分化制御遺伝子を分子標的とした口腔癌の分化誘導療法

• Project/Area Number: 14704050
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Surgical dentistry
• Research Institution: Ehime University
• Principal Investigator: 中城 公一 愛媛大学, 医学部附属病院, 講師 (90314880)
• Project Period (FY): 2002 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥25,870,000 (Direct Cost: ¥19,900,000、Indirect Cost: ¥5,970,000); Fiscal Year 2004: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2003: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2002: ¥15,080,000 (Direct Cost: ¥11,600,000、Indirect Cost: ¥3,480,000)
• Keywords: 口腔癌 / 分化誘導療法 / PPARγ / トログリタゾン / troglitazone / troglitaxone / P27^<kip1> / Skp2 / EIF-2α

Research Abstract

従来の治療法に抵抗を示す難治性腫瘍に対して、近年分化誘導療法などの新しい治療法の開発が試みられている。われわれは種々の分化制御遺伝子を分子標的としたヒト口腔癌細胞の分化誘導実験を計画した。脂肪細胞の分化制御遺伝子として機能しているperoxisome proliferator-activated receptorγ(PPARγ)の合成リガンドであるトログリタゾンが口腔扁平上皮癌および唾液腺癌両細胞の増殖を著明に抑制した。その分子機構の解析により、口腔扁平上皮癌に対する抗腫瘍活性はPPARγ非依存的で、非特異的な蛋白質合成阻害によるものであった。一方、唾液腺癌に対する抗腫瘍活性はPPARγを介する経路を有し、Skp2合成低下に伴うp27Kip1の蓄積による細胞増殖抑制効果によるものであった。さらに、ヒト唾液腺癌細胞のヌードマウス背部皮下腫瘍におけるトログリタゾンの抗腫瘍効果は、ヒト全遺伝子型マイクロアレイを用いた結果、hypoxia-inducible factor 1 (HIF-1)の転写活性抑制因子であるfactor inhibiting HIF-1 (FIH-1)の発現誘導に伴うvascular endothelial growth factor (VEGF)の合成低下による血管新生阻害によるものであることが明らかとなった。また、DNAチェックポイント機構に関わる分子の関与も明らかとなった。最終的に口腔癌細胞の脂肪細胞への分化を観察することはできなかったが、放射線および化学療法に抵抗性を示し、著明な浸潤、転移能を有する難治性の唾液腺癌に対してトログリタゾンを用いた治療が有用である可能性が示唆された。

Research Products

• [Journal Article] Phenotypic switch from paracrine to autocrine role of hepatocyte growth factor in an androgen-independent human prostatic carcinoma cell line, CWR22R. (2004)
  • Author(s): Nakashiro K et al.
  • Journal Title: Am.J.Pathol. 165・2 Pages: 533-540
• [Journal Article] Constitutive activation of Stat3 correlates with increased expression of the c-Met/HGF receptor in oral squamous cell carcinoma. (2004)
  • Author(s): Klosek SK, Nakashiro K et al.
  • Journal Title: Oncol.Rep. 12・2 Pages: 293-296
• [Journal Article] Intraoperative real-time genetic diagnosis for sentinel node navigation surgery. (2004)
  • Author(s): Hamakawa H et al.
  • Journal Title: Int.J.Oral Maxillofac.Surg. 33・7 Pages: 670-675
• [Journal Article] Growth regulated oncogene 1 expression is associated with angiogenesis and lymphnode metastasis in human oral cancer. (2004)
  • Author(s): Shintani S et al.
  • Journal Title: Oncology 66・4 Pages: 316-322
• [Journal Article] Overexpression of cyclooxygenase-2 is associated with radioresistance in oral squamous cell carcinoma. (2004)
  • Author(s): Terakado N et al.
  • Journal Title: Oral Oncol. 40・4 Pages: 383-389
• [Journal Article] Expression of vascular endothelial growth factor A,B,C, and D in oral squamous cell carcinoma. (2004)
  • Author(s): Shintani S et al.
  • Journal Title: Oral Oncol. 40・1 Pages: 13-20
• [Publications] Nakashiro K et al.: "Thiazolidinediones inhibit cell growth of human oral squamous cell carcinoma in vitro independent of peroxisome proliferator-activated receptor γ."Oral Oncol.. 39・8. 855-861 (2003)
• [Publications] Shintani S et al.: "Skp2 and Jab1 expression are associated with inverse expression of p27(KIP1) and poor prognosis in oral squamous cell carcinomas."Oncology. 65・4. 355-362 (2003)
• [Publications] Shintani S et al.: "Enhancement of tumor radioresponse by combined treatment with gefitinib (Iressa, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, is accompanied by inhibition of DMA damage repair and cell growth in oral cancer."Int.J.Cancer. 107・6. 1030-1037 (2003)
• [Publications] Uchida D et al.: "Possible role of stromal-cell-derived factor-1/CXCR4 signaling on lymph node metastasis of oral squamous cell carcinoma."Exp.Cell Res.. 290・2. 289-302 (2003)
• [Publications] Shintani S et al.: "Up-regulation of DNA-dependent protein kinase correlates with radiation resistance in oral squamous cell carcinoma."Cancer Sci.. 94・10. 894-900 (2003)
• [Publications] Ohnishi A et al.: "Basic and clinical studies on quantitative analysis of lymph node micrometastasis in oral cancer."Oncol.Rep.. 11・1. 33-39 (2004)
• [Publications] Begum NM et al.: "Expression of peroxisome proliferator-activated receptor γ and the growth inhibitory effect of its synthetic ligands in human salivary gland cancer cell lines"Int. J. Oncology. 20・3. 599-605 (2002)
• [Publications] Omotehara F et al.: "Vesnarinone, a differentiation inducing drug, directly activates p21(wafl) gene promoter via Sp1 sites in a human salivary gland cancer cell line"Br. J. Cancer. 87・9. 1042-1046 (2002)
• [Publications] Hoque MO et al.: "Dysfunction of the p53 tumor suppressor pathway in head and neck cancer"Int. J. Oncology. 21・1. 119-126 (2002)
• [Publications] Li C et al.: "Infiltration of tumor-associated macrophages in human oral squamous cell carcinoma"Oncol. Rep.. 9・6. 1219-1223 (2002)
• [Publications] Mihara M et al.: "Flavopiridol, a cyclin dependent kinase(CDK) inhibitor, induces apoptosis by regulating Bcl-x in oral cancer cells"Oral Oncol.. 39・1. 49-55 (2003)
• [Publications] Shinagawa Y et al.: "Evaluation of the chemosensitivity of head and neck cancer cells based on the diverse function of mutated-p53"Int. J. Oncol.. 22・2. 383-389 (2003)