High expression of carbonic anhydrase IX is significantly associated with glandular lesions in gastroesophageal junction and with tumorigenesis markers BMI1, MCM4 and MCM7

BMC Gastroenterology

Zhongren Zhou⁴  Tongtong Wu¹  David Dean³  Jun Sun²  Dongfeng Tan⁵  Aaron R. Huber⁴ 

[1] Department of Biostatistics and Computational Biology, University of Rochester, Rochester, NY, USA;Biochemistry, Rush University Medical Center, Chicago, IL, USA;Department of Pediatrics, University of Rochester, Rochester, NY, USA;Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester 14642, NY, USA;Department of Pathology, MD Anderson Cancer Institute, Houston, TX, USA

关键词: BMI1;    Gastroesophageal reflux disease;    Barrett’s esophagus;    Esophageal squamous cell carcinoma;    Esophageal adenocarcinoma;    CA9;   

Others  :  1224297
DOI  :  10.1186/s12876-015-0310-6

 received in 2015-06-15, accepted in 2015-06-29,  发布年份 2015

【 摘 要 】

Background

Carbonic anhydrase IX (CA9) is a transmembrane glycoprotein related to hypoxia. Increased CA9 expression has been associated with decreased survival and cancer progression and has been targeted as a potential therapy for several cancers, including esophageal cancer. The reported percentages of expression of CA9 in esophageal adenocarcinoma vary, and CA9 expression in precancerous esophageal lesions has not been well studied.

Methods

In this study, we investigated CA9 expression in esophageal cancers and in precancerous lesions and explored the association of CA9 expression with prognostic factors and with stem cell and tumorigenesis-related markers including BMI1, cyclin E, ki67, MCM4 and MCM7 expression. Previously constructed tissue microarrays consisting of samples of 7 tissue types (columnar cell metaplasia, Barrett esophagus, low- and high-grade dysplasia, esophageal adenocarcinoma, squamous epithelium, and squamous cell carcinoma) were used for the immunostaining of CA9, BMI1, cyclin E, Ki67, MCM4 and MCM7.

Results and discussion

CA9 high expression occurred more frequently in glandular mucosa with or without dysplasia than in squamous epithelium or squamous cell carcinoma. Survival duration of esophageal adenocarcinoma did not significantly differ between patients with high CA9 expression and those with low expression. High CA9 expression is significantly associated with BMI1, cyclin E, Ki67, MCM4 and MCM7 expression.

Conclusions

High CA9 expression may be related to the acidic environment caused by gastroesophageal reflux disease in the gastroesophageal junction and associated with tumorigenesis through BMI1, MCM4 and MCM7.

