Application of RUNX3 in the diagnosis and treatment of gastric cancer

2004 Fiscal Year Final Research Report Summary

• Project/Area Number: 15390404
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kyoto prefectural University of Medicine
• Principal Investigator: SAKAKURA Chouhei Kyoto prefectural University of Medicine, Department of Digestive Surgery, Stuff, 医学研究科, 助手 (10285257)
• Co-Investigator(Kenkyū-buntansha): OKUDA Tsukasa Kyoto prefectural University of Medicine, Department of Digestive Surgery, Subprofessor, 医学研究科, 助教授 (30291587) ; HAGIWARA Akeo Kyoto prefectural University of Medicine, Department of Digestive Surgery, Subprofessor, 医学研究科, 助教授 (90198648)
• Project Period (FY): 2003 – 2004
• Keywords: Gastric cancer / Tumor suppressor gene / RUNX3

Research Abstract

Our previous results suggest that a lack of RUNX3 function is causally related to the genesis of human gastric cancer, but the role of RUNX3 in progression and metastases has not yet been clarified. We examined the expression of RUNX3 in clinical samples of peritoneal metastases in gastric cancers. Furthermore, change of metastatic potential in animal experiments using RUNX3-stable transfectants of gastric cancer cells and global expression changes using cDNA microarray was analyzed.
Significant downregulation of RUNX3 through methylation on the promoter region was observed in all clinical samples of peritoneal metastases (14/14, 100%) by quantitative RT-PCR and methylation specific PCR(MSP). Although stable transfection of RUNX3 did not inhibit cell proliferation, TGF-β induced antiproliferative effect and apoptosis was slightly observed. Interestingly, it strongly inhibited peritoneal metastases of gastric cancers in animal model (p<0.01). Furthermore, we performed globally analyzed e xpression profiles of approximately 21000 genes in parent cells and stable transfectant of RUNX3 using a cDNA microarray. Microarray analysis identified approximately 28 candidate genes (known genes and ESTs) under the possible down-stream control of RUNX3, some of these genes were considered to be possibly involved in peritoneal metastases, which were related to signal transduction (vav3, toll-like receptor, MAPKK, MET, S100A11, Cathepsin E), apoptosis (caspase 9), immune response (CD55, TLR10), and cell adhesion (sialyltransferase1, galectin 4). Some of them are known to be involved in TGF-β signaling pathway. Same expression pattern with cDNA microarray in some of the selected genes are confirmed using quantitative RT-PCR in clinical samples of peritoneal metastases.
These results indicate that silencing of RUNX3 affect the expression of important genes involved in metastases including cell adhesion, proliferation and apoptosis, and promote the peritoneal metastases of gastric cancer. Identification of such genes could then lead to new therapeutic modalities as well as therapeutic targets.

