Skip to main content
Top
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

Prognostic value of carbonic anhydrase VII expression in colorectal carcinoma

Authors: Guang-Zhen Yang, Liang Hu, Jian Cai, Hai-Yang Chen, Yu Zhang, Dan Feng, Chen-Ye Qi, Yan-Xia Zhai, Hui Gong, Hao Fu, Qing-Ping Cai, Chun-Fang Gao

Published in: BMC Cancer | Issue 1/2015

Login to get access

Abstract

Background

Carbonic anhydrases (CAs) have been implicated in the pathogenesis of human cancers. Carbonic anhydrase VII (CA7), a member of the CA gene family, was recently demonstrated to be expressed in several human tissues including colon. Nevertheless, the expression and clinical relevance of CA7 in colorectal carcinoma (CRC) has not been investigated.

Methods

Real-time PCR, western blot, and immunohistochemistry analyses were used to determine CA7 expression in CRC clinical samples. The correlation of CA7 expression with clinicopathologic features was assessed in 228 patients from Luoyang, China (training cohort) and validated in 151 patients from Shanghai, China (validation cohort). Kaplan-Meier and Cox proportional regression analyses were used to estimate the association between CA7 expression and patients’ survival.

Results

CA7 expression was frequently downregulated in CRC tissues at both the mRNA and protein levels. Reduced expression of CA7 was significantly correlated with poor differentiation, positive lymph node metastasis, advanced TNM stage and unfavorable clinical outcome not only in the training cohort but also in the validation set. Survival analysis indicated that patients with lower CA7 expression had a significantly shorter disease-specific survival (DSS) than those with higher CA7 expression. Importantly, further stage-based analyses revealed that decreased CA7 expression significantly predicted poor DSS and was an independent adverse prognostic indicator for patients with early stage tumors in both cohorts.

