GRIM-19及其靶基因产物STAT3与结直肠癌恶性程度的关系

Correlations of GRIM-19 and Its Target Gene Product STAT3 to Malignancy of Human Colorectal Carcinoma

背景与目的:干扰素/维甲酸联合应用诱导细胞凋亡相关的基因(gene associated with retinoid-interferon-induced mortality-19,GRIM-19)属转录信号转导子与激活子3(signal transducers and activators of transcription 3,STAT3)特异性抑制蛋白,STAT3及其介导的信号转导通路参与调节细胞的增殖、凋亡与分化,并介导细胞的恶性转化。本研究分析GRIM-19及其靶基因STAT3在结直肠癌组织中的表达情况,探讨GRIM-19及其靶基因产物在结直肠癌发病中的作用。方法:采用免疫组织化学染色及Western blot检测40例结直肠正常组织及癌组织中GRIM-19、STAT3、p-STAT3蛋白表达,对各表达情况与不同临床病理特征进行统计学分析。采用逆转录-聚合酶链反应(reverse transcription-polymerase chain reaction,RT-PCR)方法及测序检测结肠癌细胞系SW480及23例结直肠正常组织及癌组织中GRIM-19mRNA有无基因突变及在mRNA的表达情况。结果:在结直肠癌组织中STAT3及p-STAT3蛋白均高表达,而GRIM-19mRNA及蛋白表达在癌组织中明显低于正常组织,且GRIM-19蛋白表达水平与结直肠癌分化程度和临床分期相关(P<0.05)。GRIM-19与STAT3和p-STAT3在结直肠癌组织中表达情况呈负相关,GRIM-19基因阳性时,STAT3基因趋向阴性(χ2=9.95,P<0.01),p-STAT3基因也趋向阴性(χ2=5.10,P=0.02)。结直肠癌组织中GRIM-19mRNA无基因突变情况。结论:GRIM-19蛋白在结直肠癌组织中的低表达或缺失与结直肠癌的发生、发展及侵袭性相关,而与基因突变无关。在结直肠癌组织中存在STAT3的持续高表达和GRIM-19的低表达共存现象,可能与细胞更易发生恶性转化和异常增殖,促进了结直肠癌的发生发展相关。

BACKGROUND ＆ OBJECTIVE. GRIM-19 （gene associated with retinoid-interferon-induced mortality-19） gene is a specific protein to inhibit signal transducers and activators of transcription 3 （STAT3）. STAT3 and its pathway are involved in modulating cell proliferation, apoptosis, differentiation, and mediating malignant transformation of cells. This study was to investigate the expression of GRIM-19 and its target gene STAT3 in human colorectal carcinoma tissues, and explore their roles in the tumorigenesis of colorectal carcinoma. METHODS： The expression of GRIM-19, STAT3 and its activated form p-STAT3 in 40 specimens of colorectal carcinoma, adjacent tissue, and normal tissue was determined by immunohistochemistry and Western blot. The correlations of the expression of GRIM-19, STAT3, and p-STAT3 to various clinicopathologic characteristics of colorectal carcinoma were analyzed statistically. The mRNA expression and gene mutation of GRIM-19 in colon cancer cell line SW480 and 23 specimens of colorectal carcinoma, adjacent tissue, and normal tissue were detected by reverse transcription-polymerase chain reaction （RT-PCR） and sequencing. RESULTS： The expression of both STAT3 and p-STAT3 were up-regulated in colorectal carcinoma. The mRNA and protein expression of GRIM-19 was obviously lower in colorectal carcinoma than in normal tissues. The expression of GRIM-19 was correlated to clinical stage and cell differentiation of colorectal cancer （P〈 0.05）. GRIM-19 expression in colorectal cancer was negatively correlated to STAT3 and p-STAT3 expression （X^2 = 9.95, P = 0.00; X^2 = 5.10, P = 0.02）. No mutation of GRIM-19 gene was detected in colorectal carcinoma tissues. CONCLUSIONS： The low expression or absence of GRIM-19 may play an important role in the tumorigenesis of colorectal carcinoma. The high expression of STAT3 and the low expression of GRIM-19 co-exist in colorectal carcinoma, and may be related to malignant transformation and abnormal proliferation of cells.