Increased expression of collagenase-3 (MMP-13) and MT1-MMP in oesophageal cancer is related to cancer aggressiveness.
BACKGROUND
Collagenase-3 (matrix metalloproteinase-13, MMP-13) is a recently identified human MMP with broad substrate specificity which can be activated by membrane type 1 (MT1) matrix metalloproteinase in vitro. These may play a critical role in cancer aggressiveness.


OBJECTIVE
To examine the clinical significance of collagenase-3 expression and the cooperative role of MT1-MMP in human oesophageal carcinomas.


METHODS
Forty five individuals with oesophageal carcinoma who underwent surgery without preoperative treatment.


METHODS
The tumour/normal (T/N) ratios of collagenase-3 and MT1-MMP mRNA expression in 45 human oesophageal carcinomas were determined by northern blot analysis. The production and localisation of collagenase-3 and MT1-MMP proteins were investigated by immunohistochemistry, western blot analysis, and zymography.


RESULTS
The mean T/N ratio of collagenase-3 mRNA was 3.5 and that of MT1-MMP 2.1. There was a significant correlation between collagenase-3 and MT1-MMP mRNA expression (p<0.001). Twenty two cases with a collagenase-3 T/N ratio >3.5 showed a significantly higher frequency of vascular involvement and lymph node metastasis, and tended to be at a more advanced stage than 23 cases with a T/N ratio < or =3.5 (p<0.05). Western blot analysis and zymography demonstrated production of collagenase-3 protein in tumour tissues but not in normal tissues. Immunohistochemical studies revealed that collagenase-3 was localised predominantly in tumour cells and MT1-MMP was detected in the same collagenase-3 positive cells; there was a significant association between collagenase-3 and MT1-MMP protein expression (p<0.05). With regard to prognosis, the survival time for subjects in the high collagenase-3 group (T/N ratio >3.5) was significantly worse (p<0.05).


CONCLUSIONS
These data suggest that production of collagenase-3 together with MT1-MMP is implicated in tumour aggressiveness and prognosis in human oesophageal carcinomas.
Etoh
T
T
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan.
Inoue
H
H
Yoshikawa
Y
Y
Barnard
G F
GF
Kitano
S
S
Mori
M
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015152:Blotting, Northern; D015153:Blotting, Western; D017364:Collagenases / Q000235:genetics / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D053509:Matrix Metalloproteinase 13; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D015996:Survival Rate; D016896:Treatment Outcome
D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases