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Am J Pathol. 2014 Apr;184(4):953-965. doi: 10.1016/j.ajpath.2014.01.002. Epub 2014 Feb 8.

Expression pattern of carbonic anhydrase IX in Medullary thyroid carcinoma supports a role for RET-mediated activation of the HIF pathway.

Author information

1
Department of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia; Center for Molecular Medicine, Slovak Academy of Sciences, Bratislava, Slovakia.
2
Department of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia.
3
Laboratory of Molecular Oncology, Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovakia.
4
Department of Pathology, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
5
Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
6
Department of Pathology, Jyväskylä Central Hospital, Jyväskylä, Finland.
7
Institute of Medical Technology and School of Medicine, University of Tampere, Tampere, Finland.
8
Department of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia. Electronic address: silvia.pastorekova@savba.sk.

Abstract

Medullary thyroid carcinoma is a relatively rare tumor with poor prognosis and therapy response. Its phenotype is determined by both genetic alterations (activating RET oncoprotein) and physiological stresses, namely hypoxia [activating hypoxia-inducible factor (HIF)]. Here, we investigated the cooperation between these two mechanisms. The idea emerged from the immunohistochemical analysis of carbonic anhydrases (CA) IX and XII expression in thyroid cancer. Although CAXII was present in all types of thyroid carcinomas, CAIX, a direct HIF target implicated in tumor progression, was associated with aggressive medullary and anaplastic carcinomas, and its expression pattern in medullary thyroid carcinomas suggested contribution of both hypoxic and oncogenic signaling. Therefore, we analyzed the CA9 promoter activity in transfected tumor cells expressing RET and/or the HIF-α subunit. We showed that overexpression of both wild-type and mutant RET can increase the CA9 promoter activity induced by HIF-1 (but not HIF-2) in hypoxia. Similar results were obtained with another HIF-1-regulated promoter derived from the lactate dehydrogenase A gene. Moreover, inhibition of the major kinase pathways, which transmit signals from RET and regulate HIF-1, abrogated their cooperative effect on the CA9 promoter. Thus, we brought the first experimental evidence for the crosstalk between RET and HIF-1 that can explain the increased expression of CAIX in medullary thyroid carcinoma and provide a rationale for therapy simultaneously targeting both pathways.

PMID:
24518567
DOI:
10.1016/j.ajpath.2014.01.002
[Indexed for MEDLINE]

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