Rabbit Anti-Human MMP-1 (a.a. 411-460) Polyclonal antibody

The epithelial-mesenchymal transition (EMT) is a transformation process mandatory for the local and distant progression of many malignant tumors, including hepatocellular carcinoma (HCC). Matrix metalloproteinases (MMPs) play significant roles in cellular regeneration, programmed death, angiogenesis, and many other essential tissular functions, involved in the normal development and also in pathological processes, such as the EMT. This paper reviews the roles of MMPs in the EMT involved in HCC invasion, as well as the ancillary roles that MMP cross-activation and tissue inhibitors play in modulating this process. While gelatinases MMP-2 and MMP-9 are the MMPs commonly cited in the EMT of HCC, MMPs belonging to other classes have been proven to be involved in this process, favoring not only invasion and metastasis (MMP-1, MMP-3, MMP-7, MMP-10, MMP-11, MMP-13, MMP-14, MMP-16, MMP-26, and MMP-28) but also angiogenesis (MMP-8 and MMP-10). There is also data suggesting that other MMPs with a suspected or demonstrated role in the EMT of other cancers may also have some degree of involvement in HCC. The auto- and cross-activation of MMPs may complicate this issue, as pinpointing the extent of implication of each MMP may be extremely difficult. The homeostasis between MMPs and their tissue inhibitors is essential in preventing tumor progression, and the disturbance of this stability is another entailed factor in the EMT of HCC, which is addressed herein.

The skin is a unique site in the human body that has the capacity to synthesize the active form of vitamin D, 1 alpha,25-dihydroxyvitamin D-3 (1 alpha,25(OH)(2)D-3), from 7-dehydrocholesterol (7DHC) upon UV irradiation. Keratinocytes express both 25-hydroxylase (CYP27A1 and CYP2R1) and 1 alpha-hydroxylase (CYP27B1), critical enzymes involved in active vitamin D synthesis. Here, we investigated the effect of skin-derived 1 alpha,25(OH)(2)D-3, synthesized purely within the keratinocytes, on MMP-1 expression. Treatment of human epidermal keratinocytes with 1 alpha,25(OH)(2)D-3, but not 7DHC or 25OHD(3), significantly increased MMP-1 expression. UV irradiation increases 1 alpha,25(OH)(2)D-3 levels, and ketoconazole inhibits UV-induced production of 1 alpha,25(OH)(2)D-3. Upregulation of MMP-1 by UV was reversed by inhibition of 1 alpha,25(OH)(2)D-3 synthesis using ketoconazole or CYP27B1 siRNA. In keratinocytes, 7DHC is a substrate for both cholesterol and 1 alpha,25(OH)(2)D-3 synthesis. We demonstrated that UV irradiation leads to decreased expression of DHCR7 (7-dehydrocholesterol reductase), the enzyme that converts 7DHC to cholesterol. Inhibition of DHCR7 with its inhibitor BM15766 decreased cholesterol synthesis and increased UV-induced MMP-1 expression, which was attenuated by ketoconazole. These findings suggest that UV-induced reduction of DHCR7 leads to a decrease in cholesterol synthesis, thereby increasing 7DHC availability for 1 alpha,25(OH)(2)D-3 production, which enhances MMP-1 expression. Finally, UV irradiation in human skin in vivo significantly increased CYP27B1 mRNA and decreased DHCR7 mRNA expression. Taken together, we demonstrate here that skin-derived 1 alpha,25(OH)(2)D-3 significantly increases MMP-1 expression in human keratinocytes, a previously unappreciated function of 1 alpha,25(OH)(2)D-3. Moreover, UV irradiation upregulates the enzyme CYP27B1, which leads to 1 alpha,25(OH)(2)D-3 synthesis, but downregulates the cholesterol-producing enzyme DHCR7, both of which collectively lead to increased MMP-1 expression in human keratinocytes. This pathway may be exploited to develop a novel cutaneous anti-aging agent that blocks local cutaneous 1 alpha,25(OH)(2)D(3 )synthesis.