scholarly journals Distinct Expression Patterns of Carbonic Anhydrase IX in Clear Cell, Microcystic, and Angiomatous Meningiomas

2019 ◽  
Vol 78 (12) ◽  
pp. 1081-1088
Author(s):  
Rati Chkheidze ◽  
Patrick J Cimino ◽  
Kimmo J Hatanpaa ◽  
Charles L White ◽  
Manuel Ferreira ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Clear Cell ◽  
Expression Patterns ◽  
Carbonic Anhydrase Ix ◽  
World Health ◽  
Loss Of Function ◽  
Ca Ix ◽  
Hypoxia Marker ◽  
Other World ◽  
Health Organization

Abstract Clear cell, microcytic, and angiomatous meningiomas are 3 vasculature-rich variants with overlapping morphological features but different prognostic and treatment implications. Distinction between them is not always straightforward. We compared the expression patterns of the hypoxia marker carbonic anhydrase IX (CA-IX) in meningiomas with predominant clear cell (n = 15), microcystic (n = 9), or angiomatous (n = 11) morphologies, as well as 117 cases of other World Health Organization recognized histological meningioma variants. Immunostaining for SMARCE1 protein, whose loss-of-function has been associated with clear cell meningiomas, was performed on all clear cell meningiomas, and selected variants of meningiomas as controls. All clear cell meningiomas showed absence of CA-IX expression and loss of nuclear SMARCE1 expression. All microcystic and angiomatous meningiomas showed diffuse CA-IX immunoreactivity and retained nuclear SMARCE1 expression. In other meningioma variants, CA-IX was expressed in a hypoxia-restricted pattern and was highly associated with atypical features such as necrosis, small cell change, and focal clear cell change. In conclusion, CA-IX may serve as a useful diagnostic marker in differentiating clear cell, microcystic, and angiomatous meningiomas.

scholarly journals A non-catalytic function of carbonic anhydrase IX contributes to the glycolytic phenotype and pH regulation in human breast cancer cells

2019 ◽  
Vol 476 (10) ◽  
pp. 1497-1513 ◽  
Author(s):  
Mam Y. Mboge ◽  
Zhijuan Chen ◽  
Daniel Khokhar ◽  
Alyssa Wolff ◽  
Lingbao Ai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Carbonic Anhydrase ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Expression Patterns ◽  
Extracellular Ph ◽  
Carbonic Anhydrase Ix ◽  
Monocarboxylate Transporter ◽  
Proton Efflux ◽  
Ca Ix

AbstractThe most aggressive and invasive tumor cells often reside in hypoxic microenvironments and rely heavily on rapid anaerobic glycolysis for energy production. This switch from oxidative phosphorylation to glycolysis, along with up-regulation of the glucose transport system, significantly increases the release of lactic acid from cells into the tumor microenvironment. Excess lactate and proton excretion exacerbate extracellular acidification to which cancer cells, but not normal cells, adapt. We have hypothesized that carbonic anhydrases (CAs) play a role in stabilizing both intracellular and extracellular pH to favor cancer progression and metastasis. Here, we show that proton efflux (acidification) using the glycolytic rate assay is dependent on both extracellular pH (pHe) and CA IX expression. Yet, isoform-selective sulfonamide-based inhibitors of CA IX did not alter proton flux, which suggests that the catalytic activity of CA IX is not necessary for this regulation. Other investigators have suggested the CA IX co-operates with the MCT transport family to excrete protons. To test this possibility, we examined the expression patterns of selected ion transporters and show that members of this family are differentially expressed within the molecular subtypes of breast cancer. The most aggressive form of breast cancer, triple-negative breast cancer, appears to co-ordinately express the monocarboxylate transporter 4 (MCT4) and carbonic anhydrase IX (CA IX). This supports a possible mechanism that utilizes the intramolecular H+ shuttle system in CA IX to facilitate proton efflux through MCT4.

scholarly journals A non-catalytic function of carbonic anhydrase IX contributes to the glycolytic phenotype and pH regulation in human breast cancer cells

2018 ◽  
Author(s):  
Mam Y. Mboge ◽  
Zhijuan Chen ◽  
Daniel Khokhar ◽  
Alyssa Wolff ◽  
Lingbao Ai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Carbonic Anhydrase ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Expression Patterns ◽  
Extracellular Ph ◽  
Carbonic Anhydrase Ix ◽  
Monocarboxylate Transporter ◽  
Proton Efflux ◽  
Ca Ix

