マイクロRNAを介した消化器癌転移カスケードの解明

• Project/Area Number: 21679006
• Research Category: Grant-in-Aid for Young Scientists (S)
• Allocation Type: Single-year Grants
• Research Field: General surgery
• Research Institution: Kyushu University
• Principal Investigator: 三森 功士 Kyushu University, 生体防御医学研究所, 准教授 (50322748)
• Project Period (FY): 2009 – 2013
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥80,340,000 (Direct Cost: ¥61,800,000、Indirect Cost: ¥18,540,000); Fiscal Year 2011: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000); Fiscal Year 2010: ¥21,190,000 (Direct Cost: ¥16,300,000、Indirect Cost: ¥4,890,000); Fiscal Year 2009: ¥45,890,000 (Direct Cost: ¥35,300,000、Indirect Cost: ¥10,590,000)
• Keywords: 骨髄 / CD45 / EPCAM / non coding RNA / LMD / 癌転移 / CD14 / microRNA / 転移再発 / 癌幹細胞 / EMT / 血管新生

Research Abstract

われわれは消化器癌の転移・再発のマーカーを明らかするには循環血液あるいは骨髄液中に癌細胞を検出することを目的とするのではなく、癌細胞側因子と宿主側の環境因子とにおいて転移再発と明確な関連を有する遺伝子を明らかにしたい。両面からの俯瞰的研究により転移再発機構を解明し、真の予測マーカーを求める。特に多くの遺伝子を一度に抑制しうるファインチューナーとしての役割を担うmicroRNAは、その発現の臨床的意義が注目されており、microRNA-遺伝子pathwayの同定と機能解析が急がれる。
われわれは多施設共同研究を組み、各施設毎に倫理委員会を通過した後、消化器癌患者の骨髄と末梢血液の集積を開始した。骨髄は4つの分画(癌細胞分画、マクロファージ分画、血管内皮細胞豊富分画、全血)に分けて、microRNAマイクロアレイを施行する。転移陽性症例特異的miRについてはマーカーとしての意義を明らかにすることはもちろんのこと、標的遺伝子pathwayを決め、機能解析をすすめさらに絞り込めるマーカーを求める。
<大腸癌症例>これまでに29例の症例に対して骨髄穿刺、末梢血採取を行った。Trainingセット:LMDによる原発巣癌細胞のmiRアレイ20症例,遺伝子アレイ20例。転移巣癌細胞のmiRアレイ7例遺伝子アレイ7例。骨髄をsortingして解析した結果、ITC分画miRアレイ20例、遺伝子アレイ20例。CD14分画のmiRアレイ7例、CD45分画7例、全骨髄液7例
Validationセット:miRアレイ骨髄癌細胞15例、CD14分画15例、CD45分画15例の集積を終えている。
<胃癌症例>すべてmiRアレイのみ実施している。LMDおよびマイクロアレイ解析により原発巣癌細胞6例、転移巣癌細胞10例、骨髄癌細胞分画10例、CD14分画10例、CD45分画10例、全骨髄液10例)。
<肝臓癌症例>15例の肝臓癌症例について骨髄を4分画に分けてそれぞれのmicroRNA profileを有する。このうち10例については原発巣癌細胞のmiRアレイprofileを有している。
以上の発現profileを用いて、GSEA解析等を実施し結果を求める。その成果は臨床的バイオマーカーとしての意義、あるいは転移再発機構研究の端緒となることが期待される。

Research Products

• [Journal Article] Clinical Significance of Circulating Tumor Cells, Including Cancer Stem-Like Cells, in Peripheral Blood for Recurrence and Prognosis in Patients With Dukes' Stage B and C Colorectal Cancer (2011)
  • Author(s): Iinuma, H.Watanabe, T.Mimori, K., et al.
  • Journal Title: J Clin Oncol Pages: 1547-55
  • Peer Reviewed
• [Journal Article] Identification of HLA-A*0201/-A*2402-restricted CTL epitope-peptides derived from a novel cancer/testis antigen, MCAK, and induction of a specific antitumor immune response (2011)
  • Author(s): Kawamoto, M., Tanaka, F., Mimori, K., et al.
