Regulation of cell proliferation through interaction between Arl4c and IQGAP1 in pancreatic cancer.
| Project/Area Number |
18K06956
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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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| Review Section |
Basic Section 49010:Pathological biochemistry-related
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| Research Institution | Osaka University |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | Arl4c / IQGAP1 / 膵がん / 転移 / KRas / MMP14 / アンチセンス核酸 / Wnt / GREB1 / MT1-MMP / 細胞浸潤 / Ras |
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| Outline of Final Research Achievements |
Suppression of Arl4c expression in pancreatic cancer cells strongly suppressed the invasive ability of cancer cells. Arl4c localized to the tip of the invasive pseudopod via myristic acid modification and enhanced invasive ability by inducing degradation of the extracellular matrix. IQGAP1 was identified as a novel binding protein for Arl4c, and MMP14 (MT1-MMP) was identified as an effector molecule downstream of IQGAP1. Arl4c specifically localized to the PIP3 region at the tip of the invasive pseudopod and enhanced invasive ability by recruiting IQGAP1 and MMP14 to the region. Subcutaneous administration of a modified antisense oligonucleotide (ASO) against Arl4c strongly inhibited metastasis of pancreatic cancer cells to lymph nodes in an orthotopic transplantation model.
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| Academic Significance and Societal Importance of the Research Achievements |
膵がんは9割以上の症例でKRasの変異を有する極めて予後不良な難治性がんであり、多くの症例で発見時にはすでに転移が認められ手術適応がない。転移の機構の解明と制御は、膵がんの予後改善のために極めて重要である。
本研究成果から、Arl4cによる浸潤仮足の形成を介した、膵がんの新たな浸潤機構が解明された。Arl4cに対するアンチセンス核酸の投与が膵がんの転移を抑制したことから、Arl4cが有望な治療標的である可能性が示唆された。Arl4cが膵がんの主要なドライバーである変異型KRasの下流エフェクターとして同定されたことで、今後、膵がんの病態解明と治療法開発の進展が期待される。
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Report
(5 results)
Research Products
(20 results)
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[Journal Article] RAF1-MEK/ERK pathway-dependent ARL4C expression promotes ameloblastoma cell proliferation and osteoclast formation.2021
Author(s)
Fujii S, Ishibashi T, Kokura M, Fujimoto T, Matsumoto S, Shidara S, Kurppa KJ, Pape J, Caton J, Morgan PR, Heikinheimo K, Kikuchi A, Jimi E, Kiyoshima T.
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Journal Title
J Pathol.
Volume: 256(1)
Issue: 1
Pages: 119-133
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] GREB1 induced by Wnt signaling promotes development of hepatoblastoma by suppressing TGFβ signaling.2019
Author(s)
Matsumoto S, Yamamichi T, Shinzawa K, Kasahara Y, Nojima S, Kodama T, Obika S, Takehara T, Morii E, Okuyama H, Kikuchi A.
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Journal Title
Nature Communications
Volume: 28
Issue: 1
Pages: 3882-3882
DOI
Related Report
Peer Reviewed / Open Access
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