扁平上皮がんの悪性度の解明と臨床疫学

• Project/Area Number: 12218224
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Yamaguchi University
• Principal Investigator: 加藤 紘 山口大学, 学長 (10034969)
• Co-Investigator(Kenkyū-buntansha): 住浪 義則 小野田市立病院, 産婦人科, 医長 (50253141) ; 縄田 修吾 山口大学, 医学部, 助手 (60294625) ; 村上 明弘 山口大学, 医学部附属病院, 助手 (70379965) ; 塚本 直樹 独立行政法人国立病院機構, 九州がんセンター, 院長 (30038830) ; 坂口 優子 山口大学, 医学部附属病院, 助手 (60335750)
• Project Period (FY): 2000 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥52,300,000 (Direct Cost: ¥52,300,000); Fiscal Year 2004: ¥8,900,000 (Direct Cost: ¥8,900,000); Fiscal Year 2003: ¥7,400,000 (Direct Cost: ¥7,400,000); Fiscal Year 2002: ¥12,000,000 (Direct Cost: ¥12,000,000); Fiscal Year 2001: ¥12,000,000 (Direct Cost: ¥12,000,000); Fiscal Year 2000: ¥12,000,000 (Direct Cost: ¥12,000,000)
• Keywords: SCC抗原 / 扁平上皮癌 / セルピン / アポトーシス / NK細胞 / 蛋白分解酵素 / 腫瘍形成 / 細胞浸潤能 / alternative splicing product / SCC抗原-1 / SCC抗原-2

Research Abstract

臨床上有用となる扁平上皮がんの新しい予後因子を解明することを目的として、扁平上皮がん関連蛋白SCC抗原(SCCA)の発現状態と病態の悪性度との関係、及び、SCCAの生物学的機能を検討した。SCCAには相同性の非常に高い2種類のSCCA1、SCCA2が存在したが、がんでは特にSCCA2の発現が有意に亢進していた。子宮頸部扁平上皮がん患者Ib-II期では、治療前血清中SCCA2値は予後不良因子となる可能性が示唆された。SCCAの生物学的機能については、両者とも腫瘍細胞が抗がん剤や放射線などの刺激によりアポトーシスに陥るのを抑えたり、細胞外に分泌されたSCCAが、腫瘍組織へのNK細胞の遊走を抑制することを報告してきたが、新たにマトリックスメタロプロテアーゼ(MMP)-9分泌を増加させ、腫瘍細胞の浸潤能を亢進させる可能性を見いだした。さらには、SCCA遺伝子のプロモーター領域の解析の結果、SCCA、SCCA2のイントロン1のエクソン2直前の領域に強いプロモーター活性を認めた。がんでのSCCA1、SCCA2の発現調節の相違に関して、プロモーター領域の-0.38kのところにあるSCCA2のGとTという遺伝子多型SNP(SCCA1ではT)が関与している可能性を見いだした。以上より、特にSCC2は扁平上皮がんの進展・予後に密接に関与している分子であり、その発現にはSNPが関与している可能性が示唆された。