  • Journal Title: Oncol Rep Volume: 25 Pages: 469-76
  • Peer Reviewed
• [Journal Article] STC2 : a predictive marker for lymph node metastasis in esophageal quamous-cell carcinoma (2011)
  • Author(s): Kita, Y., Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Volume: 18 Pages: 261-72
  • Peer Reviewed
• [Journal Article] The correlation between clinical laboratory data and telomeric status of male patients with metabolic disorders and no clinical history of vascular events (2011)
  • Author(s): Maeda, T., Oyama, J., Higuchi, Y., Koyanagi, M., Sasaki, M., Arima, T., Mimori, K., et al.
  • Journal Title: Aging Male Volume: 14 Pages: 21-6
  • Peer Reviewed
• [Journal Article] The physical ability of Japanese female elderly with cerebrovascular disease correlates with the telomere length and subtelomeric methylation status in their peripheral blood leukocytes (2011)
  • Author(s): Maeda, T., Oyama, J., Higuchi, Y., Nishiyama, Y., Kudo, Y., Yamori, T., Nakazono, T., Arima, T., Mimori, K., et al.
  • Journal Title: Gerontology Volume: 57 Pages: 137-43
  • Peer Reviewed
• [Journal Article] Kinesin 18A expression clinical relevance to colorectal cancer progression (2011)
  • Author(s): Nagahara, M., Nishida, N., Iwatsuki, M., Ishimaru, S., Mimori., K., et al.
  • Journal Title: Int J Cancer Volume: (online)
  • Peer Reviewed
• [Journal Article] Micro RNA-125a-5p is an independent prognostic factor in gastric cancer, and inhibits the proliferation of human gastric cancer cells in combination with trastuzumab (2011)
  • Author(s): Nishida, N., Mimori, K., et al.
  • Journal Title: Clin Cancer Res Volume: 17 Pages: 2725-33
  • Peer Reviewed
• [Journal Article] FOXC2 is a Novel Prognostic Factor in Human Esophageal Squamous Cell Carcinoma (2011)
  • Author(s): Nishida, N., Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Volume: 18 Pages: 535-42
  • Peer Reviewed
• [Journal Article] Identification of recurrence-related micro RNAs in the bone marrow of breast cancer patients (2011)
  • Author(s): Nishida, N., Mimori, K., et al.
  • Journal Title: Int J Oncol Volume: 38 Pages: 955-62
  • Peer Reviewed
• [Journal Article] Significance of Lgr5(+ve) Cancer Stem Cells in the Colon and Rectum (2011)
  • Author(s): Takahashi, H., Ishii, H., Nishida, N., Takemasa, I., Mizushima, T., Ikeda, M., Yokobori, T., Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Volume: 18 Pages: 1166-74
  • Peer Reviewed
• [Journal Article] Hypoxia-inducible Adrenomedullin in Colorectal Cancer (2011)
  • Author(s): Uemura, M., Yamamoto, H., Takemasa, I., Mimori, K., et al.
  • Journal Title: Anticancer Res Volume: 31 Pages: 507-14
  • Peer Reviewed
• [Journal Article] CD13 is a therapeutic target in human liver cancer stem cells. (2010)
  • Author(s): Haraguchi, N.Ishii, H.Mimori, K., et al.
  • Journal Title: J Clin Invest Volume: 120 Pages: 3326-39
  • Peer Reviewed
• [Journal Article] Notch pathway as candidate therapeutic target in Her2/Neu/ErbB2 receptor-negative breast tumors (2010)
  • Author(s): Hirose, H.Ishii, H.Mimor, K., et al.
  • Journal Title: Oncol Rep Volume: 23 Pages: 35-43
  • Peer Reviewed
• [Journal Article] Clinical Significance of Human Kallikrein7 Gene Expression in Colorectal Cancer. (2010)
  • Author(s): Inoue, Y.Yokobori, T.Yokoe, T.Toiyama, Y.Miki, C.Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Volume: 17 Pages: 3037-42
  • Peer Reviewed
• [Journal Article] The Clinical Significance of Vimentin-Expressing Gastric Cancer Cells in Bone Marrow (2010)
  • Author(s): Iwatsuki, M.Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Volume: 17 Pages: 2526-33
  • Peer Reviewed
• [Journal Article] Overexpression of SUGT1 in human colorectal cancer and its clinicopathological significance (2010)
  • Author(s): Iwatsuki, M.Mimori, K., et al.
