Differential expression of colon cancer associated transcript1 (CCAT1) along the colonic adenoma-carcinoma sequence

BMC Cancer

Bilal Alaiyan¹  Nadia Ilyayev¹  Alexander Stojadinovic⁴  Mina Izadjoo³  Marina Roistacher¹  Vera Pavlov¹  Victoria Tzivin¹  David Halle¹  Honguang Pan³  Barry Trink⁶  Ali O Gure²  Aviram Nissan⁵ 

[1] The Surgical Oncology Laboratory, Department of Surgery, Hadassah-Hebrew University Medical Center, Mount Scopus, POB 12000, Jerusalem, 91120, Israel

[2] Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey

[3] Diagnostics and Translational Research Center Henry M Jackson Foundation for the Advancement of Military Medicine, Gaithersburg, MD, 20879, USA

[4] The Department of Surgery, Division of Surgical Oncology, Walter Reed National Medical Center, Bethesda, MD, USA

[5] Department of Surgery, Hadassah-Hebrew University Medical Center Ein Kerem, Jerusalem, Israel

[6] Johns Hopkins School of Medicine, Baltimore, MA, USA

关键词: Carcinoma;    Adenoma;    Biomarkers;    Non-coding RNA;    Colon cancer;   

Others  :  1079795
DOI  :  10.1186/1471-2407-13-196

 received in 2012-07-14, accepted in 2013-02-21,  发布年份 2013

【 摘 要 】

Background

The transition from normal epithelium to adenoma and, to invasive carcinoma in the human colon is associated with acquired molecular events taking 5-10 years for malignant transformation. We discovered CCAT1, a non-coding RNA over-expressed in colon cancer (CC), but not in normal tissues, thereby making it a potential disease-specific biomarker. We aimed to define and validate CCAT1 as a CC-specific biomarker, and to study CCAT1 expression across the adenoma-carcinoma sequence of CC tumorigenesis.

Methods

Tissue samples were obtained from patients undergoing resection for colonic adenoma(s) or carcinoma. Normal colonic tissue (n = 10), adenomatous polyps (n = 18), primary tumor tissue (n = 22), normal mucosa adjacent to primary tumor (n = 16), and lymph node(s) (n = 20), liver (n = 8), and peritoneal metastases (n = 19) were studied. RNA was extracted from all tissue samples, and CCAT1 expression was analyzed using quantitative real time-PCR (qRT-PCR) with confirmatory in-situ hybridization (ISH).

Results

Borderline expression of CCAT1 was identified in normal tissue obtained from patients with benign conditions [mean Relative Quantity (RQ) = 5.9]. Significant relative CCAT1 up-regulation was observed in adenomatous polyps (RQ = 178.6 ± 157.0; p = 0.0012); primary tumor tissue (RQ = 64.9 ± 56.9; p = 0.0048); normal mucosa adjacent to primary tumor (RQ = 17.7 ± 21.5; p = 0.09); lymph node, liver and peritoneal metastases (RQ = 11,414.5 ± 12,672.9; 119.2 ± 138.9; 816.3 ± 2,736.1; p = 0.0001, respectively). qRT-PCR results were confirmed by ISH, demonstrating significant correlation between CCAT1 up-regulation measured using these two methods.

Conclusion

CCAT1 is up-regulated across the colon adenoma-carcinoma sequence. This up-regulation is evident in pre-malignant conditions and through all disease stages, including advanced metastatic disease suggesting a role in both tumorigenesis and the metastatic process.

