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Carbonic Anhydrase and Biomarker Research

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 28530

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Special Issue Information

Carbonic anhydrase is a widely distributed metalloenzyme catalysing the reversible hydration of CO2 to HCO3- and H+. It plays a fundamental role in a number of physiological processes, including gas exchange, pH homeostasis, electrolyte transport, metabolic reactions, bone resorption, calcification.  Recently, its involvement in several pathological conditions as well as sensitivity to chemical pollutants has advanced the research on carbonic anhydrase in the biomarker discovery field.

A biomarker is defined as a cellular, biochemical or molecular alteration that is measurable in biological media as an indicator of normal biological process, pathogenic processes, or response to an exposure or intervention. Biomarkers are useful tools in a wide range of fields, including medicine, drug discovery, environmental health and ecotoxicology.

In recent years, alteration in the expression of specific carbonic anhydrase isoforms has been proposed as diagnostic or prognostic biomarkers in the clinical field, mainly in cancer research.

Moreover, the sensitivity of specific carbonic anhydrase isoforms to environmental pollutants has given rise to new perspectives in the potential use of carbonic anhydrase as pollution biomarker.

This Special Issue of IJMS is aimed to cover the more recent insights in the research of carbonic anhydrase as promising biomarker in several areas of interest from human health to environmental sciences, opening new perspectives for translation of advances in basic sciences on this ancient enzyme into innovative applications.

Prof. Dr. Maria Giulia Lionetto
Guest Editor

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Keywords

• carbonic anhydrase
• biomarker
• pH regulation
• cancer
• tumor microenvironment
• heavy metals
• pollutant
• biomonitoring

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Published Papers (7 papers)

