한빛사 논문
Abstract
Bo Hwa Sohn12, In Young Park1, Jung Ju Lee1, Suk-Jin Yang1, Ye Jin Jang1, Kyung Chan Park1, Dong Joon Kim1, Dong Chul Lee1, Hyun Ahm Sohn1, Tae Woo Kim1, Hyang-Sook Yoo1, Jong Young Choi3, Yun Soo Bae2, Young Il Yeom1
Received 17 April 2009; received in revised form 16 November 2009; accepted 17 December 2009. published online 28 December 2009.
Abstract
Background & Aims:
Acquisition of resistance to the anti-proliferative effect of TGFβ1 is crucial for the malignant progression of cancers. TTP is a negative posttranscriptional regulator of ARE-containing mRNAs, including c-Myc. In this study, we sought to determine whether de-regulated expression of TTP confers resistance to the anti-proliferative effects of TGFβ1 on liver cancer cells and elucidate the underlying mechanisms.
Methods:
The epigenetics of TTP promoter regulation and its effects on TGFβ1 signaling were examined in hepatocellular carcinoma (HCC) cell lines and patient tissues.
Results:
TTP was down-regulated in HCC cell lines (10/11), compared to normal liver, as well as in tumor tissues (19/24) from paired HCC specimens. Methylation of a specific single CpG site located within the TGFβ1-responsive region (TRR) of the TTP promoter was significantly associated with TTP down-regulation in both HCC cell lines and tumor tissues (r=-0.606383, P<0.001). The singly methylated CpG site was specifically bound by a transcriptional repressor complex consisting of MECP2/c-Ski/DNMT3A, and abolished the TGFβ1-induced as well as basal-level expression of TTP. The epigenetic inactivation of TTP led to an increased half-life of c-Myc mRNA and blocked the cytostatic effect of TGFβ1. Statistically significant correlations were observed between the single CpG site methylation and expression levels of TTP or c-Myc in clinical samples of HCC.
Conclusions:
Abrogation of the posttranscriptional regulation of c-Myc via methylation of a specific single CpG site in the TTP promoter presents a novel mechanism for the gain of selective resistance to the anti-proliferative signaling of TGFβ1 in HCC.
Keywords: TTP, TGFβ1, Methylation, HCC, c-Myc
1 Medical Genomics Research Center, KRIBB, Daejeon, Korea
2 Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea
3 Department of Internal Medicine, Kangnam St. Mary’s Hospital, Seoul, Korea
Address requests for reprints to: Young Il Yeom, Ph.D., Medical Genomics Research Center, KRIBB, Daejeon, 305-806, Korea, Fax: (82) 42-879-8119.
PII: S0016-5085(09)02241-0
doi:10.1053/j.gastro.2009.12.044
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