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2002 Fiscal Year Final Research Report Summary

Distinct Pattern of Oncogenic β-catenin Activation in Colorectal Cancer

Research Project

Project/Area Number 13671289
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Digestive surgery
Research InstitutionKanazawa University

Principal Investigator

MINAMOTO Toshinari  Kanazawa University, Cancer Research Institute, Professor, がん研究所, 教授 (50239323)

Co-Investigator(Kenkyū-buntansha) MAI Masayoshi  Kanazawa University, Cancer Research Institute, Professor, がん研究所, 教授 (80092807)
Project Period (FY) 2001 – 2002
KeywordsColorectal cancer / Oncogene / β-catenin / Oncogenic signaling / Molecular diagnosis / APC / K-ras / βTrCP
Research Abstract

It is fairly far from our expectation at the time when β-catenin was first identified as one of the key molecules in cell adhesion machinery that it is in central in the Wnt/ β-catenin/Tcf signaling pathway, which plays pivotal roles in normal embryonic development and differentiation and in malignant transformation of cells. Different mechanisms underlie oncogenic β-catenin acivation ; i.e., mutations in its phospho-acceptor sites, failure to recruit GSK3β because of APC mutation, or inhibition of GSK3β activity by Wnt-secreted proteins or PI3K/Akt signaling ; a consequence of them is abrogation of β-catenin phosphorylation. This leads stabilization of β-catenin and its translocation to the nucleus where it exerts oncogenic activities by transactivating certain effector genes including c-myc, cyclin D1, and MMP-7.
Unlike extensive characterization of K-ras that is another oncogene of great interest, many studies to clarify basic mechanisms of β-catenin's oncogenic functions have been c … More ompetitively pursued only in experimental but not clinical settings. It is only in recent years that a small number of reports on oncogenic β-catenin activation and its relevance to patients' pathology have been available for clinical colorectal cancers, showing that oncogenic β-catenin activation is an early event in colorectal cancer development. However, little is known for clinical relevance of this oncogene activation until we currently determined, in this research project, the two distinct patterns of its oncogenic nuclear accumulation (NA), represented by diffuse NA (Nad) and selective NA in the tumor invasion front only (Nainv), respectively as early and presumably late events. The presence of different activation patterns would be supported by evidence that β-catenin is activated in most colon cancers by escaping from a degradation machinery as a result of mutations in APC, which is known to be the earliest genetic alteration in colorectal tumorigenesis, and by our results that, in contrast to Nad pattern, Nainv pattern of β-catenin activation is independent to inactivation of APC. Recently we have obtained a result suggesting that β-transducing repeat-containing protein (βTrCP), a ubiquitin ligase receptor that targets β-catenin for proteasomal degradation, affects different patterns of β-catenin activation in the tumors. Our observation that is more important than the molecular mechanisms underlying the difference in activation patterns was that oncogenic β-catenin activation in the tumor invasion front is an independent and reliable indicator of membership in a subset of colon cancer patients who are highly susceptible to tumor recurrence and have a less favorable survival rate. Furthermore we have demonstrated that although activation of β-catenin and ras is independent in the process of clinical cancer development, combined analysis of the two major oncogenes can detect most colorectal cancers and identify a subset of patients with poorer outcomes.
Apparently, activation of β-catenin is a cosequence, with few exceptions, of its escaping from ubiquitin-mediated protein degradation, the process of which includes a growing numbers of regulators and effectors. More detailed information of the involvement of β-catenin in human cancers is promising for development of molecular diagnosis and treatment targeting this oncogene and regulators/effectors of its signaling. Less

  • Research Products

    (26 results)

All Other

All Publications (26 results)

