Abstract
ObjectiveThe KLF4 gene has been shown to be inactivated in cervical carcinogenesis as a tumor suppressor. However, the mechanism of KLF4 silencing in cervical carcinomas has not yet been identified. DNA methylation plays a key role in stable suppression of gene expression.MethodsThe methylation status of the KLF4 promoter CpG islands was analyzed by bisulfite sequencing (BSQ) in tissues of normal cervix and cervical cancer. KLF4 gene expression was detected by RT-PCR, immunohistochemistry and western blot. KLF4 promoter methylation in cervical cancer cell line was determined by BSQ and methylation-specific polymerase chain reaction (MS-PCR). Cell proliferation ability was detected by cell growth curve and MTT assay.ResultsThe methylated allele was found in 41.90% of 24 cervical cancer tissues but only in 11.11% of 11 normal cervix tissues (P<0.005). KLF4 mRNA levels were significantly reduced in cervical cancer tissues compared with normal cervix tissues (P<0.01) and KLF4 mRNA expression showed a significant negative correlation with the promoter hypermethylation (r = −0.486, P = 0.003). Cervical cancer cell lines also showed a significant negative correlation between KLF4 expression and hypermethylation. After treatment with the demethylating agent 5-Azacytidine (5-Aza), the expression of KLF4 in the cervical cancer cell lines at both mRNA and protein levels was drastically increased, the cell proliferation ability was inhibited and the chemosensitivity for cisplatin was significantly increased.ConclusionKLF4 gene is inactivated by methylation-induced silencing mechanisms in a large subset of cervical carcinomas and KLF4 promoter hypermethylation inactivates the gene’s function as a tumor suppressor in cervical carcinogenesis.
Highlights
Cervical cancer is a major contributor to cancer-related death in females worldwide and accounts for 250,000 deaths each year [1]
The overexpression of exogenous KLF4 protein was found to inhibit cervical carcinoma cell growth and tumor formation both in vitro and in vivo by activating the cell cycle suppressor p27Kip1, suggesting that KLF4 works as a tumor suppressor in cervical carcinoma
The methylation status of the KLF4 promoter was examined in tissues from normal cervix and cervical carcinoma
Summary
Cervical cancer is a major contributor to cancer-related death in females worldwide and accounts for 250,000 deaths each year [1]. Several reports have suggested that the aggressive nature of human cervical carcinoma is related to a number of molecular abnormalities, including inactivation of various tumor suppressor genes and activation of various oncogenes [4]. The KLF4 gene was shown to be genetically and epigenetically inactivated in human pancreatic cancer and gastric cancer, as well as in medulloblastoma, and to be mutated in colon cancer [12,18,19,20]. The KLF4 gene was found to be inactivated and to function as a tumor suppressor in cervical carcinogenesis [21]. It remains unknown how KLF4 is silenced in cervical carcinomas
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