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Cancers 2012, 4(3), 763-776; doi:10.3390/cancers4030763
Article

Relative Expression of Vitamin D Hydroxylases, CYP27B1 and CYP24A1, and of Cyclooxygenase-2 and Heterogeneity of Human Colorectal Cancer in Relation to Age, Gender, Tumor Location, and Malignancy: Results from Factor and Cluster Analysis

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Department of Pathophysiology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria
* Author to whom correspondence should be addressed.
Received: 22 May 2012 / Revised: 6 July 2012 / Accepted: 13 July 2012 / Published: 26 July 2012
(This article belongs to the Special Issue System Biology in Cancer Research)
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Abstract

Previous studies on the significance of vitamin D insufficiency and chronic inflammation in colorectal cancer development clearly indicated that maintenance of cellular homeostasis in the large intestinal epithelium requires balanced interaction of 1,25-(OH)2D3 and prostaglandin cellular signaling networks. The present study addresses the question how colorectal cancer pathogenesis depends on alterations of activities of vitamin D hydroxylases, i.e., CYP27B1-encoded 25-hydroxyvitamin D-1a-hydroxylase and CYP24A1-encoded 25-hydroxyvitamin D-24-hydroxylase, and inflammation-induced cyclooxygenase-2 (COX-2). Data from 105 cancer patients on CYP27B1, VDR, CYP24A1, and COX-2 mRNA expression in relation to tumor grade, anatomical location, gender and age were fit into a multivariate model of exploratory factor analysis. Nearly identical results were obtained by the principal factor and the maximum likelihood method, and these were confirmed by hierarchical cluster analysis: Within the eight mutually dependent variables studied four independent constellations were found that identify different features of colorectal cancer pathogenesis: (i) Escape of COX-2 activity from restraints by the CYP27B1/VDR system can initiate cancer growth anywhere in the colorectum regardless of age and gender; (ii) variations in COX-2 expression are mainly responsible for differences in cancer incidence in relation to tumor location; (iii) advancing age has a strong gender-specific influence on cancer incidence; (iv) progression from well differentiated to undifferentiated cancer is solely associated with a rise in CYP24A1 expression.
Keywords: colon cancer; inflammation; grading; tumor progression; modeling; 1,25-dihydroxyvitamin D3; 25-hydroxyvitamin D-24-hydroxylase; 25-hydroxyvitamin D-1a-hydroxylase; vitamin D receptor colon cancer; inflammation; grading; tumor progression; modeling; 1,25-dihydroxyvitamin D3; 25-hydroxyvitamin D-24-hydroxylase; 25-hydroxyvitamin D-1a-hydroxylase; vitamin D receptor
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Brozek, W.; Manhardt, T.; Kállay, E.; Peterlik, M.; Cross, H.S. Relative Expression of Vitamin D Hydroxylases, CYP27B1 and CYP24A1, and of Cyclooxygenase-2 and Heterogeneity of Human Colorectal Cancer in Relation to Age, Gender, Tumor Location, and Malignancy: Results from Factor and Cluster Analysis. Cancers 2012, 4, 763-776.

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