Involvement of MMP-9 in peribiliary fibrosis and cholangiocarcinogenesis via Rac1-dependent DNA damage in a hamster model

Int J Cancer. 2010 Dec 1;127(11):2576-87. doi: 10.1002/ijc.25266.


Peribiliary fibrosis caused by chronic infection with Opisthorchis viverrini (OV) is a risk factor of cholangiocarcinoma (CCA) in northeastern Thailand. Matrix metalloproteinases (MMPs) are enzymes capable of degrading and remodeling the extracellular matrix in the process of fibrosis and carcinogenesis. We examined MMPs expression and their role in fibrogenesis and cholangiocarcinogenesis in hamsters treated with OV and N-nitrosodimethylamine (NDMA). We assessed the time profiles of MMPs, inducible nitric oxide synthase (iNOS), Rac1, α-smooth muscle actin (α-SMA) and DNA lesions (8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine, 8-oxodG) in relation to fibrosis and CCA development. Histopathology revealed OV and NDMA synergistically induced peribiliary fibrosis time-dependently, and CCA occurred at 3 months, whereas OV or NDMA alone induced less fibrosis. Hydroxyproline levels in the liver and plasma were positively associated with the expression of collagen I and α-SMA. MMP-9 expression was significantly increased and correlated with the accumulation of myofibroblast, fibrosis levels and cholangiocarcinogenesis. MMP-9 activity was correlated with iNOS, and immunocolocalization was observed in inflammed tissues, early and invasive CCA. OV and NDMA synergistically induced MMP-9 expression in association to Rac1. In addition, Rac1 was colocalized with iNOS, and 8-nitroguanine, in inflammed tissues and CCA. Formation of 8-nitroguanine and 8-oxodG increased with tumor progression. The results suggest that MMP-9 expression is associated with the accumulation of peribiliary fibrosis in conjunction to the induction of iNOS and Rac1 that may potentiate DNA damage and cholangiocarcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / biosynthesis
  • Animals
  • Bile Duct Diseases / genetics
  • Bile Duct Diseases / metabolism*
  • Bile Duct Diseases / pathology
  • Bile Ducts / pathology
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Cholangiocarcinoma / genetics
  • Cholangiocarcinoma / metabolism*
  • Cholangiocarcinoma / parasitology
  • Cholangiocarcinoma / pathology
  • Collagen / biosynthesis
  • Collagen / genetics
  • Collagen / metabolism
  • Cricetinae
  • DNA Damage*
  • Disease Models, Animal
  • Fibrosis
  • Liver / metabolism
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / biosynthesis
  • Matrix Metalloproteinase 9 / metabolism*
  • Mesocricetus
  • Nitric Oxide Synthase Type II / biosynthesis
  • Opisthorchiasis / genetics
  • Opisthorchiasis / metabolism
  • Opisthorchiasis / pathology
  • Opisthorchis
  • RNA, Messenger / biosynthesis
  • Urokinase-Type Plasminogen Activator / metabolism
  • rac1 GTP-Binding Protein / biosynthesis
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism*


  • Actins
  • RNA, Messenger
  • Collagen
  • Nitric Oxide Synthase Type II
  • Urokinase-Type Plasminogen Activator
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • rac1 GTP-Binding Protein