Despite the recent advances in the therapeutic modalities,colorectal cancer(CRC)remains to be one of the most common causes of cancer-related death.CRC arises through accumulation of multiple genetic and epigenetic al...Despite the recent advances in the therapeutic modalities,colorectal cancer(CRC)remains to be one of the most common causes of cancer-related death.CRC arises through accumulation of multiple genetic and epigenetic alterations that transform normal colonic epithelium into adenocarcinomas.Among crucial roles of epigenetic alterations,gene silencing by aberrant DNA methylation of promoter regions is one of the most important epigenetic mechanisms.Recent comprehensive methylation analyses on genome-wide scale revealed that sporadic CRC can be classified into distinct epigenotypes.Each epigenotype cooperates with specific genetic alterations,suggesting that they represent different molecular carcinogenic pathways.Precursor lesions of CRC,such as conventional and serrated adenomas,already show similar methylation accumulation to CRC,and can therefore be classified into those epigenotypes of CRC.In addition,specific DNA methylation already occurs in the normal colonic mucosa,which might be utilized for prediction of the personal CRC risk.DNA methylation is suggested to occur at an earlier stage than carcinoma formation,and may predict the molecular basis for future development of CRC.Here,we review DNA methylation and CRC classification,and discuss the possible clinical usefulness of DNA methylation as biomarkers for the diagnosis,prediction of the prognosis and the response to therapy of CRC.展开更多
Accumulation of mutations and alterations in the expression of various genes result in carcinogenesis,and the development of microarray technology has enabled us to identify the comprehensive gene expression alteratio...Accumulation of mutations and alterations in the expression of various genes result in carcinogenesis,and the development of microarray technology has enabled us to identify the comprehensive gene expression alterations in oncogenesis.Many studies have applied this technology for hepatocellular carcinoma(HCC),and identified a number of candidate genes useful as biomarkers in cancer staging,prediction of recurrence and prognosis,and treatment selection.Some of these target molecules have been used to develop new serum diagnostic markers and therapeutic targets against HCC to benefit patients.Previously,we compared gene expression profiling data with classification based on clinicopathological features,such as hepatitis viral infection or liver cancer progression.The next era of gene expression analysis will require systematic integration of expression profiles with other types of biological information,such as genomic locus,gene function,and sequence information.We have reported integration between expression profiles and locus information,which is effective in detecting structural genomic abnormalities,such as chromosomal gains and losses,in which we showed that gene expression profiles are subject to chromosomal bias.Furthermore,array-based comparative genomic hybridization analysis and allelic dosage analysis using genotyping arrays for HCC were also reviewed,with comparison of conventional methods.展开更多
AIM: To investigate epigenomic and gene expression alterations during cellular senescence induced by oncogenic Raf. METHODS: Cellular senescence was induced into mouse embryonic fibroblasts(MEFs) by infecting retrovir...AIM: To investigate epigenomic and gene expression alterations during cellular senescence induced by oncogenic Raf. METHODS: Cellular senescence was induced into mouse embryonic fibroblasts(MEFs) by infecting retrovirus to express oncogenic Raf(RafV 600E). RNA was collected from RafV 600 E cells as well as MEFs without infection and MEFs with mock infection, and a genome-wide gene expression analysis was performed using microarray. The epigenomic status for active H3K4me3 and repressive H3K27me3 histone marks was analyzed by chromatin immunoprecipitation-sequencing for RafV 600 E cells on day 7 and for MEFs without infection. These data for Raf-induced senescence were compared with data for Ras-induced senescence that were obtained in our previous study. Gene knockdown and overexpression were done by retrovirus infection. RESULTS: Although the expression of some genes including secreted factors was specifically altered in either Ras- or Raf-induced senescence, many genes showed similar alteration pattern in Raf- and Ras-induced senescence. A total of 841 commonly upregulated 841 genes and 573 commonly downregulated genes showed a significant enrichment of genes related to signal and secreted proteins, suggesting the importance of alterations in secreted factors. Bmp2, a secreted protein to activate Bmp2-Smad signaling, was highly upregulated with gain of H3K4me3 and loss of H3K27me3 during Raf-induced senescence, as previously detected in Ras-induced senescence, and the knockdown of Bmp2 by sh RNA lead to escape from Raf-induced senescence. Bmp2-Smad inhibitor Smad6 was strongly repressed with H3K4me3 loss in Raf-induced senescence, as detected in Ras-induced senescence, and senescence was also bypassed by Smad6 induction in Raf-activated cells. Different from Ras-induced senescence, however, gain of H3K27me3 did not occur in the Smad6 promoter region during Raf-induced senescence. When comparing genome-wide alteration between Ras- and Raf-induced senescence, genes showing loss of H3K27me3 during senescence significantly overlapped; genes showing H3K4me3 gain, or those showing H3K4me3 loss, also well-overlapped between Ras- and Raf-induced senescence. However, genes with gain of H3K27me3 overlapped significantly rarely, compared with those with H3K27me3 loss, with H3K4me3 gain, or with H3K4me3 loss.CONCLUSION: Although epigenetic alterations are partly different, Bmp2 upregulation and Smad6 repression occur and contribute to Raf-induced senescence, as detected in Ras-induced senescence.展开更多
文摘Despite the recent advances in the therapeutic modalities,colorectal cancer(CRC)remains to be one of the most common causes of cancer-related death.CRC arises through accumulation of multiple genetic and epigenetic alterations that transform normal colonic epithelium into adenocarcinomas.Among crucial roles of epigenetic alterations,gene silencing by aberrant DNA methylation of promoter regions is one of the most important epigenetic mechanisms.Recent comprehensive methylation analyses on genome-wide scale revealed that sporadic CRC can be classified into distinct epigenotypes.Each epigenotype cooperates with specific genetic alterations,suggesting that they represent different molecular carcinogenic pathways.Precursor lesions of CRC,such as conventional and serrated adenomas,already show similar methylation accumulation to CRC,and can therefore be classified into those epigenotypes of CRC.In addition,specific DNA methylation already occurs in the normal colonic mucosa,which might be utilized for prediction of the personal CRC risk.DNA methylation is suggested to occur at an earlier stage than carcinoma formation,and may predict the molecular basis for future development of CRC.Here,we review DNA methylation and CRC classification,and discuss the possible clinical usefulness of DNA methylation as biomarkers for the diagnosis,prediction of the prognosis and the response to therapy of CRC.