【 授权许可】

   
2013 Alaiyan et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ: Cancer statistics 2009. CA Cancer J Clin 2009, 59:225-249.
• [2]Edwards BK, Ward E, Kohler BA, Eheman C, Zauber AG, Anderson RN, Jemal A, Schymura MJ, Lansdorp-Vogelaar I, Seeff LC, van Ballegooijen M, Goede SL, Ries LA: Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer 2010, 116:544-573.
• [3]Edge SB: American Joint Committee on Cancer: AJCC Cancer Staging Manual. 7th edition. New York: Springer; 2010.
• [4]Barugel ME, Vargas C, Krygier Waltier G: Metastatic colorectal cancer: recent advances in its clinical management. Expert Rev Anticancer Ther 2009, 9:1829-1847.
• [5]Rousseau B, Chibaudel B, Bachet JB, Larsen AK, Tournigand C, Louvet C, André T, de Gramont A: GERCOR (french oncology research group): stage II and stage III colon cancer: treatment advances and future directions. Cancer J 2010, 16:202-209.
• [6]Zitt M, Zitt M, Muller HM: DNA methylation in colorectal cancer-impact on screening and therapy monitoring modalities? Dis Markers 2007, 23:51-71.
• [7]Potack J, Itzkowitz SH: Practical advances in stool screening for colorectal cancer. J Natl Compr Canc Netw 2010, 8:81-92.
• [8]Fernandes LC, Kim SB, Matos D: Cytokeratins and carcinoembryonic antigen in diagnosis, staging and prognosis of colorectal adenocarcinoma. World J Gastroenterol 2005, 11:645-648.
• [9]Blake KE, Dalbow MH, Concannon JP, Hodgson SE, Brodmerkel GJ Jr, Panahandeh AH, Zimmerman K, Headings JJ: Clinical significance of the preoperative plasma carcinoembryonic antigen (CEA) level in patients with carcinoma of the large bowel. Dis Colon Rectum 1982, 25:24-32.
• [10]Paganuzzi M, Onetto M, de Paoli M, Castagnola M, de Salvo L, Civalleri D, Grossi CE: Carcinoembryonic antigen (CEA) in serum and bile of colorectal cancer patients with or without detectable liver metastases. Anticancer Res 1994, 14:1409-1412.
• [11]Castaldi F, Marino M, Beneduce L, Belluco C, De Marchi F, Mammano E, Nitti D, Lise M, Fassina G: Detection of circulating CEA-IgM complexes in early stage colorectal cancer. Int J Biol Markers 2005, 20:204-208.
• [12]O’Connell MJ, Lavery I, Yothers G, Paik S, Clark-Langone KM, Lopatin M, Watson D, Baehner FL, Shak S, Baker J, Cowens JW, Wolmark N: Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J Clin Oncol 2010, 28:3937-3944.
• [13]Jubb AM, Bell SM, Quirke P: Methylation and colorectal cancer. J Pathol 2001, 195:111-134.
• [14]Schetter AJ, Leung SY, Sohn JJ, Zanetti KA, Bowman ED, Yanaihara N, Yuen ST, Chan TL, Kwong DL, Au GK, Liu CG, Calin GA, Croce CM, Harris CC: MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 2008, 299:425-436.
• [15]Ng EK, Chong WW, Jin H, Lam EK, Shin VY, Yu J, Poon TC, Ng SS, Sung JJ: Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening. Gut 2009, 58:1375-1381.
• [16]Wang YX, Zhang XY, Zhang BF, Yang CQ, Chen XM, Gao HJ: Initial study of microRNA expression profiles of colonic cancer without lymph node metastasis. J Dig Dis 2010, 11:50-54.
• [17]Huang Z, Huang D, Ni S, Peng Z, Sheng W, Du X: Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer. Int J Cancer 2010, 127:118-126.
• [18]Sandhu S, Garzon R: Potential applications of MicroRNAs in cancer diagnosis, prognosis, and treatment. Semin Oncol 2011, 38:781-787.
• [19]Shen L, Toyota M, Kondo Y, Lin E, Zhang L, Guo Y, Hernandez NS, Chen X, Ahmed S, Konishi K, Hamilton SR, Issa JP: Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proc Natl Acad Sci U S A 2007, 104:18654-18659.
• [20]Notterman DA, Alon U, Sierk AJ, Levine AJ: Transcriptional gene expression profiles of colorectal adenoma, adenocarcinoma, and normal tissue examined by oligonucleotide arrays. Cancer Res 2001, 61:3124-3130.
• [21]Sabates-Bellver J, Van der Flier LG, de Palo M, Cattaneo E, Maake C, Rehrauer H, Laczko E, Kurowski MA, Bujnicki JM, Menigatti M, Luz J, Ranalli TV, Gomes V, Pastorelli A, Faggiani R, Anti M, Jiricny J, Clevers H, Marra G: Transcriptome profile of human colorectal adenomas. Mol Cancer Res 2007, 5:1263-1275.
• [22]Cheng J, Kapranov P, Drenkow J, Dike S, Brubaker S, Patel S, Long J, Stern D, Tammana H, Helt G, Sementchenko V, Piccolboni A, Bekiranov S, Bailey DK, Ganesh M, Ghosh S, Bell I, Gerhard DS, Gingeras TR: Transcriptional maps of 10 human chromosomes at 5-nucleotide resolution. Science 2005, 308:1149-1154.
• [23]Yu JK, Chen YD, Zheng S: An integrated approach to the detection of colorectal cancer utilizing proteomics and bioinformatics. World J Gastroenterol 2004, 10:3127-3131.
• [24]Ward DG, Suggett N, Cheng Y, Wei W, Johnson H, Billingham LJ, Ismail T, Wakelam MJ, Johnson PJ, Martin A: Identification of serum biomarkers for colon cancer by proteomic analysis. Br J Cancer 2006, 94:1898-1905.