【 授权许可】

   
2015 Huber et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

【 参考文献 】

• [1]Corley DA, Kubo A, Levin TR, Block G, Habel L, Rumore G, Quesenberry C, Buffler P: Race, ethnicity, sex and temporal differences in Barrett’s oesophagus diagnosis: a large community-based study, 1994–2006. Gut 2009, 58(2):182-8.
• [2]Zhang Y: Epidemiology of esophageal cancer. World J Gastroenterol 2013, 19(34):5598-606.
• [3]Chen X, Yang CS: Esophageal adenocarcinoma: a review and perspectives on the mechanism of carcinogenesis and chemoprevention. Carcinogenesis 2001, 22(8):1119-29.
• [4]McDonald PC, Winum JY, Supuran CT, Dedhar S: Recent developments in targeting carbonic anhydrase IX for cancer therapeutics. Oncotarget 2012, 3(1):84-97.
• [5]Potter C, Harris AL: Hypoxia inducible carbonic anhydrase IX, marker of tumour hypoxia, survival pathway and therapy target. Cell Cycle 2004, 3(2):164-7.
• [6]Swietach P, Hulikova A, Vaughan-Jones RD, Harris AL: New insights into the physiological role of carbonic anhydrase IX in tumour pH regulation. Oncogene 2010, 29(50):6509-21.
• [7]Kivela AJ, Kivela J, Saarnio J, Parkkila S: Carbonic anhydrases in normal gastrointestinal tract and gastrointestinal tumours. World J Gastroenterol 2005, 11(2):155-63.
• [8]Luong-Player A, Liu H, Wang HL, Lin F: Immunohistochemical reevaluation of carbonic anhydrase IX (CA IX) expression in tumors and normal tissues. Am J Clin Pathol 2014, 141(2):219-25.
• [9]Sedlakova O, Svastova E, Takacova M, Kopacek J, Pastorek J, Pastorekova S: Carbonic anhydrase IX, a hypoxia-induced catalytic component of the pH regulating machinery in tumors. Front Physiol 2014, 4:400.
• [10]Schweiger T, Kollmann D, Nikolowsky C, Traxler D, Guenova E, Lang G, Birner P, Klepetko W, Ankersmit HJ, Hoetzenecker K: Carbonic anhydrase IX is associated with early pulmonary spreading of primary colorectal carcinoma and tobacco smoking. Eur J Cardiothorac Surg 2014, 46(1):92-9.
• [11]Tanaka N, Kato H, Inose T, Kimura H, Faried A, Sohda M, Nakajima M, Fukai Y, Miyazaki T, Masuda N, et al.: Expression of carbonic anhydrase 9, a potential intrinsic marker of hypoxia, is associated with poor prognosis in oesophageal squamous cell carcinoma. Br J Cancer 2008, 99(9):1468-75.
• [12]Driessen A, Landuyt W, Pastorekova S, Moons J, Goethals L, Haustermans K, Nafteux P, Penninckx F, Geboes K, Lerut T, et al.: Expression of carbonic anhydrase IX (CA IX), a hypoxia-related protein, rather than vascular-endothelial growth factor (VEGF), a pro-angiogenic factor, correlates with an extremely poor prognosis in esophageal and gastric adenocarcinomas. Ann Surg 2006, 243(3):334-40.
• [13]Jubb AM, Cesario A, Ferguson M, Congedo MT, Gatter KC, Lococo F, Mule A, Pezzella F: Vascular phenotypes in primary non-small cell lung carcinomas and matched brain metastases. Br J Cancer 2011, 104(12):1877-81.
• [14]Turner JR, Odze RD, Crum CP, Resnick MB: MN antigen expression in normal, preneoplastic, and neoplastic esophagus: a clinicopathological study of a new cancer-associated biomarker. Hum Pathol 1997, 28(6):740-4.
• [15]Schoppmann SF, Jesch B, Friedrich J, Jomrich G, Maroske F, Birner P: Phosphorylation of signal transducer and activator of transcription 3 (STAT3) correlates with Her-2 status, carbonic anhydrase 9 expression and prognosis in esophageal cancer. Clin Exp Metastasis 2012, 29(6):615-24.
• [16]Wichert M, Krall N: Targeting carbonic anhydrase IX with small organic ligands. Curr Opin Chem Biol 2015, 26C:48-54.
• [17]Birner P, Jesch B, Friedrich J, Riegler M, Zacherl J, Hejna M, Wrba F, Schultheis A, Schoppmann SF: Carbonic anhydrase IX overexpression is associated with diminished prognosis in esophageal cancer and correlates with Her-2 expression. Ann Surg Oncol 2011, 18(12):3330-7.
• [18]Grabmaier K, AdW MC, Verhaegh GW, Schalken JA, Oosterwijk E: Strict regulation of CAIX(G250/MN) by HIF-1alpha in clear cell renal cell carcinoma. Oncogene 2004, 23(33):5624-31.
• [19]Shareef MM, Udayakumar TS, Sinha VK, Saleem SM, Griggs WW: Interaction of HIF-1alpha and Notch3 is required for the expression of carbonic anhydrase 9 in breast carcinoma cells. Genes Cancer 2013, 4(11-12):513-23.
• [20]Ashida S, Nishimori I, Tanimura M, Onishi S, Shuin T: Effects of von Hippel-Lindau gene mutation and methylation status on expression of transmembrane carbonic anhydrases in renal cell carcinoma. J Cancer Res Clin Oncol 2002, 128(10):561-8.
• [21]Siddique HR, Saleem M: Role of BMI1, a stem cell factor, in cancer recurrence and chemoresistance: preclinical and clinical evidences. Stem Cells 2012, 30(3):372-8.
• [22]Liu PW, Lin Y, Chen XY: Expression of B-cell-specific Moloney murine leukemia virus integration site 1 mRNA and protein in gastric cancer. J Dig Dis 2014, 15(4):166-73.
