Investigation for involvement of COX-2 in invasion and metastasis of oral cancer and inhibitory effect by selective COX-2 inhibitors

COX-2参与口腔癌侵袭转移及选择性COX-2抑制剂抑制作用的研究

• 批准号: 15390630
• 负责人: URADE MASAHIRO
• 金额: $ 8.9万
• 依托单位: Hyogo College of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390630/
• 关键词: oral cancer; cyclooxygenase (COX)-2; invasion and matastasis; prognostic factor; metalloproteinases; nude mouse transplantation model; hamster cheek pouch carcinogenesis; COX-2 inhibitor; 浸潤; 転移; COX-2高発現KB細胞; MMP; 腫瘍増殖抑制; DNA-トポイソメラーゼIIα; 予

This study was designed to elucidate the involvement of COX-2 in invasion and metastasis of oral cancer by examining immunohistochemical expression of COX-2 in invasive front or metastatic lesion and analyzing the effect of COX-2 gene transfer and its molecular mechanism on the abilities of invasion and metastasis in cultured oral carcinoma cells. It was also investigated whether COX-2 becomes a molecular target for treatment of oral cancer by examining the inhibitory effect of selective COX-2 inhibitors on invasion and metastasis. The results obtained were as follows.1)Expression of COX-2 was significantly higher in primary lesions of oral cancer with lymph node (LN) metastasis than in those without LN metastasis, and higher in metastatic lesions than in primary lesions. The expression was increased as tumor size was increased and more in invasive front. As COX-2 expression was increased, laminin-5 γ 2 and DNA-Topo II α were also increased.2)Overall 5-year survival was poor in patient … More s with LN metastasis and high COX-2 expression and DNA-Topo II α.3)Oral carcinoma KB cell clone (KB/COX) with high COX-2 expression transfected with COX-2 cDNA produced elevated COX-2 protein and PGE-2, and showed high potentials of cell motility and invasion as compared to the control (KB/neo).4)KB/COX showed increased expression of MMP9, pro-MMP2, activated-MMP2, MT1-MMP and chemokine receptor CXCR4, and decreased expression of TIMP1, TIMP2 and E-cadherin, as compared to KB/neo.5)KB/COX demonstrated high tumorigenicity and tumor growth in subcutaneous transplantation to nude mice and aggressive local invasion in orthotopic transplantation, as compared to KB/neo. High gelatinase activity was detected in KB/COX tumor tissues.6)Intracardiac injection or orthotopic transplantation of KB/COX resulted in multiple metastasis to lung and bone and neck LN metastasis efficiently, but those of KB/neo caused few.7)COX-2 inhibitor celecoxib and sulindac inhibited the growth of head and neck cancer cell lines in a dose-dependent manner via apoptosis induction, and also inhibited PGE-2 production and COX-2 expression. Celecoxib augmented the cytotoxicity of anticancer drugs to cancer cells.8)Expression of COX-2 was increased toward DMBA-induced hamster cheek pouch carcinogenesis, and administration of celecoxib and sulindac resulted in retardation of cancerization, inhibition of tumor growth and prolonged life span via apoptosis induction and antiangiogenesis.9)Treatment with sodium butyrate or retinoic acid induced differentiation to cell keratinization in human oral squamous carcinoma SCC25 cells and inhibited tumor growth and COX-2 expression. Less

