Functional analyses and therapeutic application of novel tumor suppressor gene DUSP4 involved in invasion of pancreatic cancer
| Project/Area Number |
16K08651
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Human pathology
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| Research Institution | Oita University |
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Principal Investigator |
Hijiya Naoki 大分大学, 医学部, 准教授 (80305036)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 膵癌 / 浸潤 / MAPキナーゼ / 治療標的 / DUSP4 / がん抑制遺伝子 |
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| Outline of Final Research Achievements |
By comparing the genomic profiles of paired non-invasive and invasive carcinoma tissues collected from patients with intraductal papillary mucinous neoplasm, we demonstrate that the loss of 8p11.22-ter was more often associated with invasive tissues. Expression profiling in pancreatic cancer cell lines with and without 8p11.22-ter revealed that DUSP4, a MAPK phosphatase, was significantly downregulated in cells lacking 8p11.22-ter. Re-expression of DUSP4 in pancreatic cancer cells significantly suppressed invasiveness and anoikis resistance via ERK inactivation. Therefore, we found that blockade of ERK signaling by MEK inhibition was effective in an orthotopic xenograft model. Collectively, our findings reveal a genetic mechanism by which pancreatic intraepithelial lesions progress to invasive carcinomas, and highlight DUSP4 as a novel invasion suppressor that can be therapeutically exploited through manipulation of ERK signaling.
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| Academic Significance and Societal Importance of the Research Achievements |
膵癌は最も予後不良な癌の一つで、5年生存率は10％に満たない。その理由として、①早期に浸潤癌に進展するため、根治切除術の適応になる症例が少ないこと、②既存の抗癌剤が奏功する症例が少ないことが挙げられる。したがって、浸潤に関わる分子メカニズムを解明して、それを治療標的とする新規治療法を開発すれば、膵癌の治療成績や予後は改善されることが期待できる。
本研究によって、膵癌の新規がん抑制遺伝子DUSP4が同定され、MAPキナーゼの治療標的としての重要性が確認された。
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Report
(4 results)
Research Products
(23 results)
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[Journal Article] Complete Sequences of the HTLV-1 Proviral Genomes from Newly Established ATL cell-lines in Oita Prefecture, Japan2018
Author(s)
Takuro Fukumoto, Emi Ikebe, Masao Ogata, Kazuhiro Kohno, Madoka Kuramitsu, Yusuke Sato, Nichole Fife, Takashi Matsumoto, Takaaki Yahiro, Masanori Ikeda, Shuichi Kusano, Akihiko Okayama, Mitsuo Hori, Naoki Hijiya, Yoshiyuki Tsukamoto, Yuka Hirashita, Masatsugu Moriyama, Kamruddin Ahmed, Hiroo Hasegawa, Akira Nishizono, Masumichi Saito*, and Hidekatsu Iha*
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Journal Title
Genome Announcements
Volume: 6
Issue: 25
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Association of fibrotic remodeling and cytokines/chemokines content in epicardial adipose tissue with atrial myocardial fibrosis in patients with atrial fibrillation2018
Author(s)
Abe I, Teshima Y, Kondo H, Kaku H, Kira S, Ikebe Y, Saito S, Fukui A, Shinohara T, Yufu K, Nakagawa M, Hijiya N, Moriyama M, Shimada T, Miyamoto S, Takahashi N
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Journal Title
Heart Rhythm.
Volume: 15
Pages: 1717-1727
DOI
Related Report
Peer Reviewed
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[Journal Article] Periportal low attenuation associated with liver metastasis from colorectal cancer: evaluation using multi-detector-row CT with pathological correlation. 2017 Jan;35(1):2017
Author(s)
Takaji R, Matsumoto S, Kiyonaga M, Yamada Y, Mori H, Iwashita Y, Ohta M, Inomata M, Hijiya N, Moriyama M, Takaki H, Fukuzawa K, Yonemasu H.
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Journal Title
Japanese Journal of Radiology
Volume: 35
Issue: 1
Pages: 10-15
DOI
ISSN
1867-1071, 1867-108X
Related Report
Peer Reviewed
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[Journal Article] Overexpression of cannabinoid receptor 1 in esophageal squamous cell carcinoma is correlated with metastasis to lymph nodes and distant organs, and poor prognosis.2017
Author(s)
Hijiya N, Shibata T, Daa T, Hamanaka R, Uchida T, Matsuura K, Tsukamoto Y, Nakada C, Iha H, Inomata M, Moriyama M.
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Journal Title
Pathology International
Volume: 67
Pages: 83-90
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Genomic loss of DUSP4 contributes to the progression of intraepithelial neoplasm of pancreas to invasive carcinoma.2016
Author(s)
Hijiya N, Tsukamoto Y, Nakada C, Tung NL, Kai T, Matsuura K, Shibata K, Inomata M, Uchida T, Tokunaga A, Amada K, Shirao K, Yamada Y, Mori H, Takeuchi I, Seto M, Aoki M, Takekawa M, Moriyama M.
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Journal Title
Cancer Research
Volume: 76
Pages: 2612-25
DOI
Related Report
Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
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[Presentation] Downregulation of DUSP4 contributes to the progression of intraepithelial neoplasm of pancreas to invasive carcinoma.2016
Author(s)
泥谷 直樹, 塚本 善之, 中田 知里, 甲斐 友喜, 松浦 恵子, 猪股 雅史, 白尾 國昭, 森 宣, 瀬戸 加大, 青木 正博, 武川 睦寛, 守山 正胤
Organizer
第75回日本癌学会学術総会
Place of Presentation
パシフィコ横浜（神奈川県・横浜市）
Year and Date
2016-10-06
Related Report
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