Research Products

• [Journal Article] Frequent downregulation of the runt domain transcription factors RUNX1, RUNX3 and their cofactor CBFB in gastric cancer (2005)
  • Author(s): Sakakura C, et al.
  • Journal Title: Int J Cancer 113(2) Pages: 221-228
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Frequent loss of RUNX3 gene expression in remnant stomach cancer and adjacent mucosa with special reference to topography. (2005)
  • Author(s): Nakase Y, Sakakura C et al.
  • Journal Title: Br J Cancer 113(2) Pages: 221-228
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Frequent downregulation of the runt domain transcription factors RUNX1, RUNX3 and their cofactor CBFB in gastric cancer. (2005)
  • Author(s): Sakakura C, Hagiwara A, Miyagawa K, Nakashima S, Yoshikawa T, Kin S, Nakase Y, Ito K, Yamagishi H, Yazumi S, Chiba T, Ito Y.
  • Journal Title: Int J Cancer. 113(2) Pages: 221-228
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Frequent loss of RUNX3 gene expression in remnant stomach cancer and adjacent mucosa with special reference to topography. (2005)
  • Author(s): Nakase Y, Sakakura C, Miyagawa K, Kin S, Fukuda K, Yanagisawa A, Koide K, Morofuji N, Hosokawa Y, Shimomura K, Katsura K, Hagiwara A, Yamagishi H, Ito K, Ito Y.
  • Journal Title: Br J Cancer.
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Frequent loss of RUNX3 gene expression in human bile duct and pancreatic cancer cell lines (2004)
  • Author(s): Wada M, Yazumi S, Takaishi S, Sawada M, Sakakura C et al.
  • Journal Title: Oncogene 23(13) Pages: 2401-2407
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Differential gene expression profiles of radioresistant oesophageal cancer cell lines established by continuous fractionated irradiation. (2004)
  • Author(s): Fukuda K, Sakakura C, et al.
  • Journal Title: Br J Cancer 91(8) Pages: 1543-1550
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Management of postoperative follow-up and surgical treatment for Krukenberg tumor from colorectal cancers. (2004)
  • Author(s): Sakakura C, et al.
  • Journal Title: Hepatogastroenterology. 51(59) Pages: 1350-1359
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Differential gene expression profiles of radioresistant oesophageal cancer cell lines established by continuous fractionated irradiation. (2004)
  • Author(s): Fukuda K, Sakakura C, Miyagawa K, Kuriu Y, Kin S, Nakase Y, Hagiwara A, Mitsufuji S, Okazaki Y, Hayashizaki Y, Yamagishi
  • Journal Title: Br J Cancer. 91(8) Pages: 1543-1550
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Management of postoperative follow-up and surgical treatment for Krukenberg tumor from colorectal cancers. (2004)
  • Author(s): Sakakura C, Hagiwara A, Yamazaki J, Takagi T, Hosokawa K, Shimomura K, Kin S, Nakase Y, Fukuda K, Yamagishi H.
  • Journal Title: Hepatogastroenterology. 51(59) Pages: 1350-1353
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Frequent loss of RUNX3 gene expression in human bile duct and pancreatic cancer cell lines. (2004)
  • Author(s): Wada M, Yazumi S, Takaishi S, Hasegawa K, Sawada M, Tanaka H, Ida H, Sakakura C, Ito K, Ito Y, Chiba T.
  • Journal Title: Oncogene. 23(13) Pages: 2401-2407
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Intratumoral administration of methotrexate bound to activated carbon particles : antitumor effectiveness against human colon carcinoma xenografts and acute toxicity in mice. (2004)
  • Author(s): Nakase Y, Hagiwara A, Kin S, Fukuda K, Ito T, Takagi T, Fujiyama J, Sakakura C, Otsuji E, Yamagishi H.
  • Journal Title: J Pharmacol Exp Ther. 311(1) Pages: 382-387
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Combination of L-3-phosphoserine phosphatase and CEA using real-time RT-PCR improves accuracy in detection of peritoneal micrometastasis of gastric cancer. (2004)
  • Author(s): Shimomura K, Sakakura C, Takemura M, Takagi T, Fukuda K, Kin S, Nakase Y, Miyagawa K, Ohgaki M, Fujiyama J, Fujita Y, Nakanishi M, Hagiwara A, Shirane M, Okazaki Y, Hayashizaki Y, Yamagishi H.
  • Journal Title: Anticancer Res. 24(2C) Pages: 1113-1120
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Poor prognostic factors of hepatectomy in patients with resectable small hepatocellular carcinoma and cirrhosis. (2004)
  • Author(s): Ochiai T, Sonoyama T, Ichikawa D, Fujiwara H, Okamoto K, Sakakura C, Ueda Y, Otsuji E, Itoi H, Hagiwara A, Yamagishi H.
  • Journal Title: J Cancer Res Clin Oncol. 130(4) Pages: 197-202
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Possible involvement of inositol 1,4,5-trisphosphate receptor type 3 (IP3R3) in the peritoneal dissemination of gastric cancers. (2003)
  • Author(s): Sakakura C, et al.
  • Journal Title: Anticancer Res 23(5A) Pages: 3691-3697
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Mutations in exon 11 of the c-kit gene in a myogenic tumor and a neurogenic tumor as well as in gastrointestinal stromal tumors. Utility of c-kit mutation as a prognostic biomarker for gastrointestinal mesenchymal tumor. (2003)
  • Author(s): Yasuoka R, Sakakura C, Shimomura K, Fujita Y, Nakanishi M, Aragane H, Hagiwara A, Bamba M, Abe T, Yamagishi H.
  • Journal Title: Dig Surg. 20(3) Pages: 183-191
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cisplatin incorporated in microspheres : development and fundamental studies for its clinical application. (2003)
  • Author(s): Fujiyama J, Nakase Y, Osaki K, Sakakura C, Yamagishi H, Hagiwara A.
  • Journal Title: J Control Release. 89(3) Pages: 397-408
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Successful treatment of intractable esophagothoracic fistula using covered self-expandable stent. (2003)
  • Author(s): Sakakura C, Hagiwara A, Kato D, Deguchi K, Hamada T, Itoi Y, Mitsufuji S, Kashima K, Yamagishi H.
  • Journal Title: Hepatogastroenterology. 50(49) Pages: 77-79
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Chromosome arm 20q gains and other genomic alterations in esophageal squamous cell carcinoma, as analyzed by comparative genomic hybridization and fluorescence in situ hybridization. (2003)
  • Author(s): Fujita Y, Sakakura C, Shimomura K, Nakanishi M, Yasuoka R, Aragane H, Hagiwara A, Abe T, Inazawa J, Yamagishi H.
  • Journal Title: Hepatogastroenterology. 50(54) Pages: 1857-1863
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Possible involvement of inositol 1,4,5-trisphosphate receptor type 3 (IP3R3) in the peritoneal dissemination of gastric cancers. (2003)
  • Author(s): Sakakura C, Hagiwara A, Fukuda K, Shimomura K, Takagi T, Kin S, Nakase Y, Fujiyama J, Mikoshiba K, Okazaki Y, Yamagishi H.
  • Journal Title: Anticancer Res. 23(5A) Pages: 3691-3697
  • Description: 「研究成果報告書概要(欧文)」より