Abstract
In contrast to human carbonic anhydrase IX (hCA IX) that has been extensively studied with respect to its molecular and functional properties as well as regulation and expression, the mouse ortholog has been investigated primarily in relation to tissue distribution and characterization of CA IX-deficient mice. Thus, no data describing transcriptional regulation and functional properties of the mouse CA IX (mCA IX) have been published so far, despite its evident potential as a biomarker/target in pre-clinical animal models of tumor hypoxia. Here, we investigated for the first time, the transcriptional regulation of the Car9 gene with a detailed description of its promoter. Moreover, we performed a functional analysis of the mCA IX protein focused on pH regulation, cell–cell adhesion, and migration. Finally, we revealed an absence of a soluble extracellular form of mCA IX and provided the first experimental evidence of mCA IX presence in exosomes. In conclusion, though the protein characteristics of hCA IX and mCA IX are highly similar, and the transcription of both genes is predominantly governed by hypoxia, some attributes of transcriptional regulation are specific for either human or mouse and as such, could result in different tissue expression and data interpretation.
Highlights
Hypoxia, as a hallmark of most solid tumors, is a negative prognostic factor and is associated with an aggressive tumor phenotype and resistance to therapy
The majority of the transcription factor (TF) found via MatInspector analysis of the Car9 sequence were similar to the human ortholog (e.g., HIF-1, SP1, AP1), and we decided to analyze their role in the transcriptional regulation of Car9
All the results obtained in this study provide a complex overview of the mouse CA IX transcriptional regulation, expression, and protein function
Summary
As a hallmark of most solid tumors, is a negative prognostic factor and is associated with an aggressive tumor phenotype and resistance to therapy. The cellular response to hypoxia is predominantly executed via hypoxia-inducible factor (HIF-1)—a heterodimeric protein consisting of an oxygen-dependent α subunit and a constitutively expressed β subunit. HIF-1, as a transcription factor, upregulates the expression of several tens of genes, including those involved in angiogenesis, erythropoiesis, glucose metabolism, pH regulation, and apoptosis [2]. HIF-1 transcriptional activity is mediated through hypoxia-responsive elements (HREs; 5 -RCGTG-3 ) present in the promoters of a wide spectrum of target genes. Due to the unique position of HRE within the CA9 promoter, CA IX is considered as one of the best endogenous sensors of HIF-1 activity and serves as a reliable marker of tumor hypoxia
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