J. Cancer Mol. 5: 73-78, 2010

[Research Paper]

Cancer-Associated Carbonic Anhydrases IX and XII: Effect of Growth Factors on Gene Expression in Human Cancer Cell Lines

Heini Kallio, Alejandra Rodriguez Martinez, Mika Hilvo, Alise Hyrskyluoto, and Seppo Parkkila

Institute of Medical Technology and School of Medicine, University of Tampere and Tampere University Hospital, Tampere, Finland

Abstract: 

AIM: Carbonic anhydrase IX (CA9) and carbonic anhydrase XII (CA12) are cancer-associated enzymes that are strongly up-regulated by hypoxia via hypoxia-inducible factor HIF-1, but whether these isozymes are regulated by other mechanisms is not well understood.  In the present study, we investigated the effects of certain hormones and growth factors on the levels of CA9 and CA12 mRNA expression in human cancer cell lines.

METHODS: Seven human cell lines were selected for the study.  The cells were treated with several hormones and growth factors for 24 h.  Changes in the levels of human CA9 and CA12 transcripts were detected using quantitative real-time PCR.

RESULTS: Different growth factors or hormones had different effects on CA9 and CA12 mRNA expression in different cancer cells.  The strongest up-regulation of CA9 and CA12 expression was observed after deferoxamine mesylate treatment, which was used to induce a hypoxia-like response.  Additionally, CA12 expression could be stimulated by growth factors like IGF-1, TGF-beta1 and EGF in U373, MCF-7, Caki-1, and A-498 cells.  Induction of CA9 expression was obvious only in U373 cells.  Conversely, CA12 expression was reduced in human endothelial cells after growth factor treatments.

CONCLUSION: The results suggest that the increase in CA9 and CA12 stimulated by IGF-1, TGF-alpha, TGF-beta1 and EGF is mediated through HIF-1alpha protein expression, which has been shown to be up-regulated by several growth factors under normal oxygenation conditions in human cell lines.  This could represent a novel regulatory mechanism for CA9 and CA12 expression.

(Keywords: carbonic anhydrase; HIF-1alpha; deferoxamine mesylate; growth factor)

Received 2/17/09; Revised 6/3/09; Accepted 6/10/09.

1. Correspondence: Heini Kallio, Institute of Medical Technology, University of Tampere, Biokatu 6, 33520 Tampere, Finland.  Phone: 358-3-31175564. Fax: 358-3-35517710. E-mail: heini.kallio@uta.fi

2. Abbreviations: CA, carbonic anhydrase; HIF-1, hypoxia-inducible transcription factor 1; pVHL, von Hippel-Lindau protein; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase.

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