Role of Carbonic Anhydrase IX in Human Tumor Cell Growth, Survival, and Invasion

Robertson, Naomi; Potter, Christian; Harris, Adrian L.

doi:10.1158/0008-5472.can-03-2224

Cited by 273 publications

(225 citation statements)

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“…This idea is consistent with the findings that the catalytic activity of CA IX is regulated by hypoxia and suggests that the capacity of CA IX to modulate pH is vital for the survival of hypoxic tumour cells. The latter suggestion has been indirectly supported also by RNAi experiments by Robertson et al (2004). However, it is also possible that the AS protein released to the culture medium can modulate spheroid formation via binding to the transport unrelated receptor and stimulate or block signal transduction in autocrine or paracrine fashion.…”

Section: Discussionmentioning

confidence: 84%

Alternative splicing variant of the hypoxia marker carbonic anhydrase IX expressed independently of hypoxia and tumour phenotype

et al. 2007

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CA IX is a hypoxia-induced, cancer-associated carbonic anhydrase isoform with functional involvement in pH control and cell adhesion. Here we describe an alternative splicing variant of the CA9 mRNA, which does not contain exons 8 -9 and is expressed in tumour cells independently of hypoxia. It is also detectable in normal tissues in the absence of the full-length transcript and can therefore produce false-positive data in prognostic studies based on the detection of the hypoxia-and cancer-related CA9 expression. The splicing variant encodes a truncated CA IX protein lacking the C-terminal part of the catalytic domain. It shows diminished catalytic activity and is intracellular or secreted. When overexpressed, it reduces the capacity of the full-length CA IX protein to acidify extracellular pH of hypoxic cells and to bind carbonic anhydrase inhibitor. HeLa cells transfected with the splicing variant cDNA generate spheroids that do not form compact cores, suggesting that they fail to adapt to hypoxic stress. Our data indicate that the splicing variant can functionally interfere with the full-length CA IX. This might be relevant particularly under conditions of mild hypoxia, when the cells do not suffer from severe acidosis and do not need excessive pH control. British Journal of Cancer (2008) Carbonic anhydrase IX (CA IX) is one of 12 enzymatically active carbonic anhydrase isoforms expressed in the human body. These zinc metalloenzymes catalyse a reversible conversion of carbon dioxide to bicarbonate and proton, and thereby contribute to modulation of ion transport and maintenance of acid-base balance. The CA isoforms show remarkable diversity in their enzyme activity, kinetic properties, distribution in tissues, localisation in subcellular compartments and sensitivity to inhibitors. This diversity enables them to fulfill specific roles in metabolically active organs and in various physiological situations .In contrast to the majority of CA isoforms that are mostly present in differentiated cells of the normal tissues, CA IX expression is predominantly associated with a broad range of tumours derived from cells, which contain no or low level of CA IX (Potter and Harris, 2003). The only normal tissues that show moderate-to-abundant expression of CA IX belong to gastrointestinal tract and comprise epithelia of the glandular stomach, small intestine, and gallbladder (Pastorekova et al, 1997).The tumour-related expression pattern of CA IX is principally determined by a strong activation of CA9 gene transcription via a hypoxia-inducible factor (HIF), which binds to hypoxia responsive element (HRE) localised in the minimal CA9 promoter proximal to transcription start site at À10/À3 position (Wykoff et al, 2000). The HIF transcription factor significantly changes the expression profile of weakly oxygenated tumour cells by the activation of genes that either support their survival and adaptation to hypoxic stress or lead to their death. As a result, hypoxia selects more aggressive tumour cells with increased capability...

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Section: Discussionmentioning

confidence: 84%

Alternative splicing variant of the hypoxia marker carbonic anhydrase IX expressed independently of hypoxia and tumour phenotype

et al. 2007

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“…Carbonic anhydrase isozyme IX is involved in maintaining the extracellular pH (Ivanov et al, 2001) by catalysing the reversible chemical reaction in which carbon dioxide is hydrated to carbonic acid and further to bicarbonate (Wykoff et al, 2000;Brennan et al, 2006). Thus, it is an important enzyme for cancer cells in hypoxic and normoxic conditions (Wykoff et al, 2000;Robertson et al, 2004) in the regulation of acid-base balance (Hilvo et al, 2007). Interestingly, in CRC samples studied by cDNA microarray (Talvinen et al, 2006), CA9 was found to be the most upregulated gene.…”