本研究通过免疫组织化学方法检测考克斯-2在口腔癌浸润前沿和转移灶中的表达，分析考克斯-2基因转染对口腔癌细胞侵袭和转移能力的影响及其分子机制，探讨考克斯-2在口腔癌侵袭和转移中的作用。还通过检查选择性考克斯-2抑制剂对侵袭和转移的抑制效果来研究考克斯-2是否成为治疗口腔癌的分子靶标。结果表明：（1）口腔癌原发灶中考克斯-2的表达在有淋巴结转移者中明显高于无淋巴结转移者，在转移灶中明显高于原发灶。随着肿瘤体积的增大，表达增强，且在浸润前沿表达增强。随着考克斯-2表达的增加，层粘连蛋白5 γ 2和DNA-Topo II α也增加。 ...更多信息 3）考克斯-2高表达的口腔癌KB细胞克隆（KB/COX）与对照（KB/neo）相比，考克斯-2高表达的KB细胞克隆（KB/COX）产生了高水平的考克斯-2蛋白和PGE-2，并显示出更高的细胞运动和侵袭能力。4）KB/考克斯显示MMP 9、pro-MMP 2、activated-MMP 2、与KB/neo相比，KB/考克斯具有更高的致瘤性和裸鼠皮下移植瘤生长能力，原位移植瘤的局部侵袭能力更强。KB/考克斯肿瘤组织中检测到高明胶酶活性。6）KB/考克斯心内注射或原位移植可有效地导致肺、骨和颈部淋巴结转移，而KB/neo引起的转移较少。7）考克斯-2抑制剂塞来昔布和舒林酸通过诱导凋亡以剂量依赖方式抑制头颈癌细胞系的生长，抑制PGE-2的产生和考克斯-2的表达。塞来昔布增强了抗癌药物对癌细胞的细胞毒性。8）考克斯-2的表达在DMBA诱导的仓鼠颊囊癌变过程中增加，塞来昔布和舒林酸的给药导致癌变延迟，通过细胞凋亡诱导和抗血管生成抑制肿瘤生长和延长寿命。9）丁酸钠或维甲酸可诱导人口腔鳞癌SCC 25细胞向角化方向分化，并抑制肿瘤生长和考克斯-2表达。少

项目成果

Apoptosis induction and enhancement of cytotoxicity of anticancer drugs by celecoxib, a selective COX-2 inhibitor, in head and neck carcinoma cell lines.

选择性 COX-2 抑制剂塞来昔布在头颈癌细胞系中诱导细胞凋亡并增强抗癌药物的细胞毒性。

• 发表时间: 2003
• 期刊: Int.J.Oncol. 23
• 作者: Susumu Hashitani;et al.
• 通讯作者: et al.

Increased expression of cyclooxygenase(COX)-2 in DMBA-induced hamster cheek pouch carcinogenesis and chemopreventive effect of a selective COX-2 iinhibitor celecoxib.

DMBA 诱导的仓鼠颊囊癌发生中环氧合酶 (COX)-2 的表达增加以及选择性 COX-2 抑制剂塞来昔布的化学预防作用。

• 发表时间: 2004
• 期刊: J.Oral Pathol.Med. 33
• 作者: Norihiko Nishimura;et al.
• 通讯作者: et al.

Promotion of cell differentiation, and suppression of cell growth and cyclooxygenase-2 expression by differentiation-inducing agents in human oral squamous carcinoma SCC25 cells.

• DOI: 10.3892/ijo.26.2.361
• 发表时间: 2005-02
• 期刊: International journal of oncology
• 影响因子: 5.2
• 作者: Junko Kuroda;M. Urade;H. Kishimoto;K. Noguchi;S. Hashitani;K. Sakurai;Norihiko Nishimura;T. Hashimoto‐Tamaoki

Increased expression of cyclooxygenase (COX)-2 in DMBA-induced hamster cheek pouch carcinogenesis and chemopreventive effect of a selective COX-2 inhibitor celecoxib

• DOI: 10.1111/j.1600-0714.2004.00254.x
• 发表时间: 2004-11-01
• 期刊: JOURNAL OF ORAL PATHOLOGY & MEDICINE
• 影响因子: 3.3
• 作者: Nishimura, N;Urade, M;Sakurai, K
• 通讯作者: Sakurai, K

Promotion of cell differentiation, and suppression of cell growth and cyclooxygenase-2 expression by differentiation-inducing agents in human oral carcinoma SCC25 cells

分化诱导剂促进人口腔癌SCC25细胞分化、抑制细胞生长和环氧合酶2表达

• 发表时间: 2005
• 期刊: Int.J.Oncol. 26
• 作者: Junko Kuroda;et al.
• 通讯作者: et al.