The Molecular mechanism of trastuzumab for gastric cancer via microRNA –gene pathway

• Project/Area Number: 25462027
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kumamoto University
• Principal Investigator: IWATSUKI Masaaki 熊本大学, 大学院生命科学研究部(医), 助教 (50452777)
• Co-Investigator(Kenkyū-buntansha): WATANABE Masayuki 公益財団法人がん研究会, その他部局等, 食道担当部長 (80254639) ; ISHIMOTO Takatsugu 熊本大学, 国際先端医学研究機構, 客員准教授 (00594889)
• Research Collaborator: KURASHIGE Junji 熊本大学, 医学部附属病院, 特任助教 ; ETO Kojiro 公益財団法人がん研究会, その他部局等, 医員
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 胃癌 / トラスツズマブ耐性 / microRNA / Trastuzumab耐性 / CGH array / マイクロアレイ / FBXW7 / microRNA array

Outline of Final Research Achievements

The aim of this study was to identify microRNA- gene pathway that regulates the sensitivity of HER2-positive GC cells to trastuzumab. We performed following experiments: (i) trastuzumab-resistant GC cell: We cultured the HER2-positive cell line in the presence of trastuzumab (ii) microRNA array: We examined the miR expression profile using miR array analysis. (iii) novel miR-gene pathway: We focused on miR-223-FBXW7 pathway based on miRarray analysis.
Results: (i) We established resistant cell without significant changes in HER2 in the presence of trastuzumab continuously for 6 months. (ii) We identified 23 miRs up-regulated in the resistant cells. (iii) the miR-223/FBXW7 pathway regulates the sensitivity of a HER2-positive GC cell line to trastuzumab. In conclusion, this study suggested that the miR-223-FBXW7 pathway can be a crucial clue to the mechanism of resistance to trastuzumab in GC.

