2002 Fiscal Year Annual Research Report

ヒトがんの発生・進展における遺伝子異常の解明、ならびにがん診療への応用

Research Project

Project/Area Number	12213010
Research Institution	Tohoku University
Principal Investigator	堀井明東北大学, 大学院・医学系研究科, 教授 (40249983)
Co-Investigator(Kenkyū-buntansha)	砂村真琴東北大学, 医学部附属病院, 講師 (10201584) 八重樫伸生東北大学, 大学院・医学系研究科, 教授 (00241597)
Keywords	膵癌 / 遺伝子治療 / アデノウイルス / DUSP6 / MKP-3 / SMAD4 / 染色体18q / DNAミスマッチ修復異常 / 酵母two-hybrid
Research Abstract	膵癌における高頻度欠失領域のうち12q、17p、18qの欠失が予後不良と相関する。12qのDUSP6/MKP-3は膵癌において高頻度に発現が抑制されている。免疫染色では、このタンパクはKRASのルートの下流でERKに特異的に働くphosphataseで、免疫染色により、膵のdysplasiaでは発現の増強が見られるのに対し、浸潤癌では、発現が高度に抑制され、特に低分化型において顕著であった。アデノの系で膵癌細胞に導入するとアポトーシスが誘導され、膵癌の治療への応用の可能性が示唆された。さらに、マイクロアレイにより、DUSP6/MKP-3の導入後に発現が変化する遺伝子を複数同定しており、これらの遺伝子発現の変化の発癌への関与について検討を加えている。また、膵癌で初期から高頻度に欠失が見られる18qにおいて、これまでにSMAD4以外に癌抑制遺伝子の存在を示唆してきたが、膵癌株に正常18番染色体を導入すると、SMAD4の異常の有無に無関係に増殖抑制効果が見られ、さらに、転移抑制効果も見られた。DNAミスマッチ修復異常は発がんにおいて重要な役割を果たしているが、hMLH1の異常はHNPCCの最も多い原因である。この場合、ミスセンス変異の解釈が重要であり、簡便かつ確実に、希な多型であるのかpathogenicな変異であるのかを区別できる方法が必要である。yeastのtwo-hybrid法により検討し、false positiveが見られず、きわめて高感度に異常を検出でき、本方法が極めて優れていることを明らかにした。

Research Products

(13 results)

All Other

All Publications (13 results)

[Publications] Furukawa, T., Sunamura, M., Horii, A., et al.: "Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer"Am.J.Pathol.. (in press).
[Publications] Kondo, E., Horii, A., et al.: "Yeast two-hybrid assay provides a simple way to evaluate a vast majority of hMLH1 germline mutations"Cancer Res.. (in press).
[Publications] Kadota, M., Horii, A.et al.: "Loss of heterozygosity on chromosome 16p and 18q in anaplastic thyroid carcinoma"Oncol.Rep.. 10. 35-38 (2003)
[Publications] Hatada, I., Horii, A.et al.: "A microarray-based method for detecting methylated loci"J.Hum.Genet.. 47. 448-451 (2002)
[Publications] Lefter, L.P., Sunamura, M., Horii, A.et al.: "Suppression of the tumorigenic phenotype by chromosome 18transfer into pancreatic cancer cell lines"Genes Chromosomes Cancer. 27. 234-242 (2002)
[Publications] Yokoi, S., Horii, A.et al.: "A novel target gene, SKP2, within the 5p13 amplicon that is frequently detected in small cell lung cancers"Am.J.Pathol.. 161. 207-216 (2002)
[Publications] Duda, D.G., Sunamura, M., Horii, A.et al.: "Brain specific angiogenesis inhibitor 1 mediates the p53 inhibitory effect on tumor angiogenesis by the downregulation of collagenase expression"Br.J.Cancer. 86. 490-496 (2002)
[Publications] Sunamura, M., et al.: "Gene therapy for pancreatic cancer based on its genetic characterization"J.Hep.Bil.Pancreat.Surg.. 9. 32-38 (2002)
[Publications] Mikami, Y., Sunamura, M., et al.: "Peritoneal inflammatory cells in acute pancreatitis : Relationship of infiltration dynamics and cytokine production with severity of illness"Surgery. 132. 86-92 (2002)
[Publications] Hoshida, T., Sunamura, M., et al.: "Gene Therapy for pancreatic cancer using an adenovirus vector encoding soluble flt-1 vascular endothelial growth factor receptor"Pancreas. 25. 111-121 (2002)
[Publications] Oonuma, M., Sunamura, M.et al.: "Gene therapy for intraperitoneally disseminated pancreatic cancers by Escherichia coli Uracil Phosphoribosiltransferase (UPRT) gene mediated by restricted replication-competent adenoviral vectors"Int.J.Cancer. 102. 51-59 (2002)
[Publications] Kadowaki, M., Yaegashi, N.et al.: "Prediction of the effects of gonadotropin-releasing hormone agonist therapy in uterine leiomyoma by contrast-enhanced magnetic resonance imaging sequences"Fertil.Steril.. 5. 1081-1082 (2002)
[Publications] Yokomizo, R., Yaegashi, N.et al.: "Erythropoietin and erythropoietin receptor expresiion in human endometrium throughout the menstrual cyst"Mol.Hum.Reproduct.. 8. 441-446 (2002)