  • Journal Title: Int J Oncol Volume: 36 Pages: 569-75
  • Peer Reviewed
• [Journal Article] Epithelial-mesenchymal transition in cancer development and its clinical significance (2010)
  • Author(s): Iwatsuki, M.Mimori, K., et al.
  • Journal Title: Cancer Sci Volume: 101 Pages: 293-9
  • Peer Reviewed
• [Journal Article] STC2 : A Predictive Marker for Lymph Node Metastasis in Esophageal Squamous-Cell Carcinoma (2010)
  • Author(s): Kita, Y.Mimori, K.., et al.
  • Journal Title: Ann Surg Oncol Pages: 261-72
  • Peer Reviewed
• [Journal Article] Expression of C4.4A at the invasive front is a novel prognostic marker for disease recurrence of colorectal cancer (2010)
  • Author(s): Konishi, K.Yamamoto, H.Mimori, K., et al.
  • Journal Title: Cancer Sci Volume: 101 Pages: 2269-77
  • Peer Reviewed
• [Journal Article] FHIT Suppresses Inflammatory Carcinogenic Activity by Inducing Apoptosis in Esophageal Epithelial Cells (2010)
  • Author(s): Mimori, K., et al.
  • Journal Title: J Nucleic Acid Invest Volume: 101 Pages: 2269-77
  • Peer Reviewed
• [Journal Article] Identification of recurrence-related microRNAs in the bone marrow of breast cancer patients. (2010)
  • Author(s): Ota D, Mimori K, Yokobori T, Iwatsuki M, Kataoka A, Masuda N, Ishii H, Ohno S, Mori M.
  • Journal Title: Int J Oncol 38 Volume: 38(4) Issue: 4 Pages: 955-962
  • DOI: 10.3892/ijo.2011.926
  • Peer Reviewed
• [Journal Article] Serum Matrix-Metalloproteinase-1 is a Bona Fide Prognostic Marker for Colorectal Cancer (2010)
  • Author(s): Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Pages: 3362-9
  • Peer Reviewed
• [Journal Article] Abnormal Expression of PFDN4 in Colorectal Cancer : A Novel Marker for Prognosis (2010)
  • Author(s): Miyoshi, N.Ishii, H.Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Volume: 17 Pages: 3030-6
  • Peer Reviewed
• [Journal Article] TDGF1 is a novel predictive marker for metachronous metastasis of colorectal cancer (2010)
  • Author(s): Mimori, K., et al.
  • Journal Title: Int J Oncol Volume: 36 Pages: 563-8
  • Peer Reviewed
• [Journal Article] SCRN1 is a novel marker for prognosis in colorectal cancer (2010)
  • Author(s): Miyoshi, N.Ishii, H.Mimori.K, et al.
  • Journal Title: J Surg Oncol Volume: 101 Pages: 156-9
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• [Journal Article] TGM2 is a novel marker for prognosis and therapeutic target in colorectal cancer (2010)
  • Author(s): Miyoshi, N.Ishii, H.Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Volume: 17 Pages: 967-72
  • Peer Reviewed
• [Journal Article] ATP11A is a novel predictive marker for metachronous metastasis of colorctal cancer (2010)
  • Author(s): Miyoshi, N.Ishii, H.Mimori, K., et al.
  • Journal Title: Oncol Rep Volume: 23 Pages: 505-10
  • Peer Reviewed
• [Journal Article] Defined factors induce reprogramming of gastrointestinal cancer cells (2010)
  • Author(s): Miyoshi, N.Ishii, H., Mimori.K., et al.
  • Journal Title: Proc Natl Acad Sci USA Volume: 107 Pages: 40-5
  • Peer Reviewed
• [Journal Article] Clinicopathological and prognostic significance of PDCD4 and micro RNA-21 in human gastric cancer (2010)
  • Author(s): Miyoshi, N.Ishii, H.Mimori, K., et al.
  • Journal Title: Int J Oncol Volume: 36 Pages: 1089-95
  • Peer Reviewed
• [Journal Article] Correlated expression of CD47 and SIRPA in bone marrow and in peripheral blood predicts recurrence in breast cancer patients (2010)
  • Author(s): Nagahara, M.Mimori, K, et al.
