Targeting epigenetic alterations in a mouse model of E-cadherin/p53-deficient diffuse-type gastric cancer

• Project/Area Number: 25830074
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Shimada Shu 東京医科歯科大学, 医歯(薬)学総合研究科, 助教 (20609705)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 胃がん / マウスモデル / E-cadherin / p53 / エピジェネティクス / 分子標的治療

Outline of Final Research Achievements

Diffuse-type gastric cancer (DGC) exhibits rapid disease progression and a poor patient prognosis. We have established an E-cadherin/p53 double conditional knockout (DCKO) mouse line as the first genetically engineered one, which morphologically and molecularly recapitulates human DGC. In this study, we derived mouse DGC (MDGC) cell lines from primary tumors and lymph node metastases of the DCKO mice. We identified that the expression levels of epigenetic regulators and frequently methylated genes were up- and down-regulated in mouse primary DGC, respectively. Treatment with some epigenetic inhibitors could markedly induce differentiation and attenuate sphere formation of the MDGC cell lines in vitro. Moreover, these agents demonstrated enhanced tumor-suppressor activity in vivo. These results suggest that epigenetic alteration may play significant roles in diffuse-type gastric carcinogenesis and support to develop a relevant therapeutic strategy in human DGC.

Research Products

• [Journal Article] CD73 as a therapeutic target for pancreatic neuroendocrine tumor stem cells (2016)
  • Author(s): Katsuta E, Tanaka S, Mogushi K, Shimada S, Akiyama Y, Aihara A, Matsumura S, Mitsunori Y, Ban D, Ochiai T, Kudo A, Fukamachi H, Tanaka H, Nakayama K, Arii S, Tanabe M
  • Journal Title: Int J Oncol Volume: 48 Pages: 657-69
  • Peer Reviewed
• [Journal Article] Reduced expression of SET7/9, a histone mono-methyltransferase, is associated with gastric cancer progression (2016)
  • Author(s): Akiyama Y, Koda Y, Byeon SJ, Shimada S, Nishikawaji T, Sakamoto A, Chen Y, Kojima K, Kawano T, Eishi Y, Deng D, Kim WH, Zhu WG, Yuasa Y, Tanaka S
  • Journal Title: Oncotarget Volume: 7 Pages: 3966-83
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression of connective tissue growth factor in the livers of non-viral hepatocellular carcinoma patients with metabolic risk factors (2016)
  • Author(s): Akahoshi K, Tanaka S, Mogushi K, Shimada S, Matsumura S, Akiyama Y, Aihara A, Mitsunori Y, Ban D, Ochiai T, Kudo A, Arii S, Tanabe M
  • Journal Title: J Gastroenterol Volume: -
  • Peer Reviewed
• [Journal Article] Dominant Expression of DCLK1 in Human Pancreatic Cancer Stem Cells Accelerates Tumor Invasion and Metastasis (2016)
  • Author(s): Ito H, Tanaka S, Akiyama Y, Shimada S, Adikrisna R, Matsumura S, Aihara A, Mitsunori Y, Ban D, Ochiai T, Kudo A, Arii S, Yamaoka S, Tanabe M
  • Journal Title: PLoS One Volume: 11
  • Peer Reviewed / Open Access
• [Journal Article] 幹細胞に着目した新薬の可能性 (2016)
  • Author(s): 島田周, 田中真二
  • Journal Title: 大腸がんperspective Volume: 2 Pages: 262-269
• [Journal Article] DNA Methylation in the Exon 1 Region and Complex Regulation of Twist1 Expression in Gastric Cancer Cells (2015)
  • Author(s): Sakamoto A, Akiyama Y, Shimada S, Zhu WG, Yuasa Y, Tanaka S
  • Journal Title: PLoS One Volume: 10
  • Peer Reviewed / Open Access
• [Journal Article] CD49f^<high> cells retain sphere-forming and tumor-initiating activities in human gastric tumors (2013)
  • Author(s): Fukamachi H, Seol HS, Shimada S, Funasaka C, Baba K, Kim JH, Park YS, Kawachi H, Yook JH, Eishi Y, Kojima K, Kim WH, Jang SJ, Yuasa Y
  • Journal Title: PLoS One Volume: 8 Issue: 8 Pages: e72438-e72438