2002 Fiscal Year Annual Research Report

ヒトがんの発生・進展における遺伝子異常の解明、ならびにがん診療への応用

Principal Investigator

堀井 明 東北大学, 大学院・医学系研究科, 教授 (40249983)

Research Products

[Publications] Furukawa, T., Sunamura, M., Horii, A., et al.: "Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer"Am.J.Pathol.. (in press).

[Publications] Kondo, E., Horii, A., et al.: "Yeast two-hybrid assay provides a simple way to evaluate a vast majority of hMLH1 germline mutations"Cancer Res.. (in press).

[Publications] Kadota, M., Horii, A.et al.: "Loss of heterozygosity on chromosome 16p and 18q in anaplastic thyroid carcinoma"Oncol.Rep.. 10. 35-38 (2003)

[Publications] Hatada, I., Horii, A.et al.: "A microarray-based method for detecting methylated loci"J.Hum.Genet.. 47. 448-451 (2002)

[Publications] Lefter, L.P., Sunamura, M., Horii, A.et al.: "Suppression of the tumorigenic phenotype by chromosome 18transfer into pancreatic cancer cell lines"Genes Chromosomes Cancer. 27. 234-242 (2002)

[Publications] Yokoi, S., Horii, A.et al.: "A novel target gene, SKP2, within the 5p13 amplicon that is frequently detected in small cell lung cancers"Am.J.Pathol.. 161. 207-216 (2002)

[Publications] Duda, D.G., Sunamura, M., Horii, A.et al.: "Brain specific angiogenesis inhibitor 1 mediates the p53 inhibitory effect on tumor angiogenesis by the downregulation of collagenase expression"Br.J.Cancer. 86. 490-496 (2002)

[Publications] Sunamura, M., et al.: "Gene therapy for pancreatic cancer based on its genetic characterization"J.Hep.Bil.Pancreat.Surg.. 9. 32-38 (2002)

[Publications] Mikami, Y., Sunamura, M., et al.: "Peritoneal inflammatory cells in acute pancreatitis : Relationship of infiltration dynamics and cytokine production with severity of illness"Surgery. 132. 86-92 (2002)

[Publications] Hoshida, T., Sunamura, M., et al.: "Gene Therapy for pancreatic cancer using an adenovirus vector encoding soluble flt-1 vascular endothelial growth factor receptor"Pancreas. 25. 111-121 (2002)

[Publications] Oonuma, M., Sunamura, M.et al.: "Gene therapy for intraperitoneally disseminated pancreatic cancers by Escherichia coli Uracil Phosphoribosiltransferase (UPRT) gene mediated by restricted replication-competent adenoviral vectors"Int.J.Cancer. 102. 51-59 (2002)

[Publications] Kadowaki, M., Yaegashi, N.et al.: "Prediction of the effects of gonadotropin-releasing hormone agonist therapy in uterine leiomyoma by contrast-enhanced magnetic resonance imaging sequences"Fertil.Steril.. 5. 1081-1082 (2002)

[Publications] Yokomizo, R., Yaegashi, N.et al.: "Erythropoietin and erythropoietin receptor expresiion in human endometrium throughout the menstrual cyst"Mol.Hum.Reproduct.. 8. 441-446 (2002)

堀井明東北大学, 大学院・医学系研究科, 教授 (40249983)