Aberrant promoter methylation of insulin-like growth factor binding protein-3 gene in human cancers
International Journal of Cancer. 2007 Feb 1;120(3):566-73. [Link]
Kunitoshi Tomii 1, Kazunori Tsukuda 1, Shinichi Toyooka 1 *, Hideaki Dote 1, Tadashi Hanafusa 2, Hiroaki Asano 1, Minoru Naitou 1, Hiroyoshi Doihara 1, Takumi Kisimoto 3, Hideki Katayama 4, Harvery I. Pass 5, Hiroshi Date 1, Nobuyoshi Shimizu 1
1Department of Cancer and Thoracic Surgery, Shikata Laboratory, Advanced Science Research Center, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
2Department of Radiation Research, Shikata Laboratory, Advanced Science Research Center, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
3Department of Internal Medicine, Okayama Rousai Hospital, Okayama, Japan
4Department of Respiratory Medicine, National Sanyo Hospital, Respiratory Disease Center, Ube, Japan
5Division of Thoracic Surgery and Thoracic Oncology, Department of Cardiothoracic Surgery, NYU School of Medicine and NCI Cancer Center, New York, NY
email: Shinichi Toyooka (s_toyooka@nigeka2.hospital.okayama-u.ac.jp)
*Correspondence to Shinichi Toyooka, Department of Cancer and Thoracic Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan
Abstract
Insulin-like growth factor binding protein-3 (IGFBP-3) is postulated to be a mediator of growth suppression signals. Here, we examined the methylation status of IGFBP-3 to correlate to clinicopathological factors in human cancers. The methylation status of IGFBP-3 was determined by bisulfite DNA sequencing and was correlated with expression semi-quantified by real-time RT-PCR to develop a methylation-specific PCR (MSP) assay for IGFBP-3. Using the MSP assay, we examined the methylation status of IGFBP-3 in gastric cancer (GC), colorectal cancer (CRC), breast cancer (BC) and malignant mesothelioma (MM). IGFBP-3 methylation was detected in 6 of 13 (46%) and 16 of 24 (67%) GC cell lines and tumors, respectively; 4 of 8 (50%) and 15 of 26 (58%) CRC cell lines and tumors, respectively; 3 of 11 (27%) and 7 of 39 (18%) BC cell lines and tumors, respectively and 1 of 5 (20%) and 18 of 56 (32%) MM cell lines and tumors, respectively. Interestingly, the methylation status of MM specimens from Japanese patients (75%, 12 out of 16 patients) was significantly higher than those from the USA (15%, 6 out of 40 patients) (p < 0.0001), suggesting the presence of ethnic differences in the IGFBP-3 methylation status. We also found that IGFBP-3 methylation was preferentially present in GCs arising in the lower-third of the stomach (p = 0.079). In summary, our results showed that IGFBP-3 methylation played an important role in the silencing of its expression, suggesting that IGFBP-3 may act as a tumor suppressor gene in several human cancers examined.
