Kloth Judith N, Gorter Arko, ter Haar Natalja, Corver Willem E, Jordanova Ekaterina S, Kenter Gemma G, Fleuren Gert Jan
Department of Pathology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
Mol Immunol. 2008 Jan;45(1):152-9. doi: 10.1016/j.molimm.2007.04.028. Epub 2007 Jun 8.
Infection with oncogenic human papillomavirus (HPV) is considered to be the major etiologic event for cervical cancer. Tumor necrosis factor alpha (TNFalpha), a proinflammatory cytokine, may be involved in orchestrating an antitumor immune response against human papillomavirus expressing cervical cancer cells. Hence, loss of TNFalpha could be advantageous for tumor cells to escape immune clearance. The aim of our study was to investigate TNFalpha gene expression and epigenetic characteristics associated with the loss of TNFalpha expression in cervical cancer. To this end, we examined TNFalpha expression, loss of heterozygosity (LOH) at 6p21.3, the locus of TNFalpha, mutational status of the TNFalpha locus, loss of the TNFalpha promoter variant 2 allele and CpG hypermethylation of the TNFalpha promoter. RNA in situ hybridization showed absence of TNFalpha expression in 45% of 63 tumors. LOH occurred in 57% of the tumors and was not concordant with absence of TNFalpha mRNA. No mutations in the TNFalpha gene were identified in 15 cases deficient in TNFalpha expression exhibiting LOH. Furthermore, lack of TNFalpha expression did not correlate with promoter methylation. In conclusion, TNFalpha mRNA expression is absent in nearly half of the cervical tumors analyzed. Neither promoter methylation nor genetic causes for lack of expression were evident.
致癌性人乳头瘤病毒（HPV）感染被认为是宫颈癌的主要病因。肿瘤坏死因子α（TNFα）是一种促炎细胞因子，可能参与对表达人乳头瘤病毒的宫颈癌细胞进行抗肿瘤免疫反应的调控。因此，TNFα的缺失可能有利于肿瘤细胞逃避免疫清除。我们研究的目的是调查宫颈癌中TNFα基因表达以及与TNFα表达缺失相关的表观遗传学特征。为此，我们检测了TNFα表达、TNFα基因座6p21.3处的杂合性缺失（LOH）、TNFα基因座的突变状态、TNFα启动子变体2等位基因的缺失以及TNFα启动子的CpG高甲基化。RNA原位杂交显示63例肿瘤中有45%不存在TNFα表达。57%的肿瘤发生了LOH，且与TNFα mRNA的缺失不一致。在15例表现出LOH且TNFα表达缺失的病例中未发现TNFα基因的突变。此外，TNFα表达的缺乏与启动子甲基化无关。总之，在近一半分析的宫颈肿瘤中不存在TNFα mRNA表达。缺乏表达的启动子甲基化和遗传原因均不明显。
