Investigation for involvement of COX-2 in invasion and metastasis of oral cancer and inhibitory effect by selective COX-2 inhibitors
Grant-in-Aid for Scientific Research (B)
|Allocation Type||Single-year Grants|
|Research Institution||Hyogo College of Medicine|
URADE MASAHIRO Hyogo College of Medicine, School of Medicine, Professor and Chair, 医学部, 教授 (70104883)
SAKURAI KAZUNARI Hyogo College of Medicine, School of Medicine, Assistant Professor, 医学部, 講師 (30129118)
HASHITANI SUSUMU Hyogo College of Medicine, School of Medicine, Research Associate, 医学部, 助手 (00330449)
NISHIMURA NORIHIKO Hyogo College of Medicine, School of Medicine, Research Associate, 医学部, 助手 (90330448)
|Project Period (FY)
2003 – 2005
Completed(Fiscal Year 2005)
|Budget Amount *help
¥13,900,000 (Direct Cost : ¥13,900,000)
Fiscal Year 2005 : ¥3,000,000 (Direct Cost : ¥3,000,000)
Fiscal Year 2004 : ¥3,700,000 (Direct Cost : ¥3,700,000)
Fiscal Year 2003 : ¥7,200,000 (Direct Cost : ¥7,200,000)
|Keywords||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 / 予後 / in vitro浸潤能 / シスプラチン感受性|
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
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
Research Products (8results)