Adrenomedullin production is increased in colorectal adenocarcinomas; its relation to matrix metalloproteinase-9

• Published in: Peptides (New York, N.Y. : 1980) N.Y. : 1980), 2011-09, Vol.32 (9), p.1825-1831
• Main Authors: Hikosaka, Tomomi, Tsuruda, Toshihiro, Nagata, Sayaka, Kuwasako, Kenji, Tsuchiya, Kazuyo, Hoshiko, Shinri, Inatsu, Haruhiko, Chijiiwa, Kazuo, Kitamura, Kazuo
• Format: Article
• Language: English
• Subjects: adenocarcinoma; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adrenomedullin; Adult; Aged; Aged, 80 and over; AM2/IMD; Asian Continental Ancestry Group; Biological and medical sciences; calcitonin; Calcitonin Receptor-Like Protein - genetics; Calcitonin Receptor-Like Protein - metabolism; Cancer; Chromatography, High Pressure Liquid - methods; colorectal neoplasms; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Concerts; Correlation; Female; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; gelatinase B; Gene expression; Gene Expression Regulation, Neoplastic; genes; Human; Humans; Immunohistochemistry; Male; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Matrix metalloproteinases; Medical sciences; messenger RNA; Metastasis; Middle Aged; MMP-9; neoplasm cells; pathogenesis; Peptide Hormones - genetics; Peptide Hormones - metabolism; Peptides; Polymerase Chain Reaction - methods; Protein Precursors - genetics; Protein Precursors - metabolism; Receptor Activity-Modifying Protein 2 - genetics; Receptor Activity-Modifying Protein 2 - metabolism; Receptor Activity-Modifying Protein 3 - genetics; Receptor Activity-Modifying Protein 3 - metabolism; Receptors; reverse transcriptase polymerase chain reaction; RNA, Messenger - analysis; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Stroma; tissues; Tumors; vascular endothelial growth factor A; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; VEGF; Vertebrates: endocrinology
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2011.07.012

► Gene expression and peptide concentration of adrenomedullin (AM) were highly expressed in colorectal cancer tissues. ► The level of preproAM mRNA was positively correlated with MMP-9, but not with VEGF-A. ► Immunoreactivity of AM was present in cancer cells, while MMP-9 localized in stroma cells surrounding the tumors. 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.