• [25]Nissan A, Stojadinovic A, Mitrani-Rosenbaum S, Halle D, Grinbaum R, Roistacher M, Bochem A, Dayanc BE, Ritter G, Gomceli I, Bostanci EB, Akoglu M, Chen YT, Old LJ, Gure AO: Colon cancer associated transcript-1: A novel RNA expressed in malignant and pre-malignant human tissues. Int J Cancer 2012, 130:1598-1606.
• [26]Zanke BW, Greenwood CMT, Rangrej J, Kustra R, Tenesa A, Farrington SM, Prendergast J, Olschwang S, Chiang T, Crowdy E, Ferretti V, Laflamme P, Sundararajan S, Roumy S, Olivier JF, Robidoux F, Sladek R, Montpetit A, Campbell P, Bezieau S, O’Shea AM, Zogopoulos G, Cotterchio M, Newcomb P, McLaughlin J, Younghusband B, Green R, Green J, Porteous ME, Campbell H: Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet 2007, 8:989-994.
• [27]Yeager M, Orr N, Hayes RB, Kraft P, Wacholder S, Minichiello MJ, Fearnhead P, Yu K, Chatterjee N, Wang Z, Welch R, Staats BJ, Calle EE, Feigelson HS, Thun MJ, Rodriguez C, Albanes D, Virtamo J, Weinstein S, Schumacher FR, Giovannucci E, Willett WC, Cancel-Tassin G, Cussenot O, Valeri A, Andriole GL, Gelmann EP, Tucker M, Gerhard DS, Fraumeni JF Jr: Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 2007, 39:645-649.
• [28]Darby IA, Hewitson TD: In Situ. Hybridization Protocols. third edition. Totowa, NJ: Humana Press; 2006. Press
• [29]Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM, Bos JL: Genetic alterations during colorectal-tumor development. N Engl J Med 1988, 319:525-532.
• [30]Kim MS, Lee J, Sidransky D: DNA methylation markers in colorectal cancer. Cancer Metastasis Rev 2010, 29:181-206.
• [31]Ratto C, Sofo L, Ippoliti M, Merico M, Bossola M, Vecchio FM, Doglietto GB, Crucitti F: Accurate lymph-node detection in colorectal specimens resected for cancer is of prognostic importance. Dis Colon Rectum 1999, 142:143-157.
• [32]Broll R, Schauer V, Schimmelpenning H, Strik M, Woltmann A, Best R, Bruch HP, Duchrow M: Prognostic relevance of occult tumor cells in lymph nodes of colorectal carcinomas: an immunohistochemical study. Dis Colon Rectum 1997, 140:1465-1470.
• [33]Bilchik A, Nissan A, Wainberg Z, Shen P, McCarter M, Protic M, Howard R, Elashoff D, Tyler J, Peoples GE, Stojadinovic A: Surgical quality and nodal ultrastaging is associated with long-term disease-free survival in early colorectal cancer: an analysis of 2 international multicenter prospective trials. Ann Surg 2010, 252:467-474.
• [34]Stojadinovic A, Nissan A, Protic M, Adair CF, Prus D, Usaj S, Howard RS, Radovanovic D, Breberina M, Shriver CD, Grinbaum R, Nelson JM, Brown TA, Freund HR, Potter JF, Peretz T, Peoples GE: Prospective randomized study comparing sentinel lymph node evaluation with standard pathologic evaluation for the staging of colon carcinoma: results from the united states military cancer institute clinical trials group study GI-01. Ann Surg 2007, 245:846-857.
• [35]Ariel I, Ayesh S, Perlman EJ, Pizov G, Tanos V, Schneider T, Erdmann VA, Podeh D, Komitowski D, Quasem AS, de Groot N, Hochberg A: The product of the imprinted H19 gene is an oncofetal RNA. Mol Pathol 1997, 50:34-44.
• [36]Fellig Y, Ariel I, Ohana P, Schachter P, Sinelnikov I, Birman T, Ayesh S, Schneider T, de Groot N, Czerniak A, Hochberg A: H19 expression in hepatic metastases from a range of human carcinomas. J Clin Pathol 2005, 58:1064-1068.
• [37]Stein U, Walther W, Arlt F, Schwabe H, Smith J, Fichtner I, Birchmeier W, Schlag PM: MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis. Nat Med 2009, 15:59-67.
• [38]Stein U, Burock S, Herrmann P, Wendler I, Niederstrasser M, Wernecke KD, Schlag PM: Circulating MACC1 transcripts in colorectal cancer patient plasma predict metastasis and prognosis. PLoS One 2012, 7:e49249.
• [39]Boardman LA: Overexpression of MACC1 leads to downstream activation of HGF/MET and potentiates metastasis and recurrence of colorectal cancer. Genome Med 2009, 1:36. BioMed Central Full Text
• [40]Herszényi L, Farinati F, Cardin R, István G, Molnár LD, Hritz I, De Paoli M, Plebani M, Tulassay Z: Tumor marker utility and prognostic relevance of Cathepsin B, Cathepsin L, urokinase-type plasminogen activator, plasminogen activator inhibitor type-1, CEA and CA 19-9 in colorectal cancer. BMC Cancer 2008, 8:194. BioMed Central Full Text
• [41]Sturgeon CM, Duffy MJ, Hofmann BR, Lamerz R, Fritsche HA, Gaarenstroom K, Bonfrer J, Ecke TH, Grossman HB, Hayes P, Hoffmann RT, Lerner SP, Löhe F, Louhimo J, Sawczuk I, Taketa K, Diamandis EP: National academy of clinical biochemistry: national academy of clinical biochemistry laboratory medicine practice guidelines for use of tumor markers in liver, bladder, cervical, and gastric cancers. Clin Chem 2010, 56:e1-e48.