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Research

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8 pages, 2843 KiB  
Article
Cellular Localization of Carbonic Anhydrase Nce103p in Candida albicans and Candida parapsilosis
by Jiří Dostál, Jan Blaha, Romana Hadravová, Martin Hubálek, Olga Heidingsfeld and Iva Pichová
Int. J. Mol. Sci. 2020, 21(3), 850; https://doi.org/10.3390/ijms21030850 - 28 Jan 2020
Cited by 2 | Viewed by 3030
Abstract
Pathogenic yeasts Candida albicans and Candida parapsilosis possess a ß-type carbonic anhydrase Nce103p, which is involved in CO2 hydration and signaling. C. albicans lacking Nce103p cannot survive in low CO2 concentrations, e.g., in atmospheric growth conditions. Candida carbonic anhydrases are orthologous [...] Read more.
Pathogenic yeasts Candida albicans and Candida parapsilosis possess a ß-type carbonic anhydrase Nce103p, which is involved in CO2 hydration and signaling. C. albicans lacking Nce103p cannot survive in low CO2 concentrations, e.g., in atmospheric growth conditions. Candida carbonic anhydrases are orthologous to the Saccharomyces cerevisiae enzyme, which had originally been detected as a substrate of a non-classical export pathway. However, experimental evidence on localization of C. albicans and C. parapsilosis carbonic anhydrases has not been reported to date. Immunogold labeling and electron microscopy used in the present study showed that carbonic anhydrases are localized in the cell wall and plasmatic membrane of both Candida species. This localization was confirmed by Western blot and mass spectrometry analyses of isolated cell wall and plasma membrane fractions. Further analysis of C. albicans and C. parapsilosis subcellular fractions revealed presence of carbonic anhydrases also in the cytosolic and mitochondrial fractions of Candida cells cultivated in shaken liquid cultures, under the atmospheric conditions. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Biomarker Research)
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14 pages, 3907 KiB  
Article
Carbonic Anhydrase XII Expression Is Modulated during Epithelial Mesenchymal Transition and Regulated through Protein Kinase C Signaling
by Daniele Vergara, Sara Ravaioli, Eugenio Fonzi, Loredaria Adamo, Marina Damato, Sara Bravaccini, Francesca Pirini, Antonio Gaballo, Raffaela Barbano, Barbara Pasculli, Julien Franck, Isabelle Fournier, Michel Salzet and Michele Maffia
Int. J. Mol. Sci. 2020, 21(3), 715; https://doi.org/10.3390/ijms21030715 - 22 Jan 2020
Cited by 12 | Viewed by 4269
Abstract
Members of the carbonic anhydrase family are functionally involved in the regulation of intracellular and extracellular pH in physiological and pathological conditions. Their expression is finely regulated to maintain a strict control on cellular homeostasis, and it is dependent on the activation of [...] Read more.
Members of the carbonic anhydrase family are functionally involved in the regulation of intracellular and extracellular pH in physiological and pathological conditions. Their expression is finely regulated to maintain a strict control on cellular homeostasis, and it is dependent on the activation of extracellular and intracellular signaling pathways. Combining RNA sequencing (RNA-seq), NanoString, and bioinformatics data, we demonstrated that the expression of carbonic anhydrase 12 (CAXII) is significantly different in luminal and triple negative breast cancer (BC) models and patients, and is associated with the activation of an epithelial mesenchymal transition (EMT) program. In BC models, the phorbol ester 12-myristate 13-acetate (PMA)-mediated activation of protein kinase C (PKC) induced a down-regulation of CAXII with a concomitant modulation of other members of the transport metabolon, including CAIX and the sodium bicarbonate cotransporter 3 (NBCn1). This is associated with a remodeling of tumor glycolytic metabolism induced after PKC activation. Overall, this analysis highlights the dynamic nature of transport metabolom and identifies signaling pathways finely regulating this plasticity. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Biomarker Research)
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21 pages, 2553 KiB  
Article
Carbonic Anhydrase IX—Mouse versus Human
by Martina Takacova, Monika Barathova, Miriam Zatovicova, Tereza Golias, Ivana Kajanova, Lenka Jelenska, Olga Sedlakova, Eliska Svastova, Juraj Kopacek and Silvia Pastorekova
Int. J. Mol. Sci. 2020, 21(1), 246; https://doi.org/10.3390/ijms21010246 - 30 Dec 2019
Cited by 8 | Viewed by 3146
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Biomarker Research)
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12 pages, 3132 KiB  
Article
Quantitative Analysis of Carbonic Anhydrase IX Uncovers Hypoxia-Related Functional Differences in Classical Hodgkin Lymphoma Subtypes
by Orsolya Matolay, Lívia Beke, Andrea Gyurkovics, Mónika Francz, Gabriella Varjasi, László Rejtő, Árpád Illés, Judit Bedekovics and Gábor Méhes
Int. J. Mol. Sci. 2019, 20(14), 3463; https://doi.org/10.3390/ijms20143463 - 15 Jul 2019
Cited by 5 | Viewed by 2841
Abstract
Upregulation of carbonic anhydrase IX (CAIX) was found to be associated with unfavorable prognosis and resistance to treatment in a broad spectrum of malignancies, recently also in classical Hodgkin’s lymphoma (cHL). As demonstrated, variable CAIX expression in a significant number of cHL cases [...] Read more.
Upregulation of carbonic anhydrase IX (CAIX) was found to be associated with unfavorable prognosis and resistance to treatment in a broad spectrum of malignancies, recently also in classical Hodgkin’s lymphoma (cHL). As demonstrated, variable CAIX expression in a significant number of cHL cases was associated with poor treatment response. The current study focused on the quantification CAIX immunopositivity and its relative expression compared to the total CD30+ neoplastic pool using digital image analysis. One hundred and one lymph node samples featuring cHL histology were analyzed for both CD30 and CAIX by immunohistochemistry. Whole histological slides were scanned and immunopositivity was determined as the histoscore (H-score) using the DensitoQuant software module (3DHistech Kft., Budapest, Hungary). CAIX positivity was observed in the HRS-cells of 56/101 cases (55.44%) and frequently observed in the proximity of necrotic foci. CAIX H-scores were highly variable (range: 2.16–90.36, mean 18.7 ± 18.8). Individual CAIX values were independent of the much higher CD30 values (range 3.46–151.3, mean 52.37 ± 30.74). The CAIX/CD30 index proved to be the highest in the aggressive lymphocyte-depleted (LD) subtype (CAIX/CD30: 0.876). The CAIX expression and the CAIX/CD30 relative index can be precisely determined by image analysis, and values reflect the extent of a tumor mass undergoing hypoxic-stress-related adaptation in the most aggressive forms of cHL. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Biomarker Research)
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19 pages, 7621 KiB  
Article
CAIX Regulates Invadopodia Formation through Both a pH-Dependent Mechanism and Interplay with Actin Regulatory Proteins
by Michaela Debreova, Lucia Csaderova, Monika Burikova, Lubomira Lukacikova, Ivana Kajanova, Olga Sedlakova, Martin Kery, Juraj Kopacek, Miriam Zatovicova, Jozef Bizik, Silvia Pastorekova and Eliska Svastova
Int. J. Mol. Sci. 2019, 20(11), 2745; https://doi.org/10.3390/ijms20112745 - 4 Jun 2019
Cited by 47 | Viewed by 5737
Abstract
Tumor metastasis is tightly linked with invasive membrane protrusions, invadopodia, formed by actively invading tumor cells. Hypoxia and pH modulation play a role in the invadopodia formation and in their matrix degradation ability. Tumor-associated carbonic anhydrase IX (CAIX), induced by hypoxia, is essential [...] Read more.
Tumor metastasis is tightly linked with invasive membrane protrusions, invadopodia, formed by actively invading tumor cells. Hypoxia and pH modulation play a role in the invadopodia formation and in their matrix degradation ability. Tumor-associated carbonic anhydrase IX (CAIX), induced by hypoxia, is essential for pH regulation and migration, predisposing it as an active component of invadopodia. To investigate this assumption, we employed silencing and inhibition of CA9, invadopodia isolation and matrix degradation assay. Quail chorioallantoic membranes with implanted tumor cells, and lung colonization assay in murine model were used to assess efficiency of in vivo invasion and the impact of CAIX targeting antibodies. We showed that CAIX co-distributes to invadopodia with cortactin, MMP14, NBCe1, and phospho-PKA. Suppression or enzymatic inhibition of CAIX leads to impaired invadopodia formation and matrix degradation. Loss of CAIX attenuated phosphorylation of Y421-cortactin and influenced molecular machinery coordinating actin polymerization essential for invadopodia growth. Treatment of tumor cells by CAIX-specific antibodies against carbonic or proteoglycan domains results in reduced invasion and extravasation in vivo. For the first time, we demonstrated in vivo localization of CAIX within invadopodia. Our findings confirm the key role of CAIX in the metastatic process and gives rationale for its targeting during anti-metastatic therapy. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Biomarker Research)
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9 pages, 559 KiB  
Communication
Activity of Carbonic Anhydrase VI is Higher in Dental Biofilm of Children with Caries
by Daniele C. R. Picco, Lenita Marangoni-Lopes, Thaís M. Parisotto, Renata Mattos-Graner and Marinês Nobre-dos-Santos
Int. J. Mol. Sci. 2019, 20(11), 2673; https://doi.org/10.3390/ijms20112673 - 30 May 2019
Cited by 16 | Viewed by 3069
Abstract
This study investigated pH, activity and concentration of carbonic anhydrase VI (CA VI) in dental biofilm of caries and caries-free children of 7–9 years old. Seventy-four children were selected and divided into two groups. The caries diagnosis was performed according to the WHO [...] Read more.
This study investigated pH, activity and concentration of carbonic anhydrase VI (CA VI) in dental biofilm of caries and caries-free children of 7–9 years old. Seventy-four children were selected and divided into two groups. The caries diagnosis was performed according to the WHO criteria, including the early caries lesion. After biofilm collection and pH determination, CA VI concentration and activity were determined by ELISA and Zimography respectively. The data were submitted to a Mann-Whitney test and to Pearson and Spearman correlation analyses. Means and standard deviations of dental caries for the caries group were of 3.162 ± 1.385. The biofilm pH was significantly higher in the caries-free group. The CA VI activity was significantly higher in biofilm of children with caries. The CA VI concentration was significantly higher in biofilm of caries-free children. In caries-free children, there was a moderate negative correlation between CA VI activity and concentration in dental biofilm as well as between pH and CA VI activity. A negative correlation between biofilm pH and CA VI concentration was found in the caries group. In conclusion, CA VI was shown to be more active in the biofilm of school children with caries in order to contribute to neutralization of biofilm acid. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Biomarker Research)
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Review