文摘Accumulation of mutations and alterations in the expression of various genes result in carcinogenesis,and the development of microarray technology has enabled us to identify the comprehensive gene expression alterations in oncogenesis.Many studies have applied this technology for hepatocellular carcinoma(HCC),and identified a number of candidate genes useful as biomarkers in cancer staging,prediction of recurrence and prognosis,and treatment selection.Some of these target molecules have been used to develop new serum diagnostic markers and therapeutic targets against HCC to benefit patients.Previously,we compared gene expression profiling data with classification based on clinicopathological features,such as hepatitis viral infection or liver cancer progression.The next era of gene expression analysis will require systematic integration of expression profiles with other types of biological information,such as genomic locus,gene function,and sequence information.We have reported integration between expression profiles and locus information,which is effective in detecting structural genomic abnormalities,such as chromosomal gains and losses,in which we showed that gene expression profiles are subject to chromosomal bias.Furthermore,array-based comparative genomic hybridization analysis and allelic dosage analysis using genotyping arrays for HCC were also reviewed,with comparison of conventional methods.
基金Supported by The CREST program,Japan Agency for Medical Research and Development to Kaneda Agrants from the Uehara Memorial Foundation+1 种基金Takeda Science FoundationPublic Trust Surgery Research Fund to Kaneda A
文摘AIM: To investigate epigenomic and gene expression alterations during cellular senescence induced by oncogenic Raf. METHODS: Cellular senescence was induced into mouse embryonic fibroblasts(MEFs) by infecting retrovirus to express oncogenic Raf(RafV 600E). RNA was collected from RafV 600 E cells as well as MEFs without infection and MEFs with mock infection, and a genome-wide gene expression analysis was performed using microarray. The epigenomic status for active H3K4me3 and repressive H3K27me3 histone marks was analyzed by chromatin immunoprecipitation-sequencing for RafV 600 E cells on day 7 and for MEFs without infection. These data for Raf-induced senescence were compared with data for Ras-induced senescence that were obtained in our previous study. Gene knockdown and overexpression were done by retrovirus infection. RESULTS: Although the expression of some genes including secreted factors was specifically altered in either Ras- or Raf-induced senescence, many genes showed similar alteration pattern in Raf- and Ras-induced senescence. A total of 841 commonly upregulated 841 genes and 573 commonly downregulated genes showed a significant enrichment of genes related to signal and secreted proteins, suggesting the importance of alterations in secreted factors. Bmp2, a secreted protein to activate Bmp2-Smad signaling, was highly upregulated with gain of H3K4me3 and loss of H3K27me3 during Raf-induced senescence, as previously detected in Ras-induced senescence, and the knockdown of Bmp2 by sh RNA lead to escape from Raf-induced senescence. Bmp2-Smad inhibitor Smad6 was strongly repressed with H3K4me3 loss in Raf-induced senescence, as detected in Ras-induced senescence, and senescence was also bypassed by Smad6 induction in Raf-activated cells. Different from Ras-induced senescence, however, gain of H3K27me3 did not occur in the Smad6 promoter region during Raf-induced senescence. When comparing genome-wide alteration between Ras- and Raf-induced senescence, genes showing loss of H3K27me3 during senescence significantly overlapped; genes showing H3K4me3 gain, or those showing H3K4me3 loss, also well-overlapped between Ras- and Raf-induced senescence. However, genes with gain of H3K27me3 overlapped significantly rarely, compared with those with H3K27me3 loss, with H3K4me3 gain, or with H3K4me3 loss.CONCLUSION: Although epigenetic alterations are partly different, Bmp2 upregulation and Smad6 repression occur and contribute to Raf-induced senescence, as detected in Ras-induced senescence.