  • DOI: 10.1371/journal.pone.0072438
  • Peer Reviewed
• [Presentation] Identification of selective inhibitors of diffusetype gastric cancer cells by screening of annotated compounds (2015)
  • Author(s): Shimada S, Akiyama Y, Fukamachi H, Yuasa Y, Tanaka S
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] Transcriptional regulatory mechanism of SET7/9 in gastric cancer (2015)
  • Author(s): Akiyama Y, Koda Y, Nishikawaji T, Shimada S, Sakamoto A, Yuasa Y, Tanaka S
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] Features of poorly-differentiated gastric tumor-initiating cells from patient-derived tumor xenograft tissues (2015)
  • Author(s): Fukamachi H, Shimada S, Akiyama Y, Yuasa Y, Tsuchiya K, Tanaka S
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] Oncogenic roles of SETDB2, a histone methyltransferase, in human gastric carcinogenesis (2015)
  • Author(s): Nishikawaji T, Akiyama Y, Shimada S, Yuasa Y, Tanaka S
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] Epigenetic regulation of Twist1 in diffuse-type gastric cancer cell lines of an E-cadherin/p53-deficient mouse model (2015)
  • Author(s): Sakamoto A, Shimada S, Akiyama Y, Yuasa Y, Tanaka S
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] Features of tumor-initiating cells from a poorly-differentiated gastric tumor in primary culture. (2014)
  • Author(s): Fukamachi H, Shimada S, Yuasa Y.
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Identification of selective inhibitors of mouse diffuse-type gastric cancer cells by screening a library of known drugs. (2014)
  • Author(s): Shimada S, Akiyama Y, Fukamachi H, Yuasa Y.
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Functional analyses of SETDB2, a histonemethyltransferase, in gastric cancers. (2014)
  • Author(s): Nishikawaji T, Akiyama Y, Shimada S, Yuasa Y.
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Expression changes of Twist1 in diffuse-type gastric cancer cell lines of an E-cadherin/p53-deficient mouse model (2014)
  • Author(s): Sakamoto A, Shimada S, Akiyama Y, Yuasa Y.
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Loss of SET7/9, a hitone methyltransferase, in gastric cancers. (2014)
  • Author(s): Akiyama Y, Koda Y, Nishikawaji T, Shimada S, Yuasa Y.
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Functional analyses of SETDB2, a histonemethyltransferase, in gastric cancers. (2014)
  • Author(s): Nishikawaji T, Akiyama Y, Shimada S, Yuasa Y.
  • Organizer: NRF A3 Foresight Program 2014 Seminar - Epigenetic Signatures in Gastric Carcinogenesis,
  • Place of Presentation: ソウル - 韓国
  • Year and Date: 2014-06-20 – 2014-06-23
• [Presentation] Roles and epigenetic expression changes of Twist1 in diffuse-type gastric cancer cell lines of an E-cadherin/p53-deficient mouse model. (2014)
  • Author(s): Sakamoto A, Shimada S, Akiyama Y, Yuasa Y.
  • Organizer: NRF A3 Foresight Program 2014 Seminar - Epigenetic Signatures in Gastric Carcinogenesis,
  • Place of Presentation: ソウル - 韓国
  • Year and Date: 2014-06-20 – 2014-06-23
• [Presentation] Identification of selective inhibitors of mouse E-cadherin/p53-deficient diffuse-type gastric cancer cells by screening a library of known compounds. (2014)
  • Author(s): Shimada S, Akiyama Y, Fukamachi H, Yuasa Y.
  • Organizer: NRF A3 Foresight Program 2014 Seminar - Epigenetic Signatures in Gastric Carcinogenesis,
  • Place of Presentation: ソウル - 韓国
  • Year and Date: 2014-06-20 – 2014-06-23
• [Presentation] Identification of oncogenic pathways activated in a mouse model of E-cadherin/p53-deficient diffuse-type gastric cancer (2014)