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16 pages, 560 KiB  
Review
Carbonic Anhydrase as a Biomarker of Global and Local Impacts: Insights from Calcifying Animals
by Yuri Dornelles Zebral, Juliana da Silva Fonseca, Joseane Aparecida Marques and Adalto Bianchini
Int. J. Mol. Sci. 2019, 20(12), 3092; https://doi.org/10.3390/ijms20123092 - 25 Jun 2019
Cited by 32 | Viewed by 5873
Abstract
The emission of greenhouse gases has grown in unprecedented levels since the beginning of the industrial era. As a result, global climate changes, such as heightened global temperature and ocean acidification, are expected to negatively impact populations. Similarly, industrial and urban unsustainable development [...] Read more.
The emission of greenhouse gases has grown in unprecedented levels since the beginning of the industrial era. As a result, global climate changes, such as heightened global temperature and ocean acidification, are expected to negatively impact populations. Similarly, industrial and urban unsustainable development are also expected to impose local impacts of their own, such as environmental pollution with organic and inorganic chemicals. As an answer, biomarkers can be used in environmental programs to assess these impacts. These tools are based in the quantification of biochemical and cellular responses of target species that are known to respond in a sensitive and specific way to such stresses. In this context, carbonic anhydrase has shown to be a promising biomarker candidate for the assessment of global and local impacts in biomonitoring programs, especially in marine zones, such as coral reefs, considering the pivotal role of this enzyme in the calcification process. Therefore, the aim of this review is to show the recent advances in the carbonic anhydrase research and the reasons why it can be considered as a promising biomarker to be used for calcifying organisms. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Biomarker Research)
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