结直肠癌中AMACR基因过表达的机制及意义

Alpha-methylacyl-CoA racemase (AMACR) is an enzyme that plays an important role in the β-oxidation of branched-chain fatty acids and metabolism of bile acids. Overexpression of AMACR has been reported in colorectal, prostatic and breast cancers, however, the mechanisms of AMACR gene regulation is unclear. In our previous study, we found that positivity of AMACR in microsatellite stable colorectal cancer was higher than that in microsatellite instability tumors. Moreover, nuclear expression of β-catenin was observed in the majority of AMACR over-expressed colorectal cancers. Also, there are possible TCF/β-catenin binding sites in the promoter region of AMACR. These findings indicate that activation of Wnt/β-catenin signaling pathway may directely regulate the expression of AMACR. In this research, methods for molecular biology, cell biology, molecular interaction will be performed on colorectal cancer cell lines and tissues to explore the mechanism and significance for AMACR over-expression in colorectal cancer.

AMACR(α-甲基酰基辅酶A消旋酶)是支链脂肪酸和胆汁酸代谢的关键酶，已发现其在结直肠癌、前列腺癌及乳腺癌等肿瘤中过表达。AMACR基因的扩增及启动子区突变可能与肿瘤组织中AMACR表达差异有关，但具体的调节机制仍不清楚。我们前期研究结果显示微卫星稳定型结直肠癌AMACR阳性率明显高于微卫星不稳定型肿瘤，AMACR高表达结直肠癌多数伴有β-catenin的核转位，我们推测Wnt/β-catenin信号通路可能参与了AMACR的表达调控。通过对AMACR启动子序列分析，进一步发现AMACR启动子区存在可能与TCF/β-catenin结合的位点。因此，本研究拟在上述研究基础上，运用分子生物学、细胞生物学、分子间相互作用等方法，在肿瘤组织及细胞系中，进一步确定Wnt/β-catenin通路活化对AMACR表达的调控作用，从而阐明结直肠癌中AMACR基因过表达调节机制及其对细胞生物学行为的影响。