• [23]Proctor E, Waghray M, Lee CJ, Heidt DG, Yalamanchili M, Li C, Bednar F, Simeone DM: Bmi1 enhances tumorigenicity and cancer stem cell function in pancreatic adenocarcinoma. PLoS One 2013, 8(2):e55820.
• [24]Zeng J, Ruan J, Luo L, Shi J, Cui Q, Yang J, Shen K: Molecular portraits of heterogeneity related to cancer stem cells in human ovarian cancer. Int J Gynecol Cancer 2014, 24(1):29-35.
• [25]Choy B, Bandla S, Xia Y, Tan D, Pennathur A, Luketich JD, Godfrey TE, Peters JH, Sun J, Zhou Z: Clinicopathologic characteristics of high expression of Bmi-1 in esophageal adenocarcinoma and squamous cell carcinoma. BMC Gastroenterol 2012, 12:146. BioMed Central Full Text
• [26]He XT, Cao XF, Ji L, Zhu B, Lv J, Wang DD, Lu PH, Cui HG: Association between Bmi1 and clinicopathological status of esophageal squamous cell carcinoma. World J Gastroenterol 2009, 15(19):2389-94.
• [27]Yamada A, Fujii S, Daiko H, Nishimura M, Chiba T, Ochiai A: Aberrant expression of EZH2 is associated with a poor outcome and P53 alteration in squamous cell carcinoma of the esophagus. Int J Oncol 2011, 38(2):345-53.
• [28]Lock FE, McDonald PC, Lou Y, Serrano I, Chafe SC, Ostlund C, Aparicio S, Winum JY, Supuran CT, Dedhar S: Targeting carbonic anhydrase IX depletes breast cancer stem cells within the hypoxic niche. Oncogene 2013, 32(44):5210-9.
• [29]Siu KT, Rosner MR, Minella AC: An integrated view of cyclin E function and regulation. Cell Cycle 2012, 11(1):57-64.
• [30]Stamatakos M, Palla V, Karaiskos I, Xiromeritis K, Alexiou I, Pateras I, Kontzoglou K: Cell cyclins: triggering elements of cancer or not? World J Surg Oncol 2010, 8:111. BioMed Central Full Text
• [31]Galimberti F, Thompson SL, Liu X, Li H, Memoli V, Green SR, DiRenzo J, Greninger P, Sharma SV, Settleman J, et al.: Targeting the cyclin E-Cdk-2 complex represses lung cancer growth by triggering anaphase catastrophe. Clin Cancer Res 2010, 16(1):109-20.
• [32]Liang Y, Gao H, Lin SY, Goss JA, Brunicardi FC, Li K: siRNA-based targeting of cyclin E overexpression inhibits breast cancer cell growth and suppresses tumor development in breast cancer mouse model. PLoS One 2010, 5(9):e12860.
• [33]Miller CT, Moy JR, Lin L, Schipper M, Normolle D, Brenner DE, Iannettoni MD, Orringer MB, Beer DG: Gene amplification in esophageal adenocarcinomas and Barrett’s with high-grade dysplasia. Clin Cancer Res 2003, 9(13):4819-25.
• [34]Zhou Z, Bandla S, Ye J, Xia Y, Que J, Luketich JD, Pennathur A, Peters JH, Tan D, Godfrey TE: Cyclin E involved in early stage carcinogenesis of esophageal adenocarcinoma by SNP DNA microarray and immunohistochemical studies. BMC Gastroenterol 2014, 14:78. BioMed Central Full Text
• [35]McDonald PC, Dedhar S: Carbonic anhydrase IX (CAIX) as a mediator of hypoxia-induced stress response in cancer cells. Subcell Biochem 2014, 75:255-69.
• [36]Frigola J, Remus D, Mehanna A, Diffley JF: ATPase-dependent quality control of DNA replication origin licensing. Nature 2013, 495(7441):339-43.
• [37]Yardimci H, Walter JC: Prereplication-complex formation: a molecular double take? Nat Struct Mol Biol 2014, 21(1):20-5.
• [38]Zhou YM, Zhang XF, Cao L, Li B, Sui CJ, Li YM, Yin ZF: MCM7 expression predicts post-operative prognosis for hepatocellular carcinoma. Liver Int 2012, 32(10):1505-9.
• [39]Alison MR, Hunt T, Forbes SJ: Minichromosome maintenance (MCM) proteins may be pre-cancer markers. Gut 2002, 50(3):290-1.
• [40]Hu Y, Bandla S, Godfrey TE, Tan D, Luketich JD, Pennathur A, Qiu X, Hicks DG, Peters JH, Zhou Z: HER2 amplification, overexpression and score criteria in esophageal adenocarcinoma. Mod Pathol 2011, 24(7):899-907.
• [41]Zavada J, Zavadova Z, Pastorekova S, Ciampor F, Pastorek J, Zelnik V: Expression of MaTu-MN protein in human tumor cultures and in clinical specimens. Int J Cancer 1993, 54(2):268-74.
• [42]Leppilampi M, Saarnio J, Karttunen TJ, Kivela J, Pastorekova S, Pastorek J, Waheed A, Sly WS, Parkkila S: Carbonic anhydrase isozymes IX and XII in gastric tumors. World J Gastroenterol 2003, 9(7):1398-403.
• [43]Ivanov S, Liao SY, Ivanova A, Danilkovitch-Miagkova A, Tarasova N, Weirich G, Merrill MJ, Proescholdt MA, Oldfield EH, Lee J, et al.: Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol 2001, 158(3):905-19.
• [44]Supuran CT: Inhibition of carbonic anhydrase IX as a novel anticancer mechanism. World J Clin Oncol 2012, 3(7):98-103.
• [45]Siebels M, Rohrmann K, Oberneder R, Stahler M, Haseke N, Beck J, Hofmann R, Kindler M, Kloepfer P, Stief C: A clinical phase I/II trial with the monoclonal antibody cG250 (RENCAREX(R)) and interferon-alpha-2a in metastatic renal cell carcinoma patients. World J Urol 2011, 29(1):121-6.
• [46]Opavsky R, Pastorekova S, Zelnik V, Gibadulinova A, Stanbridge EJ, Zavada J, Kettmann R, Pastorek J: Human MN/CA9 gene, a novel member of the carbonic anhydrase family: structure and exon to protein domain relationships. Genomics 1996, 33(3):480-7.