The effects of GBP-1 on dynamics of cancer cells in human salivary gland duct epithelium.

• Project/Area Number: 19K18777
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56050:Otorhinolaryngology-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Ryo MIYATA 札幌医科大学, 医学部, 助教 (00610875)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2021: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 唾液腺癌 / 正常唾液腺管上皮細胞 / GBP-1 / 3細胞間タイト結合分子 / angulin-1/LSR / p63シグナル / 悪性化 / HDAC阻害剤 / p63陽性唾液腺癌 / ３細胞間タイト結合分子 / cingulin / p63/TGF-β/JNKシグナル / ヒト唾液腺上皮細胞 / タイト結合 / 上皮バリア / 炎症性サイトカイン / IgG4関連疾患 / 唾液腺管上皮バリア機能

Outline of Research at the Start

唾液腺癌は頭頚部癌の中でも稀な腫瘍で，手術治療が基本となるが，切除不能例や遠隔転移を認める症例に対しては有効な治療法が確立されていない。Guanylate binding protein-1(GBP-1)は，癌細胞の増殖や浸潤に深く関与する細胞間接着装置であるタイト結合の発現を調整しており，近年では乳癌における新たな治療標的分子として注目されている。本研究では，唾液腺腺管上皮細胞を用い，GBP-1が唾液腺癌の病態においてどのような役割を担い，癌細胞動態にどのような影響を及ぼしているか，分子生物学的手法を用いて検討を行い，唾液腺癌の新たな治療法の開発につながる基礎的知見を得ることを目標とする。

Outline of Final Research Achievements

Salivary gland cancer is relatively rare among all head and neck cancers, and new treatments are desired for unresectable cases and distant metastases.
Guanylate-binding protein-1 (GBP-1) is an interferon-inducible large GTPase involved in the epithelial barrier at tight junctions. To investigate the role of GBP-1 in normal human salivary gland duct epithelial cells, the cells were treated with the proinflammatory cytokines including IFNγ. GBP-1 plays a crucial role in barrier function of normal human salivary gland duct epithelium and it may perform a preventive role in cancers.The p53 family p63 gene is essential for the proliferation and differentiation of various epithelial cells, and it is overexpressed in some salivary gland neoplasia. Inhibition of Histone deacetylases (HDACs) and signal transduction pathways inhibited cell proliferation and migration, induced tight junctions, and promoted differentiation in p63-positive salivary duct adenocarcinoma (SDC).

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、GBP-1の唾液腺癌の悪性化における役割を解明できただけでなく、唾液腺癌の新規悪性化の機序解明により治療法の開発にも有用であった。

Research Products

• [Journal Article] HDAC inhibitors suppress proliferation, migration and invasion of human head and neck squamous cell carcinoma cells via p63-mediated tight junction molecules and p21-mediated growth arrest. (2021)
  • Author(s): Kakiuchi A, Kakuki T, Ohwada K, Kurose M, Kondoh A, Obata K, Nomura K, Miyata R, Kaneko Y, Konno T, Kohno T, Himi T, Takano K, Kojima T.
  • Journal Title: Oncology Rep. Volume: 45 Issue: 4 Pages: 46-46
  • DOI: 10.3892/or.2021.7997
  • Peer Reviewed / Open Access
• [Journal Article] Effects of HMGB1 on Tricellular Tight Junctions via TGF-β Signaling in Human Nasal Epithelial Cells (2021)
  • Author(s): Ohwada K, Konno T, Kohno T, Nakano M, Ohkuni T, Miyata R, Kakuki T, Kondoh M, Takano K, Kojima T.
  • Journal Title: Int J Mol Sci. Volume: 22 Issue: 16 Pages: 8390-8390
  • DOI: 10.3390/ijms22168390
  • Peer Reviewed / Open Access