Research Products

• [Journal Article] Characterization of monoclonal antibodiesdirected against squamous cell carcinoma antigens : Reports of the TD-10 Workshop. (2004)
  • Author(s): Nustad, K., et al.
  • Journal Title: Tumor Biol. 25 Pages: 69-90
• [Journal Article] E1AP/PEA3 reduces the invasiveness of SiHa cervical cancer cells by activating serine proteinase Inhibitor squamous cell carcinoma (2004)
  • Author(s): Iwasaki, M., et al.
  • Journal Title: Experimental Cell Research 299 Pages: 525-532
• [Journal Article] Regulation of squamous cell carcinoma antigen production by E-cadherin mediated cell-cell adhesion in squamous cell carcinoma cell line. (2004)
  • Author(s): Hirakawa, H., et al.
  • Journal Title: Oncol.Rep. 11 Pages: 415-419
• [Journal Article] Promotor analyses of SCC antigen genes.
  • Author(s): Suminami, Y., et al.
  • Journal Title: Biochim.Biophys.Acta (In press)
• [Publications] Hirakawa H., et al.: "Regulation of squamous cell carcinoma antigen production by E-cadherin mediated cell-cell adhesion in squamous cell carcinoma cell line"Oncology Report. 11. 415-419 (2004)
• [Publications] Nawata S., et al.: "Electrophoretic analysis of the cleaved form of serpin, squamous cell carcinoma antigen-1 in normal and malignant squamous epithelial tissues"Electrophoresis. 24. 2277-2282 (2003)
• [Publications] Kawasaki K., et al.: "11q23-24 loss is associated with chromosomal instability in endometrial cancer"International Journal of Molecular Medicine. 12. 727-731 (2003)
• [Publications] Numa F., et al.: "De novo uterine sarcoma with goog response to neo-adjuvant chemotherapy"International Journal of Gynecolgical Cancer. 13. 364-367 (2003)
• [Publications] Yuyama, N., Suminami, Y., Kato, H., et al.: "Analysis of novel disease-related genes in bronchial asthma"Cytokine. 19. 287-296 (2002)
• [Publications] Umayahara, K., Nawata, S., Kato, H.et al.: "Genetic alterations related to lymph node metastasis and peritoneal dissemination in epithelial ovarian cancer"Oncol Rep.. 9. 1115-1119 (2002)
• [Publications] Umayahara, K., Suminami, Y., Kato, H.et al.: "Comparative genomic hybridization detects genetic alterations during early stages of cervical cancer progression"Genes Chromosomes Cancer. 33. 98-102 (2002)
• [Publications] Numa, F., Sakaguchi, Y., Kato, H.et al.: "Syndecan-1 expression in cancer of the uterine cervix: association with lymph node metastasi"Int J Oncol.. 20. 39-43 (2002)
• [Publications] Nawata, S., Suminami, Y., Kato, H.et al.: "Electrophoretic characterization of heat stable squamous cell carcinoma antigen"Electrophoresis. 22. 3522-3526 (2001)
• [Publications] Suminami, Y., Nawata, S., Kato, H.et al.: "Novel forms squamous cell carcinoma antigen transcripts produced by alternative splicing"Biochim. Biophys. Acta. 1519. 122-126 (2001)
• [Publications] S.Nawata: "Electrophoretic characterization of heat stable squamous cell carcinoma antigen"Electrophoresis. 22. 3522-3526 (2001)
• [Publications] Y.Suminami: "Novel forms of squamous cell carcinoma antigen transcripts produced by alternative splicing"Biochim. Biophys. Acta. 1519. 122-126 (2001)
• [Publications] Y.Suminami: "Suppression of a squamous cell carcinoma (SCC)-related serpin, SCC antigen, inhibits tumor growth with increased intra tumor infiltration of natural killer cells"Cancer Res.. 61. 1776-1780 (2001)
• [Publications] A.Murakami, al.: "Squamous cell carcinoma antigen suppresses radiation-induced cell death"Br. J. Cancer. 84. 851-858 (2001)
• [Publications] S.Nawata: "Nondenaturing two-dimensional electrophoretic analysis of loop-sheet polymerization of serpin, squamous cell carcinoma antigen-2"Electrophoresis. 22. 161-164 (2001)
• [Publications] F.Numa: "Serum Anti-p53 Antibodies in uterine and ovarian cancer : Association with DNA Sequence Copy Number Abnormalities"Tumor Biol.. 21. 162-168 (2001)
• [Publications] Suminami,Y. et al.: "Suppression of a Squamous Cell Carcinoma (SCC) -related Serpin, SCC Antigen, Inhibits Tumor Growth with Increased Intratumor Infiltration of Natural Killer Cells"Cancer Research. (in press).
• [Publications] Murakami,A. et al.: "Squamous cell carcinoma antigen suppresses radiation-induced cell death"British Journal of Cancer. (in press).
• [Publications] Nawata,S. et al.: "Nondenaturing two-dimensional electrohoretic analysis of loop-sheet polymerization of serpin, squamous cell carcinoma antigen-2"Electrohoresis. 22. 161-164 (2001)
• [Publications] Suminami,Y. et al.: "Inhibition of apoptosis in human tumor cells by tumour-associated serpin, SCC antigen-1"British Journal of Cancer. 82. 981-989 (2000)
• [Publications] Murakami,A. et al.: "Specific Detection and Quantitation of SCCAntigen-1 and SCCAntigen-2 mRNA by Fluorescence-based Asymmetric Semi-nested Reverse Transcription-PCR"Tumor Biology. 21. 224-234 (2000)