Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
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.
华支睾吸虫（OV）慢性感染引起的肝内胆小管周围纤维化是泰国东北部胆管癌（CCA）的一个危险因素。基质金属蛋白酶（MMPs）是一类能够在纤维化和癌变过程中降解和重塑细胞外基质的酶。我们研究了 MMPs 的表达及其在 OV 和 N-亚硝二甲胺（NDMA）处理的仓鼠肝纤维化和胆管癌发生中的作用。我们评估了 MMPs、诱导型一氧化氮合酶（iNOS）、Rac1、α-平滑肌肌动蛋白（α-SMA）和 DNA 损伤（8-硝基鸟嘌呤和 8-氧代-7,8-二氢-2'-脱氧鸟苷，8-氧代 dG）的时间曲线与纤维化和 CCA 发展的关系。组织病理学显示 OV 和 NDMA 协同作用可使肝内胆小管周围纤维化随时间推移而发生，并且在 3 个月时发生 CCA，而 OV 或 NDMA 单独作用时纤维化程度较轻。肝脏和血浆中的羟脯氨酸水平与胶原 I 和 α-SMA 的表达呈正相关。MMP-9 的表达显著增加，并与肌成纤维细胞的积累、纤维化程度和胆管癌发生相关。MMP-9 活性与 iNOS 相关，并且在炎症组织、早期和侵袭性 CCA 中观察到免疫组化定位。OV 和 NDMA 协同诱导 MMP-9 表达与 Rac1 相关。此外，Rac1 与 iNOS 和炎症组织及 CCA 中的 8-硝基鸟嘌呤共定位。8-硝基鸟嘌呤和 8-氧代 dG 的形成随着肿瘤的进展而增加。结果表明，MMP-9 的表达与肝内胆小管周围纤维化的积累相关，与 iNOS 和 Rac1 的诱导相关，这可能增强 DNA 损伤和胆管癌的发生。