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confidence: 99%

Expression of carbonic anhydrase IX suggests poor outcome in rectal cancer

et al. 2009

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The aim of the study is to assess the value of carbonic anhydrase isozyme IX (CA IX) expression as a predictor of disease-free survival (DFS) and disease-specific survival (DSS) in rectal cancer treated by preoperative radio-or chemoradiotherapy or surgery only. Archival tumour samples from 166 patients were analysed for CA IX expression by three different evaluations: positive/negative, proportion of positivity and staining intensity. The results of immunohistochemical analysis were confirmed by demonstrating CA IX protein in western blotting analysis. Forty-four percent of the operative samples were CA IX positive, of these 34% had weak and 66% moderate/strong staining intensity. In univariate survival analysis, intensity of CA IX expression was a predictor of DFS (P ¼ 0.003) and DSS (P ¼ 0.034), both being markedly longer in tumours with negative or weakly positive staining. In multivariate Cox model, number of metastatic lymph nodes and CA IX intensity were the only independent predictors of DFS. Carbonic anhydrase isozyme IX intensity was the only independent predictor of DSS, with HR ¼ 9.2 for dying of disease with moderate-intense CA IX expression as compared with CA IX-negative/weak cases. Negative/weak CA IX staining intensity is an independent predictor of longer DFS and DSS in rectal cancer.

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“…CA-9 also has been used as a marker of tumor hypoxia, and studies have indicated that it is important in tumor growth and survival. 7 There are at least 2 members of the HIF-a family that share close sequence homology. Although studies have shown that the majority of solid tumors express nuclear HIF-1a, HIF-2a is expressed less frequently.…”

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confidence: 99%

The relation between hypoxia‐inducible factor (HIF)‐1α and HIF‐2α expression with anemia and outcome in surgically treated head and neck cancer

Winter

Shah

Han

et al. 2006

Cancer

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BACKGROUND.Hypoxia promotes tumorigenesis through the hypoxia‐inducible factor (HIF) pathway. There are 2 main homologues of the regulatory proteins, HIF‐1α and HIF‐2α, which have different effects in genetic knock‐out experiments. Anemia may contribute to hypoxia by reducing oxygen delivery, but it is not known whether this influences HIF‐α expression in tumors.METHODS.The expression of HIF‐1α, HIF‐2α, carbonic anhydrase‐9 (CA‐9), and peripheral hemoglobin (Hb) levels in 151 patients who underwent surgery for head and neck squamous cell carcinoma (HNSCC) were analyzed and related to outcome.RESULTS.High HIF‐1α was expressed in 45 of 140 tumors (30%), HIF‐2α was expressed in 21 of 139 tumors (14%), and CA‐9 was expressed in 56 of 149 tumors (62%). There was a positive correlation between HIF‐1α expression and HIF‐2α expression (P = .0001). HIF‐1α alone was associated with a worse disease‐specific survival (DSS) (P = .05) and disease‐free survival (DFS) (P = .03) in multivariate analyses. Nine percent of tumors expressed both high HIF‐1α and high HIF‐2α. High HIF‐1α/high HIF‐2α expression was an independent prognostic factors in DSS (P = .04) and DFS (P = .005) in multivariate analyses. There was no correlation noted between Hb and HIF‐1α, HIF‐2α, or CA‐9.CONCLUSIONS.HIF‐1α alone was correlated with DSS and DFS. The additive effect of HIF‐2α on poor prognosis suggested that different pathways may be regulated by HIF‐2α. Anemia that was not related to HIF‐α expression suggests that tumor intrinsic factors regulate HIF‐α; therefore, anemia may be a surrogate marker for other factors that affect outcome. Cancer 2006. © 2006 American Cancer Society.

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Role of Carbonic Anhydrase IX in Human Tumor Cell Growth, Survival, and Invasion

Cited by 273 publications

References 15 publications

Alternative splicing variant of the hypoxia marker carbonic anhydrase IX expressed independently of hypoxia and tumour phenotype

Alternative splicing variant of the hypoxia marker carbonic anhydrase IX expressed independently of hypoxia and tumour phenotype

Expression of carbonic anhydrase IX suggests poor outcome in rectal cancer

The relation between hypoxia‐inducible factor (HIF)‐1α and HIF‐2α expression with anemia and outcome in surgically treated head and neck cancer

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