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

本研究通过检测侵袭性前沿或转移性病灶中COX-2的免疫组化表达，分析COX-2基因转移对口腔癌侵袭转移的影响及其分子机制，阐明COX-2在口腔癌侵袭转移中的作用。通过检测选择性COX-2抑制剂对侵袭和转移的抑制作用，研究了COX-2是否成为口腔癌治疗的分子靶点。 1)有淋巴结(LN)转移的口腔癌原发灶中COX-2的表达显着高于无LN转移的癌灶,且转移灶中的表达量高于原发灶。随着 COX-2 表达的增加，肿瘤大小增加，并且更多地发生在侵袭性前沿。层粘连蛋白 5 γ 2 和 DNA-Topo II α 也增加。2) 患者的总体 5 年生存率较差。 LN转移和高COX-2表达和DNA-Topo II α.3)用COX-2 cDNA转染高COX-2表达的口腔癌KB细胞克隆(KB/COX)产生升高的COX-2蛋白和PGE-2，与对照 (KB/neo) 相比，表现出较高的细胞运动和侵袭潜力。4)KB/COX 显示 MMP9、pro-MMP2、activated-MMP2 表达增加，与 KB/neo 相比，MT1-MMP 和趋化因子受体 CXCR4，TIMP1、TIMP2 和 E-cadherin 表达降低。5)KB/COX 在裸鼠皮下移植中表现出高致瘤性和肿瘤生长，在原位中表现出侵袭性局部侵袭与KB/neo相比，在KB/COX肿瘤组织中检测到高明胶酶活性。6)心内注射或原位注射。 KB/COX移植可有效引起肺、骨多处转移和颈部淋巴结转移，而KB/neo移植引起的转移很少。 7)COX-2抑制剂塞来昔布和舒林酸在一定剂量下抑制头颈癌细胞系的生长通过诱导细胞凋亡依赖方式，并且还抑制PGE-2的产生和COX-2的表达，增强抗癌药物对癌细胞的细胞毒性。8)表达。 COX-2 增加，导致 DMBA 诱导的仓鼠颊囊癌发生，塞来昔布和舒林酸的给药可通过诱导细胞凋亡和抗血管生成，延缓癌变、抑制肿瘤生长并延长寿命。 9) 丁酸钠或视黄酸诱导的治疗人口腔鳞状细胞癌 SCC25 细胞分化为细胞角化，并抑制肿瘤生长和 COX-2 表达。

项目成果

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

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 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.

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

选择性 COX-2 抑制剂塞来昔布在人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.