Conclusions

Our results indicate that decreased expression of CA7 correlates with disease progression and predicts poor prognosis in CRC, especially for patients with early stage tumors.
Appendix
Available only for authorised users
Literature
1.
go back to reference Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMed Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMed
2.
go back to reference Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.CrossRefPubMed Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.CrossRefPubMed
4.
go back to reference Guo P, Huang ZL, Yu P, Li K. Trends in cancer mortality in China: an update. Ann Oncol. 2012;23:2755–62.CrossRefPubMed Guo P, Huang ZL, Yu P, Li K. Trends in cancer mortality in China: an update. Ann Oncol. 2012;23:2755–62.CrossRefPubMed
5.
go back to reference Alterio V, Di Fiore A, D'Ambrosio K, Supuran CT, De Simone G. Multiple binding modes of inhibitors to carbonic anhydrases: how to design specific drugs targeting 15 different isoforms? Chem Rev. 2012;112:4421–68.CrossRefPubMed Alterio V, Di Fiore A, D'Ambrosio K, Supuran CT, De Simone G. Multiple binding modes of inhibitors to carbonic anhydrases: how to design specific drugs targeting 15 different isoforms? Chem Rev. 2012;112:4421–68.CrossRefPubMed
6.
go back to reference Supuran CT. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov. 2008;7:168–81.CrossRefPubMed Supuran CT. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov. 2008;7:168–81.CrossRefPubMed
7.
go back to reference Mori M, Staniunas RJ, Barnard GF, Jessup JM, Steele Jr GD, Chen LB. The significance of carbonic anhydrase expression in human colorectal cancer. Gastroenterology. 1993;105:820–6.CrossRefPubMed Mori M, Staniunas RJ, Barnard GF, Jessup JM, Steele Jr GD, Chen LB. The significance of carbonic anhydrase expression in human colorectal cancer. Gastroenterology. 1993;105:820–6.CrossRefPubMed
8.
go back to reference Kivela AJ, Saarnio J, Karttunen TJ, Kivelä J, Parkkila AK, Pastorekova S, et al. Differential expression of cytoplasmic carbonic anhydrases, CA I and II, and membrane-associated isozymes, CA IX and XII, in normal mucosa of large intestine and in colorectal tumors. Dig Dis Sci. 2001;46:2179–86.CrossRefPubMed Kivela AJ, Saarnio J, Karttunen TJ, Kivelä J, Parkkila AK, Pastorekova S, et al. Differential expression of cytoplasmic carbonic anhydrases, CA I and II, and membrane-associated isozymes, CA IX and XII, in normal mucosa of large intestine and in colorectal tumors. Dig Dis Sci. 2001;46:2179–86.CrossRefPubMed
9.
go back to reference Saarnio J, Parkkila S, Parkkila AK, Haukipuro K, Pastoreková S, Pastorek J, et al. Immunohistochemical study of colorectal tumors for expression of a novel transmembrane carbonic anhydrase, MN/CA IX, with potential value as a marker of cell proliferation. Am J Pathol. 1998;153:279–85.CrossRefPubMedPubMedCentral Saarnio J, Parkkila S, Parkkila AK, Haukipuro K, Pastoreková S, Pastorek J, et al. Immunohistochemical study of colorectal tumors for expression of a novel transmembrane carbonic anhydrase, MN/CA IX, with potential value as a marker of cell proliferation. Am J Pathol. 1998;153:279–85.CrossRefPubMedPubMedCentral
10.
go back to reference Niemelä AM, Hynninen P, Mecklin JP, Kuopio T, Kokko A, Aaltonen L, et al. Carbonic anhydrase IX is highly expressed in hereditary nonpolyposis colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2007;16:1760–6.CrossRefPubMed Niemelä AM, Hynninen P, Mecklin JP, Kuopio T, Kokko A, Aaltonen L, et al. Carbonic anhydrase IX is highly expressed in hereditary nonpolyposis colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2007;16:1760–6.CrossRefPubMed
11.
go back to reference Kivelä A, Parkkila S, Saarnio J, Karttunen TJ, Kivelä J, Parkkila AK, et al. Expression of a novel transmembrane carbonic anhydrase isozyme XII in normal human gut and colorectal tumors. Am J Pathol. 2000;156:577–84.CrossRefPubMedPubMedCentral Kivelä A, Parkkila S, Saarnio J, Karttunen TJ, Kivelä J, Parkkila AK, et al. Expression of a novel transmembrane carbonic anhydrase isozyme XII in normal human gut and colorectal tumors. Am J Pathol. 2000;156:577–84.CrossRefPubMedPubMedCentral
12.
go back to reference Kummola L, Hämäläinen JM, Kivelä J, Kivelä AJ, Saarnio J, Karttunen T, et al. Expression of a novel carbonic anhydrase, CA XIII, in normal and neoplastic colorectal mucosa. BMC Cancer. 2005;5:41.CrossRefPubMedPubMedCentral Kummola L, Hämäläinen JM, Kivelä J, Kivelä AJ, Saarnio J, Karttunen T, et al. Expression of a novel carbonic anhydrase, CA XIII, in normal and neoplastic colorectal mucosa. BMC Cancer. 2005;5:41.CrossRefPubMedPubMedCentral
13.