  • Journal Title: Clin Cancer Res Volume: 16 Pages: 4625-35
  • Peer Reviewed
• [Journal Article] FOXC2 is a Novel Prognostic Factor in Human Esophageal Squamous Cell Carcinoma (2010)
  • Author(s): Nishida, N.Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Pages: 535-42
  • Peer Reviewed
• [Journal Article] FANCD2 mRNA overexpression is a bona fide indicator of lymph nodemetastasis in human colorectal cancer (2010)
  • Author(s): Ozawa, H.Iwatsuki, M.Mimori, K., et al.
  • Journal Title: Ann Surg Oncol Volume: 17 Pages: 2341-8
  • Peer Reviewed
• [Journal Article] Strong interaction between the effects of alcohol consumption and smoking on oesophageal squamous cell carcinoma among individuals with ADH1B and/or ALDH2 risk alleles (2010)
  • Author(s): Tanaka, F.Yamamoto, K.Suzuki, S.Inoue, H.Tsurumaru, M.Kajiyama, Y.Kato, H.Igaki, H.Furuta, K.Fujita, H.Tanaka, T.Tanaka, Y.Kawashima, Y.Natsugoe, S.Setoyama, T.Tokudome, S.Mimori, K., et al.
  • Journal Title: Gut Pages: 1457-64
  • Peer Reviewed
• [Journal Article] Clinical significance of ASB9 in human colorectal cancer (2010)
  • Author(s): Tokuoka, M.Miyoshi, N.Hitora, T.Mimori, K., et al.
  • Journal Title: Int J Oncol Volume: 37 Pages: 1105-11
  • Peer Reviewed
• [Journal Article] Jumonji domain containing 1A is a novel prognostic marker for colorectal cancer : in vivo identification from hypoxic tumor cells (2010)
  • Author(s): Uemura, M.Yamamoto, H.Takemasa, I.Mimori, K., et al.
  • Journal Title: Clin Cancer Res Volume: 16 Pages: 4636-46
  • Peer Reviewed
• [Journal Article] Clinical Significance of Stanniocalcin 2 as a Prognostic Marker in Gastric Cancer (2010)
  • Author(s): Yokobori, T.Mimori, K., et al.
  • Journal Title: Ann Surg Oncol
  • Peer Reviewed
• [Journal Article] Defined factors induce reprogramming of gastrointestinal cancer cells (2010)
  • Author(s): Miyosi N., Mimori K., et al.
  • Journal Title: Proc Natl Acad Sci.(USA) 107 Pages: 40-5
  • Peer Reviewed
• [Journal Article] The Clinical Significance of Vimentin-Expressing Gastric Cancer Cells in Bone Marrow (2010)
  • Author(s): Iwatsuki M, Mimori K., et al.
  • Journal Title: Ann Surg Oncol (掲載決定)
  • Peer Reviewed
• [Journal Article] FANCD2 mRNA Overexpression is a Bona Fide Indicator of Lymph Node Metastasis in Human Colorectal Cancer (2010)
  • Author(s): Ozawa H, Iwatsuki M, Mimori K., et al.
  • Journal Title: Ann Surg Oncol (掲載決定)
  • Peer Reviewed
• [Journal Article] Notch pathway as candidate therapeutic target in Her2/Neu/ErbB2 receptor-negative breast tumors (2010)
  • Author(s): Hirose, H., Ishii, H., Mimori, K
  • Journal Title: Oncol Rep 23 Pages: 35-43
  • Peer Reviewed
• [Journal Article] p53-Altered FBXW7 expression determines poor prognosis in gastric cancer cases (2009)
  • Author(s): Yokobori T., Mimori K., et al.
  • Journal Title: Cancer Res 69 Pages: 3788-94
  • Peer Reviewed
• [Journal Article] Preoperative u-PAR gene expression in bone marrow indicates the potential power of recurrence in breast cancer cases (2009)
  • Author(s): Mimori K., et al
  • Journal Title: Ann Surg Oncol 16 Pages: 2035-41
  • Peer Reviewed
• [Journal Article] Important matters to identify robust markers for metastasis and recurrence in solid cancer (2009)
  • Author(s): Mimori K., et al.
  • Journal Title: Ann Surg Oncol 16 Pages: 1070-1
  • Peer Reviewed
• [Journal Article] Loss of FBXW7, a cell cycle regulating gene, in colorectal cancer : clinical significance (2009)
  • Author(s): Iwatsuki M., Mimori K., et al.
