Adrenomedullin production is increased in colorectal adenocarcinomas; its relation to matrix metalloproteinase-9 |
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Authors: | Hikosaka Tomomi Tsuruda Toshihiro Nagata Sayaka Kuwasako Kenji Tsuchiya Kazuyo Hoshiko Shinri Inatsu Haruhiko Chijiiwa Kazuo Kitamura Kazuo |
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Institution: | a Department of Internal Medicine, Division of Circulation and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan b Frontier Science Research Center, University of Miyazaki, Japan c Department of Surgical Oncology and Regulation of Organ Function, Faculty of Medicine, University of Miyazaki, Japan |
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Abstract: | Adrenomedullin (AM) is highly expressed in various cancer cell lines, suggesting a possible association with cancer growth. In the present study, we examined the expression and/or concentration of AM, its related peptide, adrenomedullin2/intermedin (AM2/IMD) and their receptors in human colorectal cancer and the surrounding normal tissue. In addition, we assessed the correlation between the expression of AM and AM2/IMD with that of vascular endothelial growth factor (VEGF)-A and matrix metalloproteinase (MMP)-9. Using a specific immunoradiometric assay, we found that AM concentrations were 2-11-fold higher in colorectal cancer tissues than in the surrounding normal tissues. Moreover, real-time quantitative RT-PCR showed that the expression levels of preproAM (+548%), preproAM2/IMD (+2674%), calcitonin receptor-like receptor (CLR) (+518%), receptor activity modifying protein (RAMP)2 (+281%), RAMP3 (+178%), VEGF-A (+277%) and MMP-9 (+864%) mRNAs were significantly higher in cancer tissues than in the surrounding normal tissues, and there was a positive correlation between the gene expressions of MMP-9 and preproAM (r = 0.352; p = 0.005), but not with preproAM2/IMD (r = 0.041, p = 0.406). Both AM and AM2/IMD immunoreactivity were detected mainly within cancer cells, whereas MMP-9 immunoreactivity was mostly seen in the surrounding stroma. These findings suggest that AM produced in colorectal tumors acts in concert with MMP-9 in the stroma to contribute to the pathogenesis of colorectal cancer. |
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Keywords: | Adrenomedullin AM2/IMD MMP-9 VEGF Metastasis Stroma |
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