Kyushu University Academic Staff Educational and Research Activities Database
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Koshi Mimori Last modified date:2015.9.10



Administration Post
Other


Phone
0977-27-1650
Fax
0977-27-1651
Academic Degree
MEDICAL DOCTOR
Field of Specialization
gastro intestinal surgery
Outline Activities
1)We identified the significant SNPs and environment factors in 2000 cases of CRC and 3000 of volunteer, and established profiles of genetic alterations by CGH array and of expression genes. We will get intriguing findings from them soon.

2) Clarifying mechanism of cancer metastasis in the view point of both ITC factors and the host side factors; Recent studies of cancer metastasis have also examined the role of host responses in hematogeneous metastasis and peritoneal dissemination. It is believed that the mechanisms that guide tumor cells to a specific tissue may not only involve molecular differences inherent in the tumor cells themselves, but could also be modulated by the effects of host immune cells and host progenitor cells. We are disclosing diverse mechanism of cancer metastasis in solid carcinomas by RT-PCR.
In addition, it is postulated that cancer cells might acquire the genomic alteration (mutation) during metastasis or only clonal population with specific driver mutations might be able to form metastasis. Therefore, we will perform comprehensive analysis among mutations in cancer cells from primary site to metastatic site via bone marrow by super-computational analysis.
1) we will focus on recurrence related mutations in cancer cells in bone marrow specifically as well as cancer cells from primary and metastatic site by using of NG sequencer. 2) Mutations not only in coding genes but non-coding RNA including lincRNAs will be examined in this study. 3) The super-computational analysis will dissolve the mechanism of metastasis or recurrence comprehensively by using of whole driver and passenger mutations from primary site to metastatic site via bone marrow. 4) Then, we will measure expressions of those genes or ncRNA with mutation for predicting recurrence clinically.

3) Study for cancer suppressor gene , FHIT which is susceotible to the environmental carcinogens: The FHIT gene is known to be susceptible to environmental carcinogens. Formation of prostaglandin E(2) (PGE(2)) is catalyzed by cyclooxygenase-2 (COX-2) and may influence malignant phenotype in colorectal cancer. We explored whether FHIT might play a role in progression of colorectal cancer through inflammation-associated PGE(2) activity. Additionally, there was an inverse and direct correlation between PGE(2) synthesis and FHIT in vitro, suggesting that FHIT's postulated antiaggressive effect on tumor goes through PGE(2) but not COX-2. Loss of FHIT expression in colorectal cancer suggests higher malignant potential. We conclude that FHIT suppressed cancer cell proliferation in this malignancy by directly inhibiting synthesis of PGE(2) but not affecting that of COX-2.

