Clarification of the functional significance of DUSP4 and its therapeutic application in colorectal cancers.

• Project/Area Number: 17K08696
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Oita University
• Principal Investigator: Ichimanda Michihiro 大分大学, 医学部, 客員研究員 (60770146)
• Co-Investigator(Kenkyū-buntansha): 猪股 雅史 大分大学, 医学部, 教授 (60315330) ; 衛藤 剛 大分大学, 医学部, 准教授 (00404369) ; 白下 英史 大分大学, 医学部, 講師 (50596955) ; 守山 正胤 大分大学, 医学部, 教授 (90239707) ; 泥谷 直樹 大分大学, 医学部, 准教授 (80305036)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 大腸癌 / DUSP4 / MAPキナーゼ阻害 / 細胞周期 / MAPK阻害剤 / 有効性予測因子

Outline of Final Research Achievements

We showed that, in most of colorectal cancers, constitutive activation of MAP kinases due to the downregulation of DUSP4 contributes to their progression. Furthermore, we demonstrated that both proliferation potentials and invasiveness of the cancer cells could be suppressed by abrogation of the hyper-activated MAP kinases using a specific inhibitor. On the other hand, some colorectal cancers retained the activated MAP kinases in spite of their high levels of DUSP4 expression. In these cells, knockdown of DUSP4 using siRNAs resulted in the growth suppression. Our findings suggest that DUSP4 might function as not only a tumor suppressor but also an oncogene in colorectal cancers.

Academic Significance and Societal Importance of the Research Achievements

大腸癌の増殖・浸潤におけるDUSP4の機能的意義を明らかにした。大部分の大腸癌では、「がん抑制遺伝子」DUSP4の欠失に伴って活性化されるMAPキナーゼが重要な治療標的となり得る。一方、一部の大腸癌では、DUSP4が「がん遺伝子」として機能しているため、DUSP4あるいは下流の分子が治療標的候補となる。今後、DUSP4の発現変動に伴って活性化される細胞内シグナル伝達経路の同定と、癌の悪性形質獲得に関わる分子メカニズムを詳細に解析することにより、大腸癌の新規分子標的治療法が確立されると期待する。

Research Products

• [Journal Article] A transgenic mouse expressing miR-210 in proximal tubule cells shows mitochondrial alteration: possible association of miR-210 with a shift in energy metabolism. (2020)
  • Author(s): Nakada C, Hijiya N, Tsukamoto Y, Yano S, Kai T, Uchida T, Kimoto M, Takahashi M, Daa T, Matsuura K, Shin T, Mimata H, Moriyama M.
  • Journal Title: J Pathol. Volume: in press Issue: 1 Pages: 12-25
  • DOI: 10.1002/path.5394
  • Peer Reviewed
• [Journal Article] Invasive intraductal papillary mucinous neoplasms of the pancreas: relationships between mural nodules detected on thin-section contrast-enhanced MDCT and invasive components. (2019)
  • Author(s): Kamei N, Yamada Y, Hijiya N, Takaji R, Kiyonaga M, Hongo N, Ohta M, Hirashita T, Inomata M, Matsumoto S.
  • Journal Title: Abdom Radiol Volume: 44 Issue: 9 Pages: 3139-3147
  • DOI: 10.1007/s00261-019-02084-2
  • Peer Reviewed
• [Journal Article] Downregulation of dual-specificity phosphatase 4 enhances cell proliferation and invasiveness in colorectal carcinomas (2017)
  • Author(s): Ichimanda Michihiro、Hijiya Naoki、Tsukamoto Yoshiyuki、Uchida Tomohisa、Nakada Chisato、Akagi Tomonori、Etoh Tsuyoshi、Iha Hidekatsu、Inomata Masafumi、Takekawa Mutsuhiro、Moriyama Masatsugu
  • Journal Title: Cancer Sci Volume: 109 Issue: 1 Pages: 250-258
  • DOI: 10.1111/cas.13444
  • Peer Reviewed / Open Access
• [Presentation] 大腸癌におけるDUSP4発現分布とその意義 (2018)
  • Author(s): 一万田充洋、泥谷直樹、赤木智徳、白下英史、衛藤剛、猪股雅史、守山正胤
  • Organizer: 第23回癌と遺伝子・大分外科フォーラム
  • Invited
• [Presentation] 大腸癌におけるDUSP4発現変動の意義 (2018)
  • Author(s): 一万田充洋、泥谷直樹、赤木智徳、白下英史、衛藤剛、猪股雅史、守山正胤
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] Downregulation of DUSP4 enhances cell proliferation and invasiveness in colorectal carcinomas (2017)
  • Author(s): Michihiro Ichimanda, Naoki Hijiya, Yoshiyuki Tsukamoto, Chisato Nakada, Tsuyoshi Etoh, Hidekatsu Iha, Masafumi Inomata and Masatsugu Moriyama
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 大腸癌におけるDUSP4発現パターンとバイオマーカーとしての意義 (2017)
  • Author(s): 一万田充洋、泥谷直樹、赤木智徳、白下英史、衛藤剛、猪股雅史、守山正胤
  • Organizer: 第87回大腸癌研究会