go back to reference Bootorabi F, Jänis J, Smith E, Waheed A, Kukkurainen S, Hytönen V, et al. Analysis of a shortened form of human carbonic anhydrase VII expressed in vitro compared to the full-length enzyme. Biochimie. 2010;92:1072–80.CrossRefPubMed Bootorabi F, Jänis J, Smith E, Waheed A, Kukkurainen S, Hytönen V, et al. Analysis of a shortened form of human carbonic anhydrase VII expressed in vitro compared to the full-length enzyme. Biochimie. 2010;92:1072–80.CrossRefPubMed
14.
go back to reference Birkenkamp-Demtroder K, Olesen SH, Sørensen FB, Laurberg S, Laiho P, Aaltonen LA, et al. Differential gene expression in colon cancer of the caecum versus the sigmoid and rectosigmoid. Gut. 2005;54:374–84.CrossRefPubMedPubMedCentral Birkenkamp-Demtroder K, Olesen SH, Sørensen FB, Laurberg S, Laiho P, Aaltonen LA, et al. Differential gene expression in colon cancer of the caecum versus the sigmoid and rectosigmoid. Gut. 2005;54:374–84.CrossRefPubMedPubMedCentral
15.
go back to reference Chu CM, Yao CT, Chang YT, Chou HL, Chou YC, Chen KH, et al. Gene expression profiling of colorectal tumors and normal mucosa by microarrays meta-analysis using prediction analysis of microarray, artificial neural network, classification, and regression trees. Dis Markers. 2014;2014:634123.CrossRefPubMedPubMedCentral Chu CM, Yao CT, Chang YT, Chou HL, Chou YC, Chen KH, et al. Gene expression profiling of colorectal tumors and normal mucosa by microarrays meta-analysis using prediction analysis of microarray, artificial neural network, classification, and regression trees. Dis Markers. 2014;2014:634123.CrossRefPubMedPubMedCentral
16.
go back to reference Bootorabi F, Haapasalo J, Smith E, Haapasalo H, Parkkila S. Carbonic anhydrase VII–a potential prognostic marker in gliomas. Health. 2011;3:6–12.CrossRef Bootorabi F, Haapasalo J, Smith E, Haapasalo H, Parkkila S. Carbonic anhydrase VII–a potential prognostic marker in gliomas. Health. 2011;3:6–12.CrossRef
17.
go back to reference Hu L, Chen L, Yang G, Li L, Sun H, Chang Y, et al. HBx sensitizes cells to oxidative stress-induced apoptosis by accelerating the loss of Mcl-1 protein via caspase-3 cascade. Mol Cancer. 2011;10:43.CrossRefPubMedPubMedCentral Hu L, Chen L, Yang G, Li L, Sun H, Chang Y, et al. HBx sensitizes cells to oxidative stress-induced apoptosis by accelerating the loss of Mcl-1 protein via caspase-3 cascade. Mol Cancer. 2011;10:43.CrossRefPubMedPubMedCentral
18.
go back to reference Dong LW, Yang GZ, Pan YF, Chen Y, Tan YX, Dai RY, et al. The oncoprotein p28GANK establishes a positive feedback loop in β-catenin signaling. Cell Res. 2011;21:1248–61.CrossRefPubMedPubMedCentral Dong LW, Yang GZ, Pan YF, Chen Y, Tan YX, Dai RY, et al. The oncoprotein p28GANK establishes a positive feedback loop in β-catenin signaling. Cell Res. 2011;21:1248–61.CrossRefPubMedPubMedCentral
19.
go back to reference Li L, Chen L, Hu L, Liu Y, Sun HY, Tang J, et al. Nuclear factor high-mobility group box1 mediating the activation of Toll-like receptor 4 signaling in hepatocytes in the early stage of nonalcoholic fatty liver disease in mice. Hepatology. 2011;54:1620–30.CrossRefPubMed Li L, Chen L, Hu L, Liu Y, Sun HY, Tang J, et al. Nuclear factor high-mobility group box1 mediating the activation of Toll-like receptor 4 signaling in hepatocytes in the early stage of nonalcoholic fatty liver disease in mice. Hepatology. 2011;54:1620–30.CrossRefPubMed
20.
go back to reference Tang L, Tan YX, Jiang BG, Pan YF, Li SX, Yang GZ, et al. The prognostic significance and therapeutic potential of hedgehog signaling in intrahepatic cholangiocellular carcinoma. Clin Cancer Res. 2013;19:2014–24.CrossRefPubMed Tang L, Tan YX, Jiang BG, Pan YF, Li SX, Yang GZ, et al. The prognostic significance and therapeutic potential of hedgehog signaling in intrahepatic cholangiocellular carcinoma. Clin Cancer Res. 2013;19:2014–24.CrossRefPubMed
21.
go back to reference Compton CC. Optimal pathologic staging: defining stage II disease. Clin Cancer Res. 2007;13:6862s–70.CrossRefPubMed Compton CC. Optimal pathologic staging: defining stage II disease. Clin Cancer Res. 2007;13:6862s–70.CrossRefPubMed
22.
go back to reference Peng Y, Li X, Wu M, Yang J, Liu M, Zhang W, et al. New prognosis biomarkers identified by dynamic proteomic analysis of colorectal cancer. Mol Biosyst. 2012;8:3077–88.CrossRefPubMed Peng Y, Li X, Wu M, Yang J, Liu M, Zhang W, et al. New prognosis biomarkers identified by dynamic proteomic analysis of colorectal cancer. Mol Biosyst. 2012;8:3077–88.CrossRefPubMed
23.
go back to reference Korkeila E, Talvinen K, Jaakkola PM, Minn H, Syrjänen K, Sundström J, et al. Expression of carbonic anhydrase IX suggests poor outcome in rectal cancer. Br J Cancer. 2009;24:874–80.CrossRef Korkeila E, Talvinen K, Jaakkola PM, Minn H, Syrjänen K, Sundström J, et al. Expression of carbonic anhydrase IX suggests poor outcome in rectal cancer. Br J Cancer. 2009;24:874–80.CrossRef