ABSTRACTThe most aggressive and invasive tumor cells often reside in hypoxic microenvironments and rely heavily on rapid anaerobic glycolysis for energy production. This switch from oxidative phosphorylation to glycolysis, along with up-regulation of the glucose transport system, significantly increases the release of lactic acid from cells into the tumor microenvironment. Excess lactate and proton excretion exacerbate extracellular acidification to which cancer cells, but not normal cells, adapt. We have hypothesized that carbonic anhydrases (CAs) play a role in stabilizing both intracellular and extracellular pH to favor cancer progression and metastasis. Here we show that proton efflux (acidification) using the glycolytic rate assay is dependent on both extracellular pH (pHe) and CA IX expression. Yet, isoform selective sulfonamide-based inhibitors of CA IX did not alter proton flux, which suggests that the catalytic activity of CA IX is not necessary for this regulation. Other investigators have suggested the CA IX cooperates with the MCT transport family to excrete protons. To test this possibility, we examined the expression patterns of selected ion transporters and show that members of this family are differentially expressed within the molecular subtypes of breast cancer. The most aggressive form of breast cancer, triple negative breast cancer (TNBC), appears to coordinately express the monocarboxylate transporter 4 (MCT4) and carbonic anhydrase IX (CA IX). This supports a possible mechanism that utilizes the intramolecular H+shuttle system in CA IX to facilitate proton efflux through MCT4.

scholarly journals Inhibition of Carbonic Anhydrase IX Promotes Apoptosis through Intracellular pH Level Alterations in Cervical Cancer Cells

2021 ◽  
Vol 22 (11) ◽  
pp. 6098
Author(s):  
Ebru Temiz ◽  
Ismail Koyuncu ◽  
Mustafa Durgun ◽  
Murat Caglayan ◽  
Ataman Gonel ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Intracellular Ph ◽  
Hela Cells ◽  
Protein Level ◽  
Caspase 3 ◽  
Solid Tumours ◽  
Carbonic Anhydrase Ix ◽  
Parp Activation ◽  
Ca Ix ◽  
Cervical Cancer Cells

Carbonic anhydrase IX (CAIX) is a hypoxia-related protein that plays a role in proliferation in solid tumours. However, how CAIX increases proliferation and metastasis in solid tumours is unclear. The objective of this study was to investigate how a synthetic CAIX inhibitor triggers apoptosis in the HeLa cell line. The intracellular effects of CAIX inhibition were determined with AO/EB, AnnexinV-PI, and γ-H2AX staining; measurements of intracellular pH (pHi), reactive oxygen species (ROS), and mitochondrial membrane potential (MMP); and analyses of cell cycle, apoptotic, and autophagic modulator gene expression (Bax, Bcl-2, caspase-3, caspase-8, caspase-9, caspase-12, Beclin, and LC3), caspase protein level (pro-caspase 3 and cleaved caspase-3, -8, -9), cleaved PARP activation, and CAIX protein level. Sulphonamide CAIX inhibitor E showed the lowest IC50 and the highest selectivity index in CAIX-positive HeLa cells. CAIX inhibition changed the morphology of HeLa cells and increased the ratio of apoptotic cells, dramatically disturbing the homeostasis of intracellular pHi, MMP and ROS levels. All these phenomena consequent to CA IX inhibition triggered apoptosis and autophagy in HeLa cells. Taken together, these results further endorse the previous findings that CAIX inhibitors represent an important therapeutic strategy, which is worth pursuing in different cancer types, considering that presently only one sulphonamide inhibitor, SLC-0111, has arrived in Phase Ib/II clinical trials as an antitumour/antimetastatic drug.

scholarly journals Molecular switch from MYC to MYCN expression in MYC protein negative Burkitt lymphoma cases

2019 ◽  
Vol 9 (12) ◽  
Author(s):  
Lucia Mundo ◽  
Maria Raffaella Ambrosio ◽  
Francesco Raimondi ◽  
Leonardo Del Porro ◽  
Raffaella Guazzo ◽  
...  
Keyword(s):  
Protein Expression ◽  
Burkitt Lymphoma ◽  
Human Cancer ◽  
Large Family ◽  
World Health ◽  
Loss Of Function ◽  
Interaction Interface ◽  
Mrna And Protein Expression ◽  
Bona Fide ◽  
Health Organization

AbstractMYC is the most altered oncogene in human cancer, and belongs to a large family of genes, including MYCN and MYCL. Recently, while assessing the degree of correlation between MYC gene rearrangement and MYC protein expression in aggressive B-cell lymphomas, we observed few Burkitt lymphoma (BL) cases lacking MYC protein expression despite the translocation involving the MYC gene. Therefore, in the present study we aimed to better characterize such cases. Our results identified two sub-groups of MYC protein negative BL: one lacking detectable MYC protein expression but presenting MYCN mRNA and protein expression; the second characterized by the lack of both MYC and MYCN proteins but showing MYC mRNA. Interestingly, the two sub-groups presented a different pattern of SNVs affecting MYC gene family members that may induce the switch from MYC to MYCN. Particulary, MYCN-expressing cases show MYCN SNVs at interaction interface that stabilize the protein associated with loss-of-function of MYC. This finding highlights MYCN as a reliable diagnostic marker in such cases. Nevertheless, due to the overlapping clinic, morphology and immunohistochemistry (apart for MYC versus MYCN protein expression) of both sub-groups, the described cases represent bona fide BL according to the current criteria of the World Health Organization.

