核基质结合蛋白SATB1在结直肠癌肝转移中的作用及分子机制

Distant metastasis, especially liver metastasis, is one of the main causes of treatment failure associated with Colorectal carcinoma(CRC) patients. Therefore, early detection or prediction of liver metastasis of CRC patients can lead to a more accurate evaluation of disease staging, and a more effective individualized treatment. Our previous study has shown that there was a significant association between SATB1 expression and liver metastasis (n=210，p<0.001). In addition, a series of in-vitro experiments and liver metastasis model conducted with nude mice have also demonstrated that SATB1 could promote invasion, migration and liver metastasis. In this study, we intend to expand the sample size to verify the correlation between SATB1 and liver metastasis，and we will explore whether there is a correlation between SATB1 and other clinicopathological factors or patient prognosis. We will perform a prospective study in a group of new non-Ⅳ cases to test the sensitivity and specificity of SATB1 in predicting liver metastasis. Transcriptome sequencing technology and bioinformatics would be applied to further reveal the molecular mechanism of SATB1 involved in liver metastasis. This study will help to uncover the mechanism underlying hepatic metastasis of colorectal cancer, as well as to provide a useful predictive marker, and eventually improve prognosis for CRC patients.

肝转移是导致结直肠癌患者治疗失败的主要原因之一，早期发现或预测肝转移的发生，可促进肿瘤病期的准确评估以及针对性治疗方案的制定。我们前期通过一组回顾性样本（n=210）的免疫组化发现SATB1与结直肠癌肝转移之间存在显著的相关性（p<0.001），并开展了一系列的体外实验，构建裸鼠肝转移模型，证实SATB1的确能够促进结直肠癌细胞的侵袭转移尤其是肝转移。本项目拟扩大回顾性研究的样本量以验证SATB1与结直肠癌肝转移之间的相关性，分析SATB1是否与其他临床病理因素和预后存在相关性；开展前瞻性研究，在一组新发非Ⅳ期结直肠癌患者中检验SATB1预测肝转移的灵敏度和特异度；在此基础上，结合转录组测序技术和生物信息学分析，进一步揭示SATB1影响肝转移的分子机制。为深入揭示结直肠癌肝转移的机制奠定基础，为结直肠癌肝转移提供一种有效的预测标志物，以期改善结直肠癌患者的预后。

结直肠癌肝转移是导致患者治疗失败的主要原因之一，早期发现或预测肝转移的发生，可促进肿瘤病期的准确评估以及针对性治疗方案的制定。我们前期通过一组回顾性样本（n=210）的免疫组化发现SATB1与结直肠癌肝转移之间存在显著的相关性（p<0.001），本项目通过大样本回顾性免疫组化结果进一步证实核基质结合蛋白SATB1在结直肠癌组织和癌旁正常粘膜组织的表达存在显著的差异（P<0.001），并证实SATB1的表达和病理分化程度（P<0.001），原发灶浸润深度（P=0.009），远处转移（p=0.007），和临床分期（P=0.028）相关。并且结直肠癌的SATB1表达水平增高与结直肠癌患者的预后不良相关（P=0.001），Cox多因素分析显示SATB1是结直肠癌预后的独立危险因素（P=0.009）；体内外实验证实结肠癌细胞中SATB1的表达能够促进结肠癌细胞体内外恶性生物学行为；SATB1的表达能够促进结肠癌细胞上皮-间质转化过程；SATB1能够增加结肠癌细胞对化疗药物的抵抗性，这可能是通过上调MDR1表达实现的；干扰SATB1涉及改变肿瘤细胞生长、增殖、转移、凋亡、耐药等多个方面的多个分子和通路，因此，SATB1具有作为结肠癌肝转移诊断标志物和治疗靶点的潜在可能性，为揭示结直肠癌肝转移的机制提供了一种新的思路。