24.
go back to reference Cleven AH, van Engeland M, Wouters BG, de Bruïne AP. Stromal expression of hypoxia regulated proteins is an adverse prognostic factor in colorectal carcinomas. Cell Oncol. 2007;29:229–40.PubMedPubMedCentral Cleven AH, van Engeland M, Wouters BG, de Bruïne AP. Stromal expression of hypoxia regulated proteins is an adverse prognostic factor in colorectal carcinomas. Cell Oncol. 2007;29:229–40.PubMedPubMedCentral
25.
go back to reference Pastorekova S, Parkkila S, Zavada J. Tumor-associated carbonic anhydrases and their clinical significance. Adv Clin Chem. 2006;42:167–216.CrossRefPubMed Pastorekova S, Parkkila S, Zavada J. Tumor-associated carbonic anhydrases and their clinical significance. Adv Clin Chem. 2006;42:167–216.CrossRefPubMed
26.
go back to reference Earnhardt JN, Qian M, Tu C, Lakkis MM, Bergenhem NC, Laipis PJ, et al. The catalytic properties of murine carbonic anhydrase VII. Biochemistry. 1998;37:10837–45.CrossRefPubMed Earnhardt JN, Qian M, Tu C, Lakkis MM, Bergenhem NC, Laipis PJ, et al. The catalytic properties of murine carbonic anhydrase VII. Biochemistry. 1998;37:10837–45.CrossRefPubMed
27.
go back to reference Bekku S, Mochizuki H, Takayama E, Shinomiya N, Fukamachi H, Ichinose M, et al. Carbonic anhydrase I and II as a differentiation marker of human and rat colonic enterocytes. Res Exp Med (Berl). 1998;198:175–85.CrossRef Bekku S, Mochizuki H, Takayama E, Shinomiya N, Fukamachi H, Ichinose M, et al. Carbonic anhydrase I and II as a differentiation marker of human and rat colonic enterocytes. Res Exp Med (Berl). 1998;198:175–85.CrossRef
28.
go back to reference Leppilampi M, Saarnio J, Karttunen TJ, Kivelä J, Pastoreková S, Pastorek J, et al. Carbonic anhydrase isozymes IX and XII in gastric tumors. World J Gastroenterol. 2003;9:1398–403.CrossRefPubMedPubMedCentral Leppilampi M, Saarnio J, Karttunen TJ, Kivelä J, Pastoreková S, Pastorek J, et al. Carbonic anhydrase isozymes IX and XII in gastric tumors. World J Gastroenterol. 2003;9:1398–403.CrossRefPubMedPubMedCentral
29.
go back to reference Del Giudice R, Monti DM, Truppo E, Arciello A, Supuran CT, De Simone G, et al. Human carbonic anhydrase VII protects cells from oxidative damage. Biol Chem. 2013;394:1343–8.PubMed Del Giudice R, Monti DM, Truppo E, Arciello A, Supuran CT, De Simone G, et al. Human carbonic anhydrase VII protects cells from oxidative damage. Biol Chem. 2013;394:1343–8.PubMed
30.
go back to reference Truppo E, Supuran CT, Sandomenico A, Vullo D, Innocenti A, Di Fiore A, et al. Carbonic anhydrase VII is S-glutathionylated without loss of catalytic activity and affinity for sulfonamide inhibitors. Bioorg Med Chem Lett. 2012;22:1560–4.CrossRefPubMed Truppo E, Supuran CT, Sandomenico A, Vullo D, Innocenti A, Di Fiore A, et al. Carbonic anhydrase VII is S-glutathionylated without loss of catalytic activity and affinity for sulfonamide inhibitors. Bioorg Med Chem Lett. 2012;22:1560–4.CrossRefPubMed
31.
go back to reference Sosa V, Moliné T, Somoza R, Paciucci R, Kondoh H, LLeonart ME. Oxidative stress and cancer: an overview. Ageing Res Rev. 2013;12:376–90.CrossRefPubMed Sosa V, Moliné T, Somoza R, Paciucci R, Kondoh H, LLeonart ME. Oxidative stress and cancer: an overview. Ageing Res Rev. 2013;12:376–90.CrossRefPubMed
32.
go back to reference Fang J, Seki T, Maeda H. Therapeutic strategies by modulating oxygen stress in cancer and inflammation. Adv Drug Deliv Rev. 2009;61:290–302.CrossRefPubMed Fang J, Seki T, Maeda H. Therapeutic strategies by modulating oxygen stress in cancer and inflammation. Adv Drug Deliv Rev. 2009;61:290–302.CrossRefPubMed
33.
go back to reference Perše M. Oxidative stress in the pathogenesis of colorectal cancer: cause or consequence? Biomed Res Int. 2013;2013:725710.PubMedPubMedCentral Perše M. Oxidative stress in the pathogenesis of colorectal cancer: cause or consequence? Biomed Res Int. 2013;2013:725710.PubMedPubMedCentral
34.
go back to reference Stone WL, Krishnan K, Campbell SE, Palau VE. The role of antioxidants and pro-oxidants in colon cancer. World J Gastrointest Oncol. 2014;6:55–66.PubMedPubMedCentral Stone WL, Krishnan K, Campbell SE, Palau VE. The role of antioxidants and pro-oxidants in colon cancer. World J Gastrointest Oncol. 2014;6:55–66.PubMedPubMedCentral
Metadata
Title
Prognostic value of carbonic anhydrase VII expression in colorectal carcinoma
Authors
Guang-Zhen Yang
Liang Hu
Jian Cai
Hai-Yang Chen
Yu Zhang
Dan Feng
Chen-Ye Qi
Yan-Xia Zhai
Hui Gong
Hao Fu
Qing-Ping Cai
Chun-Fang Gao
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1216-y

Other articles of this Issue 1/2015

BMC Cancer 1/2015 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine