Abstract
Carbonic anhydrase IX (CAIX) is reportedly overexpressed in several types of carcinomas and is generally considered a marker of malignancy. The current study investigated the association between membrane expression of CAIX and the clinicopathological characteristics in oral squamous cell carcinoma (OSCC) patients. The study used immunohistochemistry to examine CAIX expression in 271 OSCC specimens by tissue microarray (TMA) and assessed the effect of CAIX overexpression and knockdown on migration of oral cancer cells in vitro. We found that CAIX expression was associated with more advanced clinical stages (p = 0.030) and positive lymph node metastasis (p = 0.026). Importantly, CAIX expression was correlated with a poorer patient prognosis in a univariate survival analysis (p = 0.025). Moreover, CAIX suppression by small interfering RNA (siRNA) significantly reduced cellular migration in OECM-1 oral cancer cell. In conclusion, our study showed that the expression of CAIX in OSCC samples can predict the progression of OSCC and survival of OSCC patients in Taiwan.
Similar content being viewed by others
References
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.
Cunderlikova B, Vasovic V, Randeberg LL, Christensen E, Warloe T, Nesland JM, Peng Q. Modification of extracorporeal photopheresis technology with porphyrin precursors. Comparison between 8-methoxypsoralen and hexaminolevulinate in killing human T-cell lymphoma cell lines in vitro. Biochim Biophys Acta. 2014
Johnson NW, Warnakulasuriya S, Gupta PC, Dimba E, Chindia M, Otoh EC, et al. Global oral health inequalities in incidence and outcomes for oral cancer: causes and solutions. Adv Dent Res. 2011;23:237–46.
Bagan J, Sarrion G, Jimenez Y. Oral cancer: clinical features. Oral Oncol. 2010;46:414–7.
Chang SW, Kareem SA, Kallarakkal TG, Merican AF, Abraham MT, Zain RB. Feature selection methods for optimizing clinicopathologic input variables in oral cancer prognosis. Asian Pac J Cancer Prev APJCP. 2011;12:2659–64.
Wu JY, Yi C, Chung HR, Wang DJ, Chang WC, Lee SY, et al. Potential biomarkers in saliva for oral squamous cell carcinoma. Oral Oncol. 2010;46:226–31.
Noguti J, De Moura CF, De Jesus GP, Da Silva VH, Hossaka TA, Oshima CT, et al. Metastasis from oral cancer: an overview. Cancer Genom Proteom. 2012;9:329–35.
Ruan K, Song G, Ouyang G. Role of hypoxia in the hallmarks of human cancer. J Cell Biochem. 2009;107:1053–62.
Pastorekova S, Zatovicova M, Pastorek J. Cancer-associated carbonic anhydrases and their inhibition. Curr Pharm Des. 2008;14:685–98.
Supuran CT. Carbonic anhydrases—an overview. Curr Pharm Des. 2008;14:603–14.
Fang JS, Gillies RD, Gatenby RA. Adaptation to hypoxia and acidosis in carcinogenesis and tumor progression. Semin Cancer Biol. 2008;18:330–7.
Beketic-Oreskovic L, Ozretic P, Rabbani ZN, Jackson IL, Sarcevic B, Levanat S, et al. Prognostic significance of carbonic anhydrase IX (CA-IX), endoglin (CD105) and 8-hydroxy-2’-deoxyguanosine (8-OHdG) in breast cancer patients. Pathol Oncol Res POR. 2011;17:593–603.
Liao SY, Aurelio ON, Jan K, Zavada J, Stanbridge EJ. Identification of the MN/CA9 protein as a reliable diagnostic biomarker of clear cell carcinoma of the kidney. Cancer Res. 1997;57:2827–31.
Korkeila E, Talvinen K, Jaakkola PM, Minn H, Syrjanen K, Sundstrom J, et al. Expression of carbonic anhydrase IX suggests poor outcome in rectal cancer. Br J Cancer. 2009;100:874–80.
Choschzick M, Oosterwijk E, Muller V, Woelber L, Simon R, Moch H, et al. Overexpression of carbonic anhydrase IX (CAIX) is an independent unfavorable prognostic marker in endometrioid ovarian cancer. Virchows Archiv Int J Pathol. 2011;459:193–200.
Birner P, Jesch B, Friedrich J, Riegler M, Zacherl J, Hejna M, et al. Carbonic anhydrase IX overexpression is associated with diminished prognosis in esophageal cancer and correlates with Her-2 expression. Ann Surg Oncol. 2011;18:3330–7.
Choschzick M, Woelber L, Hess S, zu Eulenburg C, Schwarz J, Simon R, et al. Overexpression of carbonic anhydrase IX (CAIX) in vulvar cancer is associated with tumor progression and development of locoregional lymph node metastases. Virchows Archiv Int J Pathol. 2010;456:483–90.
Woelber L, Kress K, Kersten JF, Choschzick M, Kilic E, Herwig U, et al. Carbonic anhydrase IX in tumor tissue and sera of patients with primary cervical cancer. BMC Cancer. 2011;11:12.
Hynninen P, Parkkila S, Huhtala H, Pastorekova S, Pastorek J, Waheed A, et al. Carbonic anhydrase isozymes ii, IX, and XII in uterine tumors. APMIS. 2012;120:117–29.
