Expression of matrix metalloproteinase-2 and -9 and tissue inhibitor of metalloproteinase-1 and -2 in intraductal and nonintraductal growth type of cholangiocarcinoma.
BACKGROUND
The intraductal growth (IG) type of cholangiocarcinoma has a better prognosis than the mass forming (MF) and periductal infiltrating (PI) types. Matrix metalloproteinase (MMP)-2 and MMP-9, regulated by tissue inhibitor of metalloproteinases (TIMP)-2 and TIMP-1, respectively, play important roles in the degradation of the basement membrane during tumor invasion. Alteration in MMPs and TIMPs may regulate the gross morphology of cholangiocarcinoma.


METHODS
MMP-2 and MMP-9 were analyzed in 35 cholangiocarcinomas and 4 normal livers with fresh tissue using zymography and real-time reverse transcription-polymerase chain reaction (RT-PCR), and expressions of MMP-2, MMP-9, TIMP-1, and TIMP-2 were evaluated in 76 cholangiocarcinomas by immunohistochemistry.


RESULTS
Activity of MMP-2 and its active form were detected in 80% and 57% of cholangiocarcinomas respectively. The total MMP-2, active 62 kDa MMP-2, and MMP-2 mRNA increased 5.4 and 8.2 times, 4.4 and 10.9 times, and 2.9 and 5.8 times in the MF and PI types, respectively, compared to the IG type. The majority of MMP-9 was in the proform and active 82 kDa MMP-9 was detected in 9% of cholangiocarcinomas. MMP-9 revealed no significant difference in relation to the gross types. The balanced expressions of MMP-2/TIMP-2 and MMP-9/TIMP-1 were significantly decreased in the MF and PI types, compared to the IG type. In the normal and nonneoplastic livers, the expressions of MMP-2 and MMP-9 were very low without active forms.


CONCLUSIONS
The activities of MMP-2 and loss of balanced expressions of MMP-2/TIMP-2 and MMP-9/TIMP-1 are suggested as playing important roles in invasive growth related to the gross type of cholangiocarcinoma.
Jo Chae
Kwang
K
Department of Pathology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, CPO Box 8044, Seoul, Korea.
Rha
Sun Young
SY
Oh
Bong-Kyeong
BK
Koo
Ja Seung
JS
Kim
Young Joo
YJ
Choi
Jinsub
J
Park
Chanil
C
Park
Young Nyun
YN
D000328:Adult; D000368:Aged; D001650:Bile Duct Neoplasms / Q000737:chemistry* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D018281:Cholangiocarcinoma / Q000737:chemistry* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis*; D020780:Matrix Metalloproteinase 9 / Q000032:analysis*; D008875:Middle Aged; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis*
D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9