|Epigenetic silencing of PTPRR activates MAPK signaling, promotes metastasis and serves as a biomarker of invasive cervical cancer.|
Su, PH; Lin, YW; Huang, RL; Liao, YP; Lee, HY; Wang, HC; Chao, TK; Chen, CK; Chan, MW; Chu, TY; Yu, MH; Lai, HC
Epigenetic modifications are a driving force in carcinogenesis. However, their role in cancer metastasis remains poorly understood. The present study investigated the role of DNA methylation in the cervical cancer metastasis. Here, we report evidence of the overexpression of DNA methyltransferases 3B (DNMT3B) in invasive cervical cancer and of the inhibition of metastasis by DNMT3B interference. Using methyl-DNA immunoprecipitation coupled with microarray analysis, we found that the protein tyrosine phosphatase receptor type R (PTPRR) was silenced through DNMT3B-mediated methylation in the cervical cancer. PTPRR inhibited p44/42 MAPK signaling, the expression of the transcription factor AP1, human papillomavirus (HPV) oncogenes E6/E7 and DNMTs. The methylation status of PTPRR increased in cervical scrapings (n=358) in accordance with disease severity, especially in invasive cancer. Methylation of the PTPRR promoter has an important role in the metastasis and may be a biomarker of invasive cervical cancer.
|Effects of perinatal hypothyroidism on regulation of reelin and brain-derived neurotrophic factor gene expression in rat hippocampus: Role of DNA methylation and histone acetylation.|
Sui L, Li BM
Thyroid hormones have long been known to play important roles in the development and functions of the central nervous system, however, the precise molecular mechanisms that regulate thyroid hormone-responsive gene expression are not well understood. The present study investigated the role of DNA methylaion and histone acetylation in the effects of perinatal hypothyroidism on regulation of reelin and brain-derived neurotrophic factor (BDNF) gene expression in rat hippocampus. The findings indicated that the activities of DNA methyltransferase (DNMT), methylated reelin and BDNF genes were up-regulated, whereas, the activities of histone acetylases (HAT), the levels of global acetylated histone 3 (H3) and global acetylated histone 4 (H4), and acetylated H3, acetylated H4 at reelin promoter and at BDNF gene promoter for exon II were down-regulated in the hippocampus at the developmental stage of the hypothyroid animals. These results suggest that epigenetic modification of chromatin might underlie the mechanisms of hypothyroidism-induced down-regulation of reelin and BDNF gene expression in developmental rat hippocampus. Copyright © 2010 Elsevier Inc. All rights reserved.
|Inactivation of O6-methylguanine-DNA methyltransferase in soft tissue sarcomas: association with K-ras mutations.|
Jeung Il Kim,Jeung Tak Suh,Kyung Un Choi,Hyun Jeong Kang,Dong Hoon Shin,In Sook Lee,Tae Yong Moon,Won Taek Kim
The DNA-repair protein O(6)-methylguanine-DNA methyltransferase removes alkyl adducts from the O(6)-position of guanine. The adducts can mispair with T during DNA replication, resulting in a G-to-A mutation. Epigenetic inactivation of O(6)-methylguanine-DNA methyltransferase has been found in human neoplasia and is considered one of the implicated factors in chemoresistance. Sixty-two patients with soft tissue sarcomas were analyzed with regard to the status of O(6)-methylguanine-DNA methyltransferase protein expression status using immunohistochemistry and promoter hypermethylation of the MGMT gene using methylation-specific PCR. G-to-A transitions in codons 12 and 13 of the K-ras oncogene were investigated using PCR and direct automated sequencing analysis. A loss of O(6)-methylguanine-DNA methyltransferase expression was noted in 20 (32.3%) cases of 62 total soft tissue sarcomas. The MGMT promoter hypermethylation rate was 33.9% (21/62 cases). Of the 54 sarcomas evaluated, K-ras mutations were found in only 2 (3.7%) cases. Loss of O(6)-methylguanine-DNA methyltransferase expression and MGMT promoter hypermethylation showed a significant association with high American Joint Committee on Cancer stage, high French Federation of Cancer Centers grade, and aggressive behavior. On multivariate analysis, these were not an independently significant prognostic factors. However, when the group receiving chemotherapy was analyzed (n = 27), loss of O(6)-methylguanine-DNA methyltransferase expression was correlated with worse survival on multivariate analysis (P = .024). MGMT promoter hypermethylation status had a strong correlation with loss of O(6)-methylguanine-DNA methyltransferase expression (P = .000). Our results suggest that MGMT promoter hypermethylation and loss of O(6)-methylguanine-DNA methyltransferase expression tend to be associated with poor prognosis and that the loss of O(6)-methylguanine-DNA methyltransferase protein expression frequently occurs via MGMT promoter hypermethylation. However, MGMT promoter hypermethylation was not significantly associated with point mutations of K-ras at codons 12 and 13 in sarcomas.
|Expression of beta-catenin and its mechanism of delocalization in intestinal-type early gastric cancer based on mucin expression.|
S H Lee, H J Kang, D-H Shin, D-Y Cho, J M Song, H C Lee, G H Kim, G A Song, M Y Sol, J Y Kim, K U Choi, C H Lee, G Y Huh, D Y Park, Soo Han Lee, Hyun Jeong Kang, Dong-Hun Shin, Duk-Yeon Cho, Jin Mi Song, Han Cheol Lee, Gwang Ha Kim, Geun Am Song, Mee Young Sol, Jee Yeon Kim, Kyung Un Choi, Chang Hun Lee, Gi Young Huh, Do Youn Park
Histology and histopathology
The biological characteristics of intestinal-type early gastric cancers (ICs) differ based on mucin phenotypes. Beta-catenin delocalization is a predictive marker of aggressive biological behavior (submucosal invasion and lymph node metastasis) of ICs. The presumptive causative genetic alterations leading to delocalization of beta-catenin in ICs are still controversial, and there are only a few reports regarding beta-catenin expression in gastric cancer based on mucin phenotypes. Therefore, in the current study, the expression and mechanisms of delocalization of beta-catenin were elucidated on the basis of mucin phenotypes in 109 cases of ICs. There was increased cytoplasmic and nuclear beta-catenin expression (delocalization) in ICs with a predominant intestinal mucin phenotype (ICIP; 46.3% [25/54 cases]) compared to ICs with a predominant gastric mucin phenotype (ICGP; 20% [11/55 cases]). There were no beta-catenin or APC mutations in ICs. APC promoter hypermethylation was present in 49 of 105 (46.7%) cases of ICs. There was a significant relationship between APC promoter hypermethylation and beta-catenin delocalization in ICs, especially in ICIPs. There was no relationship between beta-catenin delocalization and APC gene loss of heterozygosity in ICs. In conclusion, we showed that beta-catenin delocalization was more evident in ICIPs, and APC promoter hypermethylation might play a role in delocalization of beta-catenin, especially in ICIPs.