自噬相关蛋白Beclin-1在ⅢB期结肠癌的表达及其与预后关系

Expression of Beclin-1,an Autophagy-related Protein,in Stage ⅢB Colon Cancer and Its Relationship with Prognosis

目的：自噬是细胞利用溶酶体降解自身受损的细胞器和大分子物质的过程，是真核细胞的一种死亡形式。自噬在肿瘤发生发展中的作用尚不完全清楚。Beclin-1是一种双等位抑癌基因且是哺乳动物参与自噬的特异性基因。本研究观察肿瘤细胞自噬水平变化对ⅢB期结肠癌患者预后的影响。方法：收集我院1999年1月～2003年7月经过根治性手术治疗并有完整随访资料的115例ⅢB期结肠癌组织标本，用免疫组化方法观察自噬相关蛋白Beclin-1在癌组织与癌旁正常粘膜表达情况，分析beclin-1表达水平与患者临床病理参数关系及与患者预后的关系。结果：Beclin-1蛋白表达于肿瘤细胞膜、胞浆和（或）细胞核，正常粘膜缺乏Beclin—1表达。肿瘤组织Beclin—1阳性率达85．2％（98／115）；Beclin-1表达者的5年生存率较高（67.3％VS47．1％）。此外，Beclin-1表达与患者其它临床病理参数如年龄、性别、发病部位、病理类型、细胞分化程度及T分期无相关性。结论：局部晚期结肠癌细胞保留自噬功能没有提高肿瘤细胞的生存能力，而丧失自噬功能可能促进肿瘤进展。

Objective： Autophagy is a form of eukaryotic cell death by which the cell recycles its components through self-consumption of cellular organelles and bulk cytoplasm using hydrolytic enzymes stored in lysosomes. The role of autophagy in carcinogenesis and tumor progression is elusive. Beclin-1, a key regulator of autophagy in mammals, has been considered a haploinsufficient tumor suppressor. This study investigates the expression of beclin-1 in stage Ⅲ B human colon cancer and analyzes the association of beclin-1 expression with clinocopathologic characteristics and prognosis. Methods： A total of 115 cases of colon cancer specimens were obtained from radically resected stage Ⅲ B colon cancer tumors between January 1999 and July 2003 with complete follow-up data in our center. Tissue arrays were constructed from formalin-fixed and paraffin-embedded tissues. The expression of beclin-1 in tumor tissue and adjacent normal tissue was examined with immunohistochemistry. The relationship between beclin-1 expression and clinicopathological parameters was analyzed. Results： Expression of beclin-1 was observed in the plasma membrane, cytoplasm and nucleus in tumor cells. In the tumor tissues analyzed, immunopositivity was observed for beclin-1 in 98 （85.2%） of the 115 tumor tissues. In contrast, adjacent non-cancerous tissues and normal tissues showed no or very weak expression of beclin-l. The 5-year overall survival rate for beclin-1 immunopositive cases was 67.3% and for beclin-1 immunonegative cases the rate was 47.1%. The 5-year overall survival rate was 68.9% for T3NoMo cases and 25.0% for T, NoM0 cases. There was a significant association of beclin-1 expression and T stage with 5-year overall survival rate. No significant correlation was found between beclin-1 expression and clinocopathologic characteristics including sex, age, tumor site,pathologic type, grade, and invasive depth （T stage）. Both univariate analysis and multivariate analysis showed that beclin-1 and T stage were independent prognostic factors. Cenclusien： Beclin-1 plays an important role in the regulation of the life span of human colon cells by maintaining autophagy at levels promoting cell death rather than cell survival. In locally advanced colon carcinomas, tumor cells with the potential for autophagy fail to survive. Alternatively, a deficiency in autophagy may be involved in tumor progression. Further research is warranted to elucidate the detailed mechanism.