DNA甲基化转移酶1/3b与肝癌临床病理特征和预后相关性研究

目的探讨DNA甲基化转移酶1/3b(DNMT1/3b)表达异常与肝癌临床病理特征和患者术后生存之间的相关性。 方法采用免疫组织化学技术检测89例手术切除肝癌组织中DNMT1和DNMT3b的蛋白表达情况,结合临床病理及无瘤生存期和总生存期,分析DNMT1/3b与临床病理参数、预后的相关性,并通过高通量基因芯片技术筛选肝癌相关DNMT1和DNMT3b的靶基因。 结果89例肝癌组织中DNMT1和DNMT3b皆为阳性63例,皆为阴性5例,单一阳性的分别为9例和12例。DNMT1/3b在肝癌组织中高表达与患者血清AFP(χ²=12.903,P=0.005)、乙型肝炎(χ²=9.535,P=0.023)、卫星灶(χ²=9.574,P=0.023)和肿瘤复发、转移及生存期有关,而与性别、肿瘤大小、肝硬化和肿瘤分化无关;Kaplan-Meier分析显示DNMT1/3b阳性组患者生存时间较阴性组短,差异有统计学意义(P<0.05)。高通量基因组甲基化芯片技术筛选出肝癌细胞中受DNMT1和DNMT3b调控的基因2 000多个,其中参与肿瘤侵袭转移的靶基因有112个。 结论DNMT1/3b在肝癌组织中高表达与患者血清AFP、乙型肝炎、卫星灶和肿瘤复发、转移等临床病理特征和生存期密切相关,并可能通过调控多方面肿瘤相关基因促进肝癌复发、转移等恶性表型。

Correlation between DNMT1/3b and the clinicopathology and prognosis of hepatocellular carcinoma

ObjectiveTo detect the protein expression of DNMT1 and DNMT3b, and to explore the association of DNMT1/3b with the clinicopathology and prognosis of hepatocellular carcinoma. MethodsEighty-nine cases of hepatocellular carcinoma were detected by immunohistochemistry (IHC) for analysis of the correlation between DNMT1/3b expression and clinicopathologic parameters and the tumor-free survival and overall survival. And high-throughput gene chip technology was used to screen out DNMT1 and DNMT3b target genes. ResultsBoth DNMT1 and DNMT3b expressions existed in 63 cases while 5 cases had neither DNMT1 nor DNMT3b. Nine cases had positive DNMT1 and 12 had positive DNMT3b. High level expression of DNMT1/3b was associated with serum AFP (χ²=12.903, P=0.005), HBV (χ²=9.535, P=0.023), satellite opacities (χ²=9.574, P=0.023), tumor recurrence and metastasis, and overall survival. No association was found with sex, size of tumor, liver cirrhosis and tumor differentiation. By Kaplan-Meier analysis, survival time was shorter in the patients with DNMT1 and/or 3b overexpression than in those with negative DNMT1 and 3b. More than 2 000 DNMT1 and DNMT3b target genes were screened out through high-throughput gene chip technology, and 112 of which were involved in tumor invasion and metastasis. ConclusionsThe overexpression of DNMT1 and DNMT3b are significantly related to the clinical and pathological characteristics such as serum AFP, HBV, satellite opacities, tumor recurrence and metastasis, and survival rate in hepatocellular carcinoma, and they can regulate a various tumor related genes in promoting the malignant phenotype including recurrence and metastasis of hepatocellular carcinoma.