Klatte T, Seligson DB, Rao JY, Yu H, de Martino M, Kawaoka K, et al. Carbonic anhydrase IX in bladder cancer: a diagnostic, prognostic, and therapeutic molecular marker. Cancer. 2009;115:1448–58.
Ilie M, Mazure NM, Hofman V, Ammadi RE, Ortholan C, Bonnetaud C, et al. High levels of carbonic anhydrase IX in tumour tissue and plasma are biomarkers of poor prognostic in patients with non-small cell lung cancer. Br J Cancer. 2010;102:1627–35.
Peridis S, Pilgrim G, Athanasopoulos I, Parpounas K. Carbonic anhydrase-9 expression in head and neck cancer: a meta-analysis. European archives of oto-rhino-laryngology: official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): affiliated with the German Society for Oto-Rhino-Laryngology -. Head Neck Surg. 2011;268:661–70.
Lin SH, Lin YM, Yeh CM, Chen CJ, Chen MW, Hung HF, et al. Casein kinase 1 epsilon expression predicts poorer prognosis in low T-stage oral cancer patients. Int J Mol Sci. 2014;15:2876–91.
Yang SF, Lee WJ, Tan P, Tang CH, Hsiao M, Hsieh FK, et al. Upregulation of mir-328 and inhibition of creb-DNA-binding activity are critical for resveratrol-mediated suppression of matrix metalloproteinase-2 and subsequent metastatic ability in human osteosarcomas. Oncotarget. 2015;6:2736–53.
Dworkin S, Simkin J, Darido C, Partridge DD, Georgy SR, Caddy J, Wilanowski T, Lieschke GJ, Doggett K, Heath JK, Jane SM. Grainyhead-like 3 regulation of endothelin-1 in the pharyngeal endoderm is critical for growth and development of the craniofacial skeleton. Mech Dev. 2014
Kondo Y, Yoshikawa K, Omura Y, Shinohara A, Kazaoka Y, Sano J, et al. Clinicopathological significance of carbonic anhydrase 9, glucose transporter-1, ki-67 and p53 expression in oral squamous cell carcinoma. Oncol Rep. 2011;25:1227–33.
Patard JJ, Fergelot P, Karakiewicz PI, Klatte T, Trinh QD, Rioux-Leclercq N, et al. Low CAIX expression and absence of VHL gene mutation are associated with tumor aggressiveness and poor survival of clear cell renal cell carcinoma. Int J Cancer J Int Cancer. 2008;123:395–400.
Murakami Y, Kanda K, Tsuji M, Kanayama H, Kagawa S. MN/CA9 gene expression as a potential biomarker in renal cell carcinoma. BJU Int. 1999;83:743–7.
Soyupak B, Erdogan S, Ergin M, Seydaoglu G, Kuzgunbay B, Tansug Z. Ca9 expression as a prognostic factor in renal clear cell carcinoma. Urol Int. 2005;74:68–73.
Choi SW, Kim JY, Park JY, Cha IH, Kim J, Lee S. Expression of carbonic anhydrase IX is associated with postoperative recurrence and poor prognosis in surgically treated oral squamous cell carcinoma. Hum Pathol. 2008;39:1317–22.
Perez-Sayans M, Suarez-Penaranda JM, Pilar GD, Supuran CT, Pastorekova S, Barros-Angueira F, et al. Expression of CA-IX is associated with advanced stage tumors and poor survival in oral squamous cell carcinoma patients. J Oral Pathol Med Off Publ Int Assoc Oral Pathol Am Acad Oral Pathol. 2012;41:667–74.
Beasley NJ, Wykoff CC, Watson PH, Leek R, Turley H, Gatter K, et al. Carbonic anhydrase IX, an endogenous hypoxia marker, expression in head and neck squamous cell carcinoma and its relationship to hypoxia, necrosis, and microvessel density. Cancer Res. 2001;61:5262–7.
Shin HJ, Rho SB, Jung DC, Han IO, Oh ES, Kim JY. Carbonic anhydrase IX (CA9) modulates tumor-associated cell migration and invasion. J Cell Sci. 2011;124:1077–87.
Svastova E, Pastorekova S. Carbonic anhydrase IX: a hypoxia-controlled “catalyst” of cell migration. Cell Adhes Migr. 2013;7:226–31.
Chiche J, Ilc K, Laferriere J, Trottier E, Dayan F, Mazure NM, et al. Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular ph. Cancer Res. 2009;69:358–68.
Liao SY, Darcy KM, Randall LM, Tian C, Monk BJ, Burger RA, et al. Prognostic relevance of carbonic anhydrase-IX in high-risk, early-stage cervical cancer: a gynecologic oncology group study. Gynecol Oncol. 2010;116:452–8.
Acknowledgments
This study was supported by a research grant from the National Science Council, Taiwan (NSC96-2628-B-040-021-MY3 and NSC102-2314-B-040-008-MY3), and Chung Shan Medical University Hospital, Taiwan (CSH-2015-C-015; CSH-2015-E-001-Y2). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflicts of interest
None
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yang, JS., Lin, CW., Chuang, CY. et al. Carbonic anhydrase IX overexpression regulates the migration and progression in oral squamous cell carcinoma. Tumor Biol. 36, 9517–9524 (2015). https://doi.org/10.1007/s13277-015-3692-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-015-3692-8