用机制，进一步结合临床数据确定TRIM31与直肠癌预后的关系，作为直肠癌疗效预测筛选基因，为个体化治疗提供新思路，使患者得到生存获益。

直肠癌是恶性程度较高且发病率逐年上升的肿瘤。随机临床研究显示新辅助放化疗能够显著提高直肠癌的疗效，但并非所有患者均对放化疗敏感。我们在前期工作中采用全基因表达谱芯片对直肠癌新辅助治疗敏感组和不敏感组进行比较分析，发现TRIM31基因在敏感组中表达水平明显低于不敏感组。本项目在放射敏感性不同的肠癌细胞系和动物模型中，通过过表达和干扰TRIM31基因水平，从分子、细胞及动物水平进行深入研究,明确TRIM31与直肠癌放射敏感性的关系，探索其作用机制。结果发现TRIM31在P53突变状态不同的结直肠癌细胞中对肿瘤细胞生物学特性和放射敏感性的影响不同，质谱分析鉴定出多种可能与TRIM31相互作用的蛋白，用Western blotting和免疫共沉淀的方法进一步验证它们与TRIM31的相互作用关系，发现mTOR、P70S6K和p38MAPK可能受TRIM31的调节，影响结直肠癌细胞的生长和代谢。 TRIM31可能通过与ATM、mTOR和FAK相互作用，影响放射敏感性。但是在小鼠的皮下移植瘤模型中没有发现TRIM31的表达水平对肿瘤生长和放射敏感性的影响，可能与体内复杂的环境，及TRIM31复杂的调控作用有关。