  • Journal Title: Int J Cancer 126 Pages: 1828-37
  • Peer Reviewed
• [Journal Article] Epithelial-mesenchymal transition in cancer development and its clinical significance (2009)
  • Author(s): Iwatsuki M, Mimori K., et al.
  • Journal Title: Cancer Sci 101 Pages: 293-9
  • Peer Reviewed
• [Journal Article] Bone marrow and peripheral blood expression of ID1 in human gastric carcinoma patients is a bona fide indicator of lymph node and peritoneal metastasis (2009)
  • Author(s): Iwatsuki M, Mimori K., et al.
  • Journal Title: Br J Cancer 100 Pages: 1937-42
  • Peer Reviewed
• [Journal Article] Comprehensive analysis of the clinical significance of inducing pluripotent stemness-related gene expression in colorectal cancer cells (2009)
  • Author(s): Saiki, Y., Ishimaru, S., Mimori, K.
  • Journal Title: Ann Surg Oncol 16 Pages: 2638-44
  • Peer Reviewed
• [Journal Article] Over- and under-expressed micro RNAs in human colorectal cancer (2009)
  • Author(s): Motoyama K, Mimori K
  • Journal Title: Int J Oncol 34 Pages: 1069-75
  • Peer Reviewed
• [Journal Article] Expression of uPAR mRNA in peripheral blood is a favourite marker for metastasis in gastric cancer cases (2009)
  • Author(s): Kita, Y., Fukagawa, T., Mimori, K.
  • Journal Title: Br J Cancer 100 Pages: 153-9
  • Peer Reviewed
• [Journal Article] Clinical significance of LAMB3 and COL7A1 mRNA in esophageal squamous cell carcinoma (2009)
  • Author(s): Kita, Y., Mimori, K.
  • Journal Title: Eur J Surg Oncol 35 Pages: 52-8
  • Peer Reviewed
• [Journal Article] Abnormal expression of TRIB3 in colorectal cancer : a novel marker for prognosis (2009)
  • Author(s): Miyoshi, N., Ishii, H., Mimori, K, et al.
  • Journal Title: Br J Cancer 101 Pages: 1664-70
  • Peer Reviewed
• [Presentation] Single nucleotide Polymorphism of Fibronectin 1, Determining Tumor Shape and Malignant Behavior in Colorectal Cancer Cases (2011)
  • Author(s): Mimori K., et al
  • Organizer: Society of Surgical Oncology, 2011
  • Place of Presentation: San Antonio
  • Year and Date: 2011-03-04
• [Presentation] がん転移機構にむけての新しいアプローチ(癌細胞側と宿主因子側) (2010)
  • Author(s): 三森功士
  • Organizer: 東京医科歯科大学 キャンサーボード
  • Place of Presentation: 東京医科歯科大学(招待講演)
  • Year and Date: 2010-11-18
• [Presentation] 乳癌における骨髄・末血中遊離癌細胞の臨床的意義と真の転移関連因子同定のためのアプローチ (2010)
  • Author(s): 三森功士
  • Organizer: 第13回癌と骨病変研究会
  • Place of Presentation: 東京放送会館(招待講演)
  • Year and Date: 2010-10-12
• [Presentation] Forkhead box C2 (FOXC2), an EMT Regulator, Is a Candidate Molecular Target in Human Esophageal Squamous Cell Carcinoma (2010)
  • Author(s): Mimori K., et al.
  • Organizer: 国際食道学会
  • Place of Presentation: 鹿児島城山観光ホテル(招待講演)
  • Year and Date: 2010-09-04
• [Presentation] 大腸癌細胞のゲノムCGHクラスター解析および発現アレイpathway解析による5-FU適応症例の決定 (2010)
  • Author(s): 三森功士, 他8名
  • Organizer: 第110回日本外科学会定期学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2010-04-09
• [Presentation] Identification of target gene enhanced by Wnt/TCF binding, to the predisposition SNP rs6983267 at chromosome 8q24 in colorectal cancer cases (2010)
  • Author(s): Mimori K., et al
  • Organizer: Society of Surgical Oncology, 2010
  • Place of Presentation: St.Loius
  • Year and Date: 2010-03-05