4) Identification of surface markers for cancer stem cells; our recent evidence strongly supported that the presence of cancer stem cell in cancer tissues. To my concern, I have to elucidate that the intimate relationship between cancer stem cells and metastasis.
Research
Research Interests
  • Genetic and epigenetic clonal evolution of colorectal cancer cells
    keyword : exome sequence
    2012.03~2015.03.
  • The Mutational Landscape of Esophageal squamous cell carcinoma
    keyword : exome sequencing
    2013.06~2013.06.
  • Clarification of the non-coding RNA / gene pathway regulating metastatic cascade in gastrointestinal tract cancer cases.
    keyword : Deep sequencer, non-codin RNA, metastasis, GI tract
    2011.04~2014.03.
  • Clarification of the metastatic cascade mediated through microRNA in G-I tract carcinomas.
    keyword : microRNA, non coding RNA
    2009.04~2014.03.
  • Comprehensive analysis of CRC by SNP, environmental factors and genetic alterations.
    keyword : CRC
    2004.06~2011.03.
  • FHIT Suppresses Inflammatory Carcinogenic Activity by Inducing Apoptosis in Esophageal Epithelial Cells
    keyword : fragile histidine triad, inflammation, digestive tract cancers, stemcells
    1996.10~2015.03.
Current and Past Project
  • Identification of the Bone-Fide Cancer Metastasis Regulating Factors in Solid Cancers.
    Purpose: Identification of microRNA in BM expressing specifically in metastatic cases of CRC as well as GC
    Patients and Method:
    Subset A:20 cases of metastasis (+) CRC, and GC
    Subset B:20 advanced CRC and GC metastasis(-) cases. Bone marrow is 6ml from sternum and AGPC method to ext. total RNA, stored at -80 degree. Extraction of RNA: @Kyushu University in Beppu. Then, we send total RNA to microRNA microarry. Microarray: microRNA microarray between A vs B
    Expecting Results:
    Establishment of expression profile of miRNA expressing specifically in BM from metastasis (+) cases.
    1) Then, we can identify target genes to control metastasis. 2) Validation of the identified miRNA and/or genes by in vitro and in vivo experiment. 3) Clinical significance of the identified genes in 810 cases of GC and 600 CRC cases. 4)Comparison data with the CGH array in 80 cases of CRC. (In those cases, Laser microdissection was applied, therefore, CGH data is extremely specific for cancer cell.)
  • To identify the bona-fide indicator to metastasis in peripheral blood (PB) or bone marrow (BM) from solid cancer cases, we focused not only on cancer cells but also host cells. In the current study, we organized a prospective blind study by quantitative RT-PCR assay collaborating with the Central Hospital, National Cancer Center and Kyushu Cancer Center to establish the clinical significance of ITC especially in 810 cases of gastric cancer (GC) with complete clinicopathologic data and 744 cases of breast cancer (BC), respectively. 1) In BC cases, the positive expression of ITC was significantly associated with the poor OS or DFS. 2) Identifying specific genes for metastasis, we performed microarray analysis of whole BM to compare both factors simultaneously between 6 GC cases with metastasis and 3 advanced GC cases without metastasis. 3) According to the microarray analysis, MMP14, VEGFR1 and u-PAR were picked-up as candidate prognostic markers, then, we found that those three molecules were overexpressed in GC cases as well as BC cases with metastasis or recurrence. Clinical significance of the ITC marker in PB or BM was different among cancers. As those prognostic markers were originated mainly from host side, “metastasis of solid cancer ” is generated as a final result of combined factors, such as “the host side” and “the cancer cell side”.
  • Comparative genome wide analysis of fragile sites.
Academic Activities
Papers
1. Koshi Mimori,Plastin3 is a novel marker for circulating tumor cells undergoing the epithelial-mesenchymal transition and is associated with colorectal cancer prognosis,Cancer Res,Vol.73,No.7,pp.2059-2069,2013.04.
2. Nishida N, Mimori K, Fabbri M, Yokobori T, Sudo T, Tanaka F, Shibata K, Ishii H, Doki Y, Mori M.,MicroRNA-125a-5p is an independent prognostic factor in gastric cancer,and inhibits the proliferation of human gastric cancer cells in combination with trastuzumab.,Clin Cancer Res.,Vol.17,No.9,pp.2725-33,2011.05.
3. Nishida N, Mimori K, Fabbri M, Yokobori T, Sudo T, Tanaka F, Shibata K, Ishii H, Doki Y, Mori M.,MicroRNA-125a-5p is an independent prognostic factor in gastric cancer,and inhibits the proliferation of human gastric cancer cells in combination with trastuzumab.,Clin Cancer Res.,Vol.17,No.9,pp.2725-33,2011.05.
4. Mimori K, Druck T, Inoue H, Alder H, Berk L, Mori M, Huebner K and Croce CM,Cancer-specific chromosome alterations in the constitutive fragile region FRA3B.
,Proc Natl Acad Sci (U.S.A) ,Vol.96,No.13,96: 7456-61, 1999,1999.06.
5. Mimori K, Druck T, Inoue H, Hansjuerg A, Berk L, Mori M, Huebner K, Croce CM. ,Cancer-specific chromosome alterations in the constitutive fragile region FRA3B.,Proc Natl Acad Sci (USA),Vol.96,No.13,1999.06.
Presentations
1. MAL expression is diminished in esophageal cancer cases and cell lines.
MAL expression in tumor cells exerts an anti-tumorigenic effect by Fas and/or by keratins of esophageal epithelium.
MAL expression is diminished in pre-cancerous lesions in a rat carcinogenic model, as well as in dysplastic lesions of esophageal cancer. .
2. INTRODUCTION The fragile histidine triad (FHIT) functions as a tumor suppressor and clinical benefits of adenoviral-FHIT (Ad-FHIT) may be expected. However, the pathways through which FHIT induces apoptosis and inhibits cancer cell growth are not known. To determine appropriate targets for Ad-FHIT mediated therapy, we performed microarray analysis between Ad-FHIT transfected cells and control cells using 3 kinds of squamous cancer cell lines. For this purpose, 1) we identified clusters of more repressed genes in Ad-FHIT cells compared to control cells, and 2) we compared clustered genes in apoptosis induced cells H1299 and TE4 by Ad-FHIT infection with genes in non apoptotic non-induced cell line, TE2.
METHOD Three cell lines, H1299, TE4 and TE2 were transfected individually with full length FHIT and lacZ cDNA as a control. Total RNAs extracted from Ad-FHIT or AdlacZ infected samples were labeled with Cy3-dCTP or Cy5-dCTP and hybridized with a chip printed with 19,200 oligos. 1) The Ad-FHIT/Ad-control expression ratio was derived by using a random permutation test with high reproducibility from 7 repetitive
Experiments, and 4 spots per gene on a chip. 2) The expression ratio of TE4/TE2 for eachgene was calculated to determine what genes are dominant in Ad-FHIT induced apoptotic cells.
RESULTS 1) We identified clusters of genes reduced in Ad-FHIT, such as arachidonicacid metabolism (Table 1A) and matrix metalloprotease (MMP) related genes (Table 1B). We confirmed a reduction of PGE2 synthesis to 0.75 times control cells (range 0.35 to 0.98) by ELISA assays after exposure to LPS, IL-1 beta, or PMA stimulation in FHIT expressing cells. 2) The expression ratio of TE4 (apoptosis induced) /TE2 (non-apoptosis induced), disclosed that c-Src tyrosine kinase, tyrosine-protein kinase JAK-1 and EST (#Hs.268892) were associated with apoptosis, with ratios of 2.1, 2.4 and 6.6, respectively(Table 2).

CONCLUSION 1) We anticipate that Ad-FHIT may be effective in certain pre-malignant cases involving inflammatory carcinogens, such as COX-2 which leads to the inhibition of apoptosis; invasion, cell proliferation, angiogenesis mediated by the PGE2 receptor Ep4; IL-1 beta which stimulates the release of prostaglandin; and ERG-1 which is a transcription factor for mPGES. Moreover, the MMP family could be a target of the Ad-FHIT gene. 2) Therefore we predict the induction of apoptosis by Ad-FHIT on far advanced esophageal cancer cases with activation of those signal pathways..
3. Identification of non coding RNA as carcinogenic or recurrence/metastatic markers by Next Generation Sequencer, and the magnitude for surgeons..
Membership in Academic Society
  • Society of Surgical Oncology
Awards
  • Technical assistance of miR assay
Educational
Educational Activities
Annual lectures for the 2nd grade students in Kyushu University.
Contribution of the qualification of the Medical Doctor for more than 15 junior colleagues