  • Author(s): Shimada S, Akiyama Y, Fukamachi H, Kim WH, Yuasa Y
  • Organizer: JSPS A3 Foresight Program 2014 Seminar - Epigenetic Signatures in Gastric Carcinogenesis
  • Place of Presentation: 京都
• [Presentation] Alterations of a histone lysine methyltransferase, SETDB2, in gastric cancers (2014)
  • Author(s): Nishikawaji T, Akiyama Y, Shimada S, Yuasa Y
  • Organizer: JSPS A3 Foresight Program 2014 Seminar - Epigenetic Signatures in Gastric Carcinogenesis
  • Place of Presentation: 京都
• [Presentation] ヒストン修飾関連遺伝子SET7/9の胃がんにおける発現低下と機能解析 (2013)
  • Author(s): 秋山好光, 甲田裕樹, 西川路武人, 島田周, Woo Ho Kim, Wei-Guo Zhu, 湯浅保仁
  • Organizer: 第7回日本エピジェネティクス研究会年会
  • Place of Presentation: 奈良
• [Presentation] 胃がんにおけるヒストンメチル化酵素SETDB2の異常と機能の解析 (2013)
  • Author(s): 西川路武人, 秋山好光, 島田周, 湯浅保仁
  • Organizer: 第7回日本エピジェネティクス研究会年会
  • Place of Presentation: 奈良
• [Presentation] Targeting epigenetic alterations in a mouse model of E-cadherin/p53-deficient diffuse-type gastric cancer (2013)
  • Author(s): Shimada S, Akiyama Y, Fukamachi H, Yuasa Y
  • Organizer: NRF A3 Foresight Program 2013 Seminar - Epigenetic Signatures in Gastric Carcinogenesis
  • Place of Presentation: 韓国 - 扶余
• [Presentation] Alterations of histone lysine methyltransferases, SETDB1 and SETDB2, in gastric cancers (2013)
  • Author(s): Nishikawaji T, Akiyama Y, Shimada S, Yuasa Y
  • Organizer: NRF A3 Foresight Program 2013 Seminar - Epigenetic Signatures in Gastric Carcinogenesis
  • Place of Presentation: 韓国 - 扶余
• [Presentation] びまん浸潤型胃癌マウスモデルにおけるエピジェネティクス変化の解析 (2013)
  • Author(s): 島田周
  • Organizer: 第24回日本消化器癌発生学会総会
  • Place of Presentation: 金沢
• [Presentation] Frequent loss of SET7/9 protein and its clinicopathological significance in gastric carcinoma (2013)
  • Author(s): Akiyama Y, Koda Y, Nishikawaji T, Shimada S, Yuasa Y
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: 横浜
• [Presentation] Patient-dependent differences in the features of human gastric tumor-initiating cells in primary culture (2013)
  • Author(s): Fukamachi H, Shimada S, Yuasa Y
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: 横浜
• [Presentation] Epigenetic involvement in a mouse model of E-cadherin/p53-deficient diffuse-type gastric cancer (2013)
  • Author(s): Shimada S, Akiyama Y, Fukamachi H, Yuasa Y
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: 横浜
• [Presentation] Function and expression of Twist1 in diffuse-type gastric cancer cell lines of an E-cadherin/p53-deficient mouse model (2013)
  • Author(s): Sakamoto A, Shimada S, Akiyama Y, Yuasa Y
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: 横浜
• [Presentation] Alterations of SETDB2, a histone methyltransferase, in gastric cancers (2013)
  • Author(s): Nishikawaji T, Akiyama Y, Shimada S, Yuasa Y
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: 横浜
• [Presentation] Alterations of SET7/9 and GATA4/5 in gastric cancer (2013)
  • Author(s): Akiyama Y, Shimada S, Byeon S, Deng D, Kim WH, Zhu WG, Yuasa Y
  • Organizer: NSFC A3 Foresight Program 2013 Seminar - Epigenetic Signatures in Gastric Carcinogenesis
  • Place of Presentation: 中国 - 桂林
• [Presentation] Summary of GC stem cell researches in the A3 project (2013)
  • Author(s): Fukamachi H, Seol HS, Shimada S, Kim WH, Jang SJ, Yuasa Y
  • Organizer: NSFC A3 Foresight Program 2013 Seminar - Epigenetic Signatures in Gastric Carcinogenesis
  • Place of Presentation: 中国 - 桂林
• [Presentation] Targeting epigenetic alterations in a mouse model of E-cadherin/p53-deficient diffuse-type gastric cancer (2013)
  • Author(s): Shimada S
  • Organizer: The 4th JCA-AACR Special Joint Conference
  • Place of Presentation: 舞浜
  • Invited