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

这项研究旨在通过检查Cox-2侵入性前或转移性病变的免疫组织化学表达来阐明COX-2侵袭和口腔癌转移的参与，并分析Cox-2基因转移的影响及其分子机制对培养的口腔癌细胞入侵和转移能力的分子机制对培养的口腔癌细胞的影响。还研究了COX-2是否通过检查选择性COX-2抑制剂对侵袭和转移的抑制作用，是否成为治疗口腔癌的分子靶标。所获得的结果如下。1）在口腔癌的原发性病变中，Cox-2的表达明显高于淋巴结（LN）转移的表达，而在转移性病变中的表达则比没有LN转移的那些表达高于原发性病变。随着肿瘤大小的增加，在侵入性方面增加了表达。 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 translated with COX-2 cDNA produced elevated COX-2 protein and PGE-2, and showed high与对照（KB/NEO）相比，细胞运动和侵袭的电位。4）Kb/cox表明MMP9，Pro-MMP2，激活的MMP2，MT1-MMP和趋化因子受体CXCR4和TIMP1，TIMP2，TIMP2和E-Cadherin的表达增加，与KB/Neo.5）KB相比增加了。与KB/NEO相比，对裸鼠的皮下移植和原位移植中的侵袭性局部侵袭。 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凋亡诱导，还抑制了PGE-2产生和COX-2表达。 Celecoxib增强了抗癌药物对癌细胞的细胞毒性。8）COX-2的表达增加了DMBA诱导的仓鼠脸颊袋癌的发生，以及对Celecoxib和Sulindac的给药，导致癌症的粘贴迟缓，导致肿瘤的抑制，抑制肿瘤的生长和促进型的促进型酸性跨性别范围。在人口服鳞状癌SCC25细胞中与细胞角质化的分化，并抑制肿瘤生长和COX-2表达。较少的

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.