2003 Fiscal Year Annual Research Report

消化器癌に対するDNA修復異常に立脚した治療戦略の構築

Research Project

Project/Area Number	15390400
Research Category	Grant-in-Aid for Scientific Research (B)
Research Institution	佐賀医科大学
Principal Investigator	宮崎耕治佐賀大学, 医学部, 教授 (30159173)
Co-Investigator(Kenkyū-buntansha)	濱本隆浩佐賀大学, 医学部, 助手 (80304905) 北島吉彦佐賀大学, 医学部, 講師 (30234256)
Keywords	消化器癌 / 胆道癌 / MGMT / hMLH1 / 遺伝子変異 / DNAメチル化 / アルキル化抗癌剤 / CDDP
Research Abstract	MGMTはアルキル化剤により引き起こされるDNAメチル化に対する修復酵素遺伝子であり,その発現欠失はDNAにGC/AT点突然変異を惹起し,発癌や癌の進展に関与することが知られている.我々はこれまでにアルキル化剤に暴露されうる胆管癌,胆嚢癌,肝細胞癌,胃癌において,免疫組織染色により,MGMT発現欠失は癌の悪性度と予後に強く相関することを見出した.また,肝細胞癌においてMGMT発現はpromoter領域の高メチル化によるepigenetic機構により制御されることを明らかにした.以上より,MGMT発現欠失による癌悪性化の機序として,genetic異常(遺伝子変異の蓄積),epigenetic異常(同時性のDNAメチル化)の2経路を推測し,胆道癌切除症例を用いて,遺伝子変異解析(K-ras,p53,p16,β-catenin)およびpromoter高メチル化(hMLH1,E-cadherin,p16,DAPK)の解析を行った.その結果,MGMT発現は癌関連遺伝子のGC/AT点突然変異,および広範囲の癌抑制遺伝子におけるpromoter高メチル化群と相関を示し,両者の蓄積が癌悪性度増強の一因となる機序が立証された.さらにMGMTと共にミスマッチ修復遺伝子hMLH1,hMSH2の発現を検討した結果,その発現欠失の併存により胆管癌,胆嚢癌,胃癌においてさらに悪性度を増幅し予後不良となることを明らかにした.これはミスマッチ修復による遺伝子変異のアポトーシス誘導機構が失活するためと考えられるため、これをふまえて癌治療の個別化への試みとしてMGMT(-),hMLH1(+)の胆嚢癌細胞株がアルキル化抗癌剤に対し高感受性を示すことをin vitroとin vivoで示した.MGMT(+)に対してはCDDP投与によりMGMT発現が抑制され、先行投与によるアルキル化抗癌剤の感受性増強効果を立証した.さらなる個別化を検討中である。

Research Products

(9 results)

All Other

All Publications (9 results)

[Publications] A.Miyoshi: "Snail and SIP1 increase cancer invasion by upregulating distinct MMP gene family in hepatocellular carcinoma cells/"Br J Cancer. (in press).
[Publications] H.Soejima: "Silencing of imprinted p57KIP2 gene expression is associated with loss of histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer."Oncogene. (in press).
[Publications] T.Nakagawachi: "Silencing effect of CpG island hypermethylation and histone modifications on 06-methylguanine-DNA methyltransferase (MGMT) gene expression in human cancer."Oncogene. 22. 8835-8844 (2003)
[Publications] Y.Kitajima: "Loss of Expression in DNA Repair Enzymes MGMT, hMLH1 and hMSH2 during Tumor Progression in Gastric Cancer."Gastric Cancer. 6. 86-95 (2003)
[Publications] D E.Hansel: "Identification of Novel Cellular Targets in Biliary Tract Cancers using Global Gene Expression Technology."Am J Pathol. 163(1). 217-229 (2003)
[Publications] S.Matsukura: "CpG methylation of MGMT and hMLH1 promoter in hepatocellular carcinoma associated with hepatictis viral infection."Br J Cancer. 88(4). 521-529 (2003)
[Publications] S.Matsukura: "Combined Loss of Expression of 06-Methylguanine-DNA Methyltransferase and hMLH1 Accelerates progression of Hepatocellular Carcinoma."J Surg Oncol. 82(3). 194-200 (2003)
[Publications] N.Kohya: "Effects of E-Cadherin Transfection on Gene Expression of a Gallbladder Carcinoma Cell Line : Repression of Mts1/S100A4 Gene Expression."Int J Cancer. 104. 44-53 (2003)
[Publications] M.Tanaka: "Combined evaluation of mucin antigen and E-cadherin expression is a useful biomarker to apply minimally invasive therapy to gastric carcinona."Br J Surg. 90. 95-101 (2003)

2003 Fiscal Year Annual Research Report

消化器癌に対するDNA修復異常に立脚した治療戦略の構築

Principal Investigator

宮崎 耕治 佐賀大学, 医学部, 教授 (30159173)

Research Products

[Publications] A.Miyoshi: "Snail and SIP1 increase cancer invasion by upregulating distinct MMP gene family in hepatocellular carcinoma cells/"Br J Cancer. (in press).

[Publications] H.Soejima: "Silencing of imprinted p57KIP2 gene expression is associated with loss of histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer."Oncogene. (in press).

[Publications] T.Nakagawachi: "Silencing effect of CpG island hypermethylation and histone modifications on 06-methylguanine-DNA methyltransferase (MGMT) gene expression in human cancer."Oncogene. 22. 8835-8844 (2003)

[Publications] Y.Kitajima: "Loss of Expression in DNA Repair Enzymes MGMT, hMLH1 and hMSH2 during Tumor Progression in Gastric Cancer."Gastric Cancer. 6. 86-95 (2003)

[Publications] D E.Hansel: "Identification of Novel Cellular Targets in Biliary Tract Cancers using Global Gene Expression Technology."Am J Pathol. 163(1). 217-229 (2003)

[Publications] S.Matsukura: "CpG methylation of MGMT and hMLH1 promoter in hepatocellular carcinoma associated with hepatictis viral infection."Br J Cancer. 88(4). 521-529 (2003)

[Publications] S.Matsukura: "Combined Loss of Expression of 06-Methylguanine-DNA Methyltransferase and hMLH1 Accelerates progression of Hepatocellular Carcinoma."J Surg Oncol. 82(3). 194-200 (2003)

[Publications] N.Kohya: "Effects of E-Cadherin Transfection on Gene Expression of a Gallbladder Carcinoma Cell Line : Repression of Mts1/S100A4 Gene Expression."Int J Cancer. 104. 44-53 (2003)

[Publications] M.Tanaka: "Combined evaluation of mucin antigen and E-cadherin expression is a useful biomarker to apply minimally invasive therapy to gastric carcinona."Br J Surg. 90. 95-101 (2003)

宮崎耕治佐賀大学, 医学部, 教授 (30159173)