The function of p130 Cas on the epithelial-mesenchymal transition in oral squamous cell carcinoma

• Project/Area Number: 17K11884
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Kyushu Dental College
• Principal Investigator: Yoshioka Izumi 九州歯科大学, 歯学部, 教授 (10305823)
• Co-Investigator(Kenkyū-buntansha): 松原 琢磨 九州歯科大学, 歯学部, 准教授 (00423137) ; 古株 彰一郎 九州歯科大学, 歯学部, 教授 (30448899) ; 自見 英治郎 九州大学, 歯学研究院, 教授 (40276598) ; 松尾 拡 九州歯科大学, 歯学部, 教授 (70238971) ; 大澤 賢次 九州歯科大学, 歯学部, 助教 (70638238)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 口腔扁平上皮がん / 上皮間葉移行 / p130Cas / 骨浸潤 / 口腔扁平上皮癌 / 顎骨浸潤 / TGFβシグナル / TGF-β

Outline of Final Research Achievements

TGF-β is abundantly expressed in the bone matrix and is involved in the acquisition of aggressiveness by tumors. TGF-β is also important to cytoskeletal changes during tumor progression. TGF-β induced the phosphorilaion of Smad3 and p130Cas as well as epithelial-mesenchymal transition (EMT) accompanied by the downregulation of the expression of E-cadherinand the upregulation of the expression of N-cadherin, or Snail. SB431542, a specific inhibitor of Smad2/3 signaling, abrogated the TGF-β-induced phosphorylation of p130Cas and morphological changes. Silencing p130Cas using an shRNA or siRNA in SCCVII cells suppressed TGF-β-induced cell migration, invasion, EMT, and matrix metalloproteinase-9 (MMP-9) production. Compared with control SCCVII cells, SCCVII cells with silenced p130Cas strongly suppressed zygomatic and mandibular destruction in vivo.

Academic Significance and Societal Importance of the Research Achievements

本研究ではTGF-βが誘導するがん細胞の上皮間葉移行（EMT）や骨浸潤をTGF-βの下流でp130Casが制御していることを証明した。EMTは上皮性のがん細胞がより運動性の高い間葉系細胞の表現系を獲得し、転移しやすくなった状態である。また、EMTを起こした細胞はapoptosisに抵抗性になることも報告されており、TGF-β-p130Casは口腔扁平上皮がんの骨浸潤の新しい治療法のターゲットになり得るかもしれない。

Research Products

• [Journal Article] p130Cas induces bone invasion by oral squamous cell carcinoma by regulating tumor epithelial-mesenchymal transition and cell proliferation (2020)
  • Author(s): Yaginuma T, Gao J, Nagata K, Muroya R, Fei H, Nagano H, Chishaki S, Matsubara T, Kokabu S, Matsuo K, Kiyoshima T, Yoshioka I, Jimi E
  • Journal Title: Carcinogenesis Volume: .
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Plectin stabilizes microtubules during osteoclastic bone resorption by acting as a scaffold for Src and Pyk2 (2020)
  • Author(s): Matsubara T, Yaginuma T, Addison WN, Fujita Y, Watanabe K, Yoshioka I, Hikiji H, Maki K, Baron R, Kokabu S
  • Journal Title: Bone Volume: 132 Pages: 115209-115209
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 口腔扁平上皮癌細胞のTGF-βシグナルにおけるp130Casの役割 (2019)
  • Author(s): 柳沼樹、古株彰一郎、吉岡泉
  • Organizer: 第73回日本口腔科学会学術集会
• [Presentation] 転写コリプレッサーTLE3は悪性黒色腫の悪性度と関連し増殖を促進する (2019)
  • Author(s): 古株彰一郎、小川昌洋、柳沼樹、吉岡 泉
  • Organizer: 第73回日本口腔科学会学術集会
• [Presentation] The role of p130Cas in cell morphological change, mobility, and invasion ability of oral squamous cell carcinoma by TGF-β stimulation (2019)
  • Author(s): Yaginuma T, Kokabu S, Matsubara T, Yoshioka I, Jimi E
  • Organizer: Asia-Pacific Conference in Fukuoka 2019
  • Int'l Joint Research
• [Presentation] p130CasはTGFβ刺激による口腔扁平上皮癌の形態変化、細胞移動および浸潤能の亢進に関与する (2018)
  • Author(s): 柳沼樹
  • Organizer: 第78回九州歯科学会総会・学術大会
• [Presentation] 口腔扁平上皮癌細胞の形態変化、移動・浸潤能におけるp130Casの役割 (2018)
  • Author(s): 柳沼樹
  • Organizer: 第72回NPO法人日本口腔科学会学術集会
• [Presentation] 扁平上皮癌細胞の形態変化・移動・浸潤および骨破壊におけるp130Casの役割 (2018)
  • Author(s): 柳沼樹
  • Organizer: 第60回歯科基礎医学会学術大会