Clarification of the microRNA pathway regulating resistance to Trastuzumab in gastric cancer

• Project/Area Number: 26461982
• 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: HAYASHI Naoko 熊本大学, 医学部附属病院, 非常勤診療医師 (20452899)
• Co-Investigator(Kenkyū-buntansha): 石本 崇胤 熊本大学, 大学院生命科学研究部(医), 特任講師 (00594889) ; 馬場 祥史 熊本大学, 大学院生命科学研究部(医), 講師 (20599708) ; 岩槻 政晃 熊本大学, 大学院生命科学研究部(医), 助教 (50452777)
• Research Collaborator: ETO Kojiro 公益財団法人 がん研究会, その他部局等, 医員
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 胃癌 / トラスツズマブ / microRNA / 薬剤耐性 / miR 223 / FBXW7 / MCL1 / c-Myc / c-Jun / HER2 / Trastuzumab / cisplatine / miR-21 / PTEN

Outline of Final Research Achievements

We established the Trastuzumab resistance gastric cancer (GC) cell line with continuous Trastuzumab administration. Parent GC cell line and resistance GC cell line are subjected to miR microarray. We identified miR-21 which can regulate PTEN and miR-223, which can regulate FBXW7, using miR array analysis using by resistance cell lines which we established.
Overexpression of miR-21 decreased PTEN expression and the sensitivity of gastric cancer cells to Trastuzumab, while suppression of miR-21 restored PTEN expression and the sensitivity of GC cells to Trastuzumab. Similarly, Overexpression of miR-223 decreased FBXW7 expression and the sensitivity of gastric cancer cells to Trastuzumab, while suppression of miR-223 restored FBXW7 expression and the sensitivity of GC cells to Trastuzumab. Moreover, overexpression of miR-223 significantly suppressed Trastuzumab-induced apoptosis.
These findings suggest that this pathway may be crucial 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] 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
• [Presentation] 胃癌におけるtrastuzumab二次耐性に関与する遺伝子の同定 (2016)
  • Author(s): 岩槻政晃、澤山浩、馬場祥史、坂本快郎、吉田直矢、馬場秀夫
  • Organizer: 第27回日本消化器癌発生学会総会
  • Place of Presentation: 城山観光ホテル（鹿児島県）
• [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: 東京會舘
  • 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: 東京會舘
  • Year and Date: 2014-10-31 – 2014-11-01