Research Products

• [Journal Article] The sensitivity of gastric cancer to trastuzumab is regulated by the miR-223/FBXW7 pathway (2015)
  • Author(s): Eto K, Iwatsuki M, Watanabe M, Ishimoto T, Ida S, Imamura Y, Iwagami S, Baba Y, Sakamoto Y, Miyamoto Y, Yoshida N, Baba H
  • Journal Title: Int J Cancer Volume: 136(7) Issue: 7 Pages: 1537-45
  • DOI: 10.1002/ijc.29168
  • Peer Reviewed
• [Journal Article] Repeated recurrence of a gastric gastrointestinal stromal tumor on the chest wall after initial curative resection: Report of a case (2015)
  • Author(s): Iwatsuki M, Takamori H, Eto K, Shimizu K, Ogawa K, Yamamura K, Ozaki N, Tanaka H, Sugiyama S, Ogata K, Doi K, Kamio T, Baba H
  • Journal Title: Int J Surg Case Rep Volume: 6C Pages: 36-9
  • DOI: 10.1016/j.ijscr.2014.11.033
  • Peer Reviewed
• [Journal Article] Simultaneous total laparoscopic curative resection for synchronous gastric, cecal and rectal cancer: Report of a case (2015)
  • Author(s): Iwatsuki M, Tanaka H, Shimizu K, Ogawa K, Yamamura K, Ozaki N, Sugiyama S, Ogata K, Doi K, Baba H, Takamori H
  • Journal Title: Int J Surg Case Rep Volume: 6C Pages: 129-32
  • DOI: 10.1016/j.ijscr.2014.11.065
  • Peer Reviewed
• [Journal Article] バイオマーカーをめぐるQ&A(Question5) 胃癌におけるmicroRNA21/PTEN経路を介したトラスツズマブ耐性(Q&A) (2014)
  • Author(s): 江藤 弘二郎、岩槻 政晃、石本 崇胤、馬場 秀夫
  • Journal Title: Surgery Frontier Volume: 21(2) Pages: 220-23
• [Journal Article] The microRNA-21/PTEN pathway regulates the sensitivity of HER2-positive gastric cancer cells to trastuzumab (2014)
  • Author(s): Eto K, Iwatsuki M, Watanabe M, Ida S, Ishimoto T, Iwagami S, Baba Y, Sakamoto Y, Miyamoto Y, Yoshida N, Baba H
  • Journal Title: Ann Surg Oncol Volume: 21(1) Issue: 1 Pages: 343-50
  • DOI: 10.1245/s10434-013-3325-7
  • Peer Reviewed
• [Journal Article] LINE-1 hypomethylation, DNA copy number alterations, and CDK6 amplification in esophageal squamous cell carcinoma (2014)
  • Author(s): Y. Baba, M. Watanabe, A. Murata, H. Shigaki, K. Miyake, T. Ishimoto, M. Iwatsuki, S. Iwagami, N. Yoshida, E. Oki, K. Sakamaki, M. Nakao, and H. Baba.
  • Journal Title: Clin Cancer Res. Volume: 20 Issue: 5 Pages: 1114-1124
  • DOI: 10.1158/1078-0432.ccr-13-1645
  • Peer Reviewed
• [Journal Article] Macrophage-derived reactive oxygen species suppress miR-328 targeting CD44 in cancer cells and promote redox adaptation. (2014)
  • Author(s): Ishimoto T
  • Journal Title: Carcinogenesis Volume: Epub ahead of print
  • Peer Reviewed
• [Journal Article] Small molecule agonists of PPAR-γ exert therapeutic effects in esophageal cancer. (2014)
  • Author(s): Sawayama H, Ishimoto T, Watanabe M, Yoshida N, Sugihara H, Kurashige J, Hirashima K, Iwatsuki M, Baba Y, Oki E, Morita M, Shiose Y, Baba H
  • Journal Title: Cancer Res Volume: 74 Issue: 2 Pages: 575-585
  • DOI: 10.1158/0008-5472.can-13-1836
  • Peer Reviewed
• [Journal Article] Frequency of HER2 Expression of Circulating Tumor Cells in Patients with Metastatic or Recurrent Gastrointestinal Cancer (2013)
  • Author(s): Iwatsuki M
  • Journal Title: Br J Cancer. Volume: 109 Issue: 11 Pages: 2829-32
  • DOI: 10.1038/bjc.2013.680
  • Peer Reviewed
• [Presentation] Comprehensive Analysis of secondary-resistant genes for trastuzumab in gastric cancer (2016)
  • Author(s): Masaaki Iwatsuki
  • Organizer: 2016 AACR-JCA Joint Conference
  • Place of Presentation: Hyatt Regency Maui（米国・ハワイ）
  • Year and Date: 2016-02-16
  • Int'l Joint Research
• [Presentation] Molecular mechanism of secondary-resistant for trastuzumab in gastric cancer (2016)
  • Author(s): Masaaki Iwatsuki、Eto Kojiro, Hideo Baba
  • Organizer: 2016 ASCO-GI
  • Place of Presentation: Moscone West Building（米国・サンフランシスコ）
  • Year and Date: 2016-01-21
  • Int'l Joint Research
• [Presentation] 胃癌におけるトラスツズマブ二次耐性に関与するmicroRNAの同定 (2015)
  • Author(s): 岩槻政晃、藏重淳二、江藤弘二郎、糸山明莉、黒田大介、江藤二男、小澄敬祐、馬場祥史、坂本快郎、吉田直矢、馬場秀夫
  • Organizer: 第26回 日本消化器癌発生学会総会
  • Place of Presentation: 米子全日空ホテル（鳥取県）
  • Year and Date: 2015-11-19
• [Presentation] FREQUENCY OF HER2 EXPRESSION OF CIRCULATING TUMOR CELLS IN PATIENTS WITH METASTATIC OR RECURRENT GASTROINTESTINAL CANCER (2014)
  • Author(s): Iwatsuki M
  • Organizer: 9th ISCRT
  • Place of Presentation: Tokyo
  • Year and Date: 2014-10-31 – 2014-11-01
• [Presentation] The microRNA-223/FBXW7/MCL1 pathway regulates the sensitivity of HER2-positive gastric cancer cells to Trastuzumab (2014)
  • Author(s): Eto K
  • Organizer: 9th ISCRT
  • Place of Presentation: Tokyo
  • Year and Date: 2014-10-31 – 2014-11-01
• [Presentation] 胃癌におけるFBXW7-MCL1 pathwayを介したTrastuzumab耐性機序の解明 (2014)
  • Author(s): 江藤 弘二郎
  • Organizer: 第69回日本消化器外科学会総会
  • Place of Presentation: 福島
  • Year and Date: 2014-07-16 – 2014-07-18
• [Presentation] Sensitivity to trastuzumab for gastric cancer is regulated by miR-223/FBXW7 pathway (2014)
  • Author(s): Eto K
  • Organizer: AACR Annual Meeting 2014
  • Place of Presentation: San Diego, California
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] 胃癌におけるFBXW7 を介したTrastuzumab 耐性機序の解明 (2014)
  • Author(s): 江藤 弘二郎
  • Organizer: 第114回日本外科学会定期学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-04-03 – 2014-04-05
• [Presentation] 胃癌における微量癌細胞の検出と分子生物学的特性の解明 (2013)
  • Author(s): 岩槻 政晃
  • Organizer: 第113回 日本外科学会総会
  • Place of Presentation: マリンメッセ福岡