Promotion of hematogenous metastatic potentials in human KB carcinoma cells with overexpression of cyclooxygenase-2.
To understand the role of cyclooxygenase (COX)-2 in metastatic potential of oral cancer, COX-2 overexpressing KB/COX-2 cells were inoculated orthotopically into the masseter muscle or injected into the left cardiac ventricle of nude mice. KB/COX-2 showed about 4-fold increase of COX-2 protein expression as compared to KB/Neo which was a mock transfected control. In orthotopic inoculation, metastasis to the regional lymph nodes occurred in 2 out of 15 mice, and metastasis to the lung in 3 out of 15 mice. On the other hand, in intra-cardiac injection, hematogenous metastasis to the lung and bone occurred in 8 out of 10 mice in KB/COX-2, but no metastasis occurred except for only one metastasis to the femur bone out of 10 mice in KB/Neo. Treatment of KB/COX-2 with COX-2 small interfering RNA (siRNA) inhibited the colony formation but not cell growth in vitro, and suppressed tumorigenicity and hematogenous metastasis in nude mice. When expression of adhesion molecules such as E-cadherin, alpha-catenin, beta-catenin and CD44 was examined, there was no difference in alpha- and beta-catenin between the cells. However, expression of E-cadherin was detected in KB/Neo, but not in KB/COX-2. In contrast, expression of CD44 was markedly increased in KB/COX-2 as compared to KB/Neo. Treatment with COX-2 siRNA resulted in suppression of CD44 expression and detectable expression of E-cadherin in KB/COX-2. These findings suggested that overexpression of COX-2 increased hematogenous metastasis, at least in KB cells, via down-regulating E-cadherin and up-regulating CD44 expression.
Segawa
Emi
E
Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
Kishimoto
Hiromitsu
H
Takaoka
Kazuki
K
Noguchi
Kazuma
K
Hashitani
Susumu
S
Sakurai
Kazunari
K
Urade
Masahiro
M
D000818:Animals; D015703:Antigens, CD; D001859:Bone Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000556:secondary; D015820:Cadherins / Q000378:metabolism; D002277:Carcinoma / Q000201:enzymology* / Q000235:genetics / Q000556:secondary; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007624:KB Cells; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000556:secondary; D008207:Lymphatic Metastasis; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D015854:Up-Regulation; D051178:alpha Catenin / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D015703:Antigens, CD; C497483:CD44 protein, human; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D018960:Hyaluronan Receptors; D051178:alpha Catenin; D051176:beta Catenin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human