Regulation of cell proliferation through interaction between Arl4c and IQGAP1 in pancreatic cancer.

• Project/Area Number: 18K06956
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Osaka University
• Principal Investigator: Matsumoto Shinji 大阪大学, 医学系研究科, 准教授 (20572324)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥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)
• 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

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.

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。

Research Products

• [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.
  • Journal Title: J Pathol. Volume: 256(1) Issue: 1 Pages: 119-133
  • DOI: 10.1002/path.5814
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Localization of KRAS downstream target ARL4C to invasive pseudopods accelerates pancreatic cancer cell invasion. (2021)
  • Author(s): Harada A, Matsumoto S, Yasumizu Y, Shojima K, Akama T, Eguchi H, Kikuchi A.
  • Journal Title: Elife. Volume: 10
  • DOI: 10.7554/elife.66721
  • Peer Reviewed / Open Access
• [Journal Article] TAZ inhibits acinar cell differentiation but promotes immature ductal cell proliferation in adult mouse salivary glands. (2021)
  • Author(s): Miyachi Y, Nishio M, Otani J, Matsumoto S, Kikuchi A, Mak TW, Maehama T, Suzuki A.
  • Journal Title: Genes Cells. Volume: 26(9) Issue: 9 Pages: 714-726
  • DOI: 10.1111/gtc.12879
  • NAID: 120007148944
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ARL4C is associated with initiation and progression of lung adenocarcinoma and represents a therapeutic target (2020)
  • Author(s): Kimura Kenji、Matsumoto Shinji、Harada Takeshi、Morii Eiichi、Nagatomo Izumi、Shintani Yasushi、Kikuchi Akira
  • Journal Title: Cancer Science Volume: 111 Issue: 3 Pages: 951-961
  • DOI: 10.1111/cas.14303
  • Peer Reviewed / Open Access
• [Journal Article] Palmitoylated CKAP4 regulates mitochondrial functions through an interaction with VDAC2 at ER?mitochondria contact sites (2020)
  • Author(s): Harada Takeshi、Sada Ryota、Osugi Yoshito、Matsumoto Shinji、Matsuda Tomoki、Hayashi-Nishino Mitsuko、Nagai Takeharu、Harada Akihiro、Kikuchi Akira
  • Journal Title: Journal of Cell Science Volume: 133 Issue: 21
  • DOI: 10.1242/jcs.249045
  • Peer Reviewed / Open Access
• [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.
  • Journal Title: Nature Communications Volume: 28 Issue: 1 Pages: 3882-3882
  • DOI: 10.1038/s41467-019-11533-x
  • Peer Reviewed / Open Access
• [Journal Article] Chemically Modified Antisense Oligonucleotide Against ARL4C Inhibits Primary and Metastatic Liver Tumor Growth (2019)
  • Author(s): Harada Takeshi、Matsumoto Shinji、Hirota Suguru、Kimura Hirokazu、Fujii Shinsuke、Kasahara Yuuya、Gon Hidetoshi、Yoshida Toshihiko、Itoh Tomoo、Haraguchi Naotsugu、Mizushima Tsunekazu、Noda Takehiro、Eguchi Hidetoshi、Nojima Satoshi、Morii Eiichi、Fukumoto Takumi、Obika Satoshi、Kikuchi Akira
  • Journal Title: Molecular Cancer Therapeutics Volume: 18 Issue: 3 Pages: 602-612
  • DOI: 10.1158/1535-7163.mct-18-0824
  • Peer Reviewed
• [Journal Article] Wnt/β-catenin signaling, which is activated in odontomas, reduces Sema3A expression to regulate odontogenic epithelial cell proliferation and tooth germ development (2019)
  • Author(s): Fujii Shinsuke、Nagata Kengo、Matsumoto Shinji、Kohashi Ken-ichi、Kikuchi Akira、Oda Yoshinao、Kiyoshima Tamotsu、Wada Naohisa
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 4257-4257
  • DOI: 10.1038/s41598-019-39686-1
  • Peer Reviewed / Open Access
• [Presentation] Wnt標的遺伝子GREB1の組織特異的発現制御と肝細胞がんの増殖制御機構 (2021)
  • Author(s): 松本真司
  • Organizer: 第94回日本生化学会大会
• [Presentation] 肝細胞がんにおけるWnt標的遺伝子GREB1の発現と細胞増殖制御 (2020)
  • Author(s): 瀬田 みなみ, 松本 真司, 福本 巧, 菊池 章
  • Organizer: 第93回日本生化学会大会
• [Presentation] 悪性黒色腫におけるGREB1 isoform 4の発現機構解析と治療への応用 (2020)
  • Author(s): 新沢 康英, 松本 真司, 種村 篤, 藤本 学, 菊池 章
  • Organizer: 第93回日本生化学会大会
• [Presentation] パルミトイル化CKAP4はVDAC2を介してミトコンドリア機能を制御する (2020)
  • Author(s): 原田 武志, 佐田 遼太, 大杉 祥仁, 松本 真司, 菊池 章
  • Organizer: 第93回日本生化学会大会
• [Presentation] Wntシグナル標的遺伝子GREB1によるTGFβシグナルの抑制を介した肝芽腫形成の制御 (2020)
  • Author(s): 松本 真司, 山道 拓, 新沢 康英, 奥山 宏臣, 菊池 章
  • Organizer: 第93回日本生化学会大会
• [Presentation] Recruitment of KRAS downstream target ARL4C to memblane protrusions accelerates pancreatic cancer cell invasion (2020)
  • Author(s): Akikazu Harada, Shinji Matsumoto, Akira Kikuchi
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] DKK1-CKAP4 signaling is associated with poor prognosis of HCC and CKAP4 might represent a novel therapeutic target (2020)
  • Author(s): Kosuke Iguchi, Hidetoshi Gon, Hirokazu Kimura, Shinji Matsumoto, Takumi Fukumoto, Akira Kikuchi
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 肝腫瘍に対するARL4Cを標的としたアンチセンス核酸を用いた新規がん治療法の開発 (2019)
  • Author(s): 原田武志
  • Organizer: 第92回日本生化学会大会
• [Presentation] Arl4cを標的とした新規肺腺癌治療薬の開発 (2019)
  • Author(s): 木村賢二
  • Organizer: 第72回日本癌学会
• [Presentation] Arl4cとIQGAP1の相互作用による膵がん細胞の増殖制御機構 (2018)
  • Author(s): 赤間 俊之
  • Organizer: 第91回日本生化学会大会
• [Remarks] 大阪大学医学部分子病態生化学
  • URL: https://www.med.osaka-u.ac.jp/pub/molbiobc/
• [Remarks] 大阪大学大学院 医学系研究科 分子病態生化学 ホームページ
  • URL: http://www.med.osaka-u.ac.jp/pub/molbiobc/index.html