scholarly journals Carbonic Anhydrase IX is Not a Predictor of Outcomes in Non-Metastatic Clear Cell Renal Cell Carcinoma - A Digital Analysis of Tissue Microarray

2013 ◽  
Vol 39 (4) ◽  
pp. 484-492 ◽  
Author(s):  
Marcelo Zerati ◽  
Katia R. M. Leite ◽  
Jose Pontes-Junior ◽  
Cesar Camara Segre ◽  
Sabrina Thalita Reis ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Carbonic Anhydrase ◽  
Cell Carcinoma ◽  
Tissue Microarray ◽  
Renal Cell ◽  
Clear Cell ◽  
Carbonic Anhydrase Ix ◽  
Digital Analysis ◽  
Cell Renal Cell Carcinoma

scholarly journals Lethal Violence: A Global View on Homicide

2019 ◽  
Author(s):  
Dietrich Oberwittler
Keyword(s):  
Early Modern Period ◽  
World Health ◽  
Homicide Rates ◽  
Welfare Policies ◽  
Lethal Violence ◽  
State Institutions ◽  
The Pacific ◽  
Other World ◽  
And Gender ◽  
Health Organization

As the most serious crime, homicide is both relevant and suitable for cross-national comparisons. The global homicide rate of ca. 6 per 100,000 people is an average of hugely diverging national rates ranging from 0.25 in Singapore to ca. 100 in El Salvador. The validity of global homicide statistics suffers from various differences in definitions as well as reporting and registration processes. Both criminal justice and causes of death statistics are used by the World Health Organization to construct rates, yet these are available only for a minority of countries. An overview on homicide in history and non-state societies shows that violence levels were considerably higher compared to those in today’s developed world and have dropped dramatically in Europe and North America during the early modern period. The rates first increased and then declined between ca.1960 and today in most developed nations in a synchronized manner, hinting at common influences. In recent years, homicide trends have shown a polarizing pattern, with increasing rates in Latin America and decreasing rates in most other world regions, especially East Asia and the Pacific, where rates have fallen below the European average concurrent with rising scores on the Human Development Index. Except in Eastern Europe, the frequency of homicide is strongly linked to the use of firearms, which account for 44% of homicide cases worldwide. Longitudinal studies have produced robust evidence for the pivotal role of deprivation and inequality in fostering lethal violence and of social welfare policies in reducing it. Although the transition to democratic political systems seems to increase homicide rates temporarily, the legitimacy of state institutions and the suppression of corruption are connected to lower homicide rates. Because of conceptual and methodological problems, questions concerning the generalizability of effects across space and time remain. Nevertheless, the research findings are sufficiently robust to draw important conclusions for violence prevention: reductions in poverty and income inequality, investments in welfare policies and gender equality, and improvements in the legitimacy of state institutions will help to bring homicide rates down.

Role of aryl hydrocarbon receptor in modulation of the expression of the hypoxia marker carbonic anhydrase IX

2009 ◽  
Vol 419 (2) ◽  
pp. 419-425 ◽  
Author(s):  
Martina Takacova ◽  
Tereza Holotnakova ◽  
Jan Vondracek ◽  
Miroslav Machala ◽  
Katerina Pencikova ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Aryl Hydrocarbon Receptor ◽  
Transcriptional Activation ◽  
Hypoxia Inducible Factor ◽  
Carbonic Anhydrase Ix ◽  
Independent Manner ◽  
Hypoxic Induction ◽  
Aryl Hydrocarbon ◽  
Ca Ix ◽  
Tcdd Treatment

Tumour-associated expression of CA IX (carbonic anhydrase IX) is to a major extent regulated by HIF-1 (hypoxia-inducible factor-1) which is important for transcriptional activation and consists of the oxygen-regulated subunit HIF-1α and the partner factor ARNT [AhR (aryl hydrocarbon receptor) nuclear translocator]. We have previously observed that HIF-1α competes with the AhR for interaction with ARNT under conditions when both conditionally regulated factors are activated. We have therefore investigated whether TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin)-induced activation of the AhR pathway might interfere with CA IX expression. The results from the present study suggest that TCDD treatment reduces hypoxic induction of both CA IX mRNA and protein expression. Moreover, the transcriptional activity of the CA9 promoter was significantly reduced by expression of CAAhR (constitutively active AhR), which activates transcription in a ligand-independent manner. Finally, we found that ARNT is critical for both hypoxic induction and the TCDD-mediated inhibition of CA9 expression.

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