  • [Publications] Ronai Z, Minamoto T.: "Early detection of gene mutation in cancer diagnosis"Principle and Practice of Oncology. 15・1. 1-16 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Buschmann T, Minamoto T, et al.: "Jun NH2-terminal kinase phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress"Molecular and Cellular Biology. 21・8. 2743-2754 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Minamoto T, Buschmann T, et al.: "Distinct pattern of p53 phosphorylation in human tumors"Oncogene. 20・26. 3341-3347 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ougolkov AV, Minamoto T, et al.: "Abnormal expression of E-cadherin,β-catenin and c-erbB-2 in advanced gastric cancer : its association with liver metastasis"Proceedings of 4^<th> International Gastric Cancer Congress, Monduzzi Editore S. p. A., Medimond Inc., Bologna. 765-770 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Minamoto T, Ronai Z.: "Gene mutation as target for early detection in cancer diagnosis"Critical Review in Oncology and Hematology. 40・3. 195-213 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ougolkov AV, Minamoto T, et al.: "Oncogenic β-catenin and MMP-7(matrilysin)cosegregate in late-stage clinical colon cancer"Gastroenterology. 122・1. 60-71 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hirano K, Mianamoto T, et al.: "Non-Hodgkin's lymphoma in a patient with probable hereditary nonpolyposis colorectal cancer. Report of a case and review of the literature"Disease of the Colon & Rectum. 45・2. 273-279 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ougolkov AV, Minamoto T, et al.: "Abnormal expression of E-cadherin, β-catenin and c-erbB-2 in gastric cancer with liver metastasis"International Journal of Colorectal Diseases (Clinical and Molecular Gastroenterological Surgery). 18・2. 160-166 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Minamoto T, Mai M, et al.: "Detection of oncogenes in the diagnosis of cancers with active oncogenic signaling"Expert Review of Molecular Diagnostics. 2・6. 565-575 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Okai T, Minamoto T, et al.: "Endosonographic evaluation of c-kit-positive gastrointestinal stromal tumors"Abdominal Imaging. 28(印刷中). (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kawashima A, Minamoto T, et al.: "Expression of αv integrin subfamily in gastric carcinomas : increased αvβ6 is associated with lymph node metastasis"Pathology Research and Practice. (印刷中). (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Zhang B, Minamoto T, et al.: "β-catenin and ras oncogenes detect most human colorectal cancers"Clinical Cancer Research. (印刷中). (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Minamoto T: "Molecular Toxicology Protocols/Methods of Molecular Biology"Humana Press(印刷中). (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ronai Z, Minamoto T.: "Early detection of gene mutation in cancer diagnosis"Princ Pract Oncol. 15. 1-16 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Buschmann T, Ivanov VN, Henderson S, Fried VA, Minamoto T, Alarcon-Vargas D, Pincus MR, Fuchs SY, Ronai Z.: "JNK phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress."Mol Cell Biol.. 21. 2743-2754 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Minamoto T, Buschmann T, Habelhah H, Matusevich E, Tahara H, Boerresen-Dale A-L, Harris C, Sidransky D, Ronai Z.: "Distinct pattern of p53 phosphorylation in human tumors"Oncogens. 20. 3341-3347 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ougolkov AV, Yamashita K, Omote K, Takahashi Y, Mai M, Minamoto T.: "Abnormal expression of E-cadherin, β-catenin and c-erbB-2 in advanced gastric cancer : its association with liver metastasis"Proceedings of 4^<th> International Gastric Cancer Congress, 2001, Monduzzi Editore S.p.A., Medimond Inc., Bologna. 765-770

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Minamoto T, Ronai Z.: "Gene mutation as target for early detection in cancer diagnosis"Crit Rev Oncol Hematol.. 40. 195-213 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ougolkov AV, Yamashita K, Mai M, Minamoto T.: "Oncogenic β-catenin and MMP-7 (matrilysin) cosegregate in late-stage clinical colon cancer"Gastroenterology. 122. 60-71 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hirano K, Yamashita N, Ohta T, Yamashita K, Nakazumi Y, Esumi H, Kawashima A, Mai M, Minamoto T.: "Non-Hodgkin lymphoma in a patient with probable hereditary nonpolyposis colorectal cancer. Report of a case and review of the literature"Dis Colon Rectum.. 45. 273-279 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ougolkov A, Yamashita K, Bilim V, Takahashi Y, Mai M, Minamoto T.: "Abnormal expression of E-cadherin, β-catenin and c-erbB-2 in gastric cancer with liver metastasis"Int J Colorect Dis (Clin Mol Gastroenterol Surg). 18(2). 160-166 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Minamoto T, Ougolkov A Mai M.: "Detection of oncogenes in the diagnosis of cancers with active oncogenic signaling"Exp Rev Mol Diag.. 2 (6). 565-575 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Okai T, Minamoto T, Ohtsubo K, Minato H, Kurumaya H, Oda Y, Mai M, Sawabu N.: "Endosonographic evaluation of c-kit-positive gastrointestinal stromal tumor"Abdom Imaging. 28 (3). 301-307 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kawashima A, Tsugawa S, Boku A, Kobayashi M, Minamoto T, Nakanishi I, Oda Y.: "Expression of αv integrin subfamily in gastric carcinomas : Increased αvβ6 is associated with lymph node metastasis"Pathol Res Prac.. 199 (2). 57-64 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Zhang B, Ougolkov A, Yamashita K, Takahashi Y, Mai M, Minamoto T.: "β-catenin and ras oncogenes detect most human colorectal cancers"Clin Cancer Res.. in press.

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Minamoto T.: "Molecular Toxicology Protocols/Methods of Molecular Biology."Humana Press. in press

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2004-04-14  

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