Identification of a Novel Homeobox-Containing Gene, LAGY, Which Is Downregulated in Lung Cancer (original) (raw)

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Research Articles| May 16 2003

Yuan Chen;

aInstitute of Pathology, University Hospital Charité, Berlin, Germany;

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Simone Petersen;

bExperimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md., USA

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Manuela Pacyna-Gengelbach;

Manuela Pacyna-Gengelbach

aInstitute of Pathology, University Hospital Charité, Berlin, Germany;

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Agnieszka Pietas;

aInstitute of Pathology, University Hospital Charité, Berlin, Germany;

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Iver Petersen

aInstitute of Pathology, University Hospital Charité, Berlin, Germany;

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Oncology (2003) 64 (4): 450–458.

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Abstract

We have isolated a novel gene, lung cancer-associated gene Y (LAGY), by suppression subtractive hybridization. The nucleotide sequence of LAGY predicts a small protein of 73 amino acids containing a putative homeobox domain with a molecular mass of 8.1 kD. Multiple-tissue Northern blot analysis revealed that LAGY is present in human placenta, lung, brain, heart and skeletal muscle. Gene mapping locates LAGY on chromosome 4q11–13.1. The expression of LAGY mRNA was widely lost in 18 lung tumor cell lines comprising all major histological types, as shown by Northern blot analysis and semiquantitative reverse transcription-polymerase chain reaction. In an investigation of 72 primary lung tumors, this gene was significantly downregulated in tumors compared to 9 normal lung tissue samples. There was a significant reduction of LAGY expression in squamous cell carcinoma (SCC; n = 27) with increasing grade and stage. No expression was detectable in two high-grade SCCs or two small cell and large cell lung carcinomas (n = 4 for each). In adenocarcinoma (n = 37), expression was reduced; however, this did not reach statistical significance. Since homeodomain-containing genes are known to transcriptionally regulate key cellular processes and are associated with carcinogenesis, we suggest that LAGY might be linked to lung cancer development and progression.

References

Girard L, Zöchbauer-Müller S, Virmani AK, Gazdar AF, Minna JD: Genome-wide allelotyping of lung cancer identifies new regions of allelic loss, differences between small cell lung cancer and non-small cell lung cancer, and loci clustering. Cancer Res 2000;60:4894–4906.

Sekido Y, Fong KM, Minna JD: Progress in understanding the molecular pathogenesis of human lung cancer. Biochim Biophys Acta 1998;1378:F21–F59.

Ried T, Petersen I, Holtgreve-Grez H, Speicher MR, Schröck E, du Manoir S, Cremer T: Mapping of multiple DNA gains and losses in primary small cell lung carcinomas by comparative genomic hybridization. Cancer Res 1994;54:1801–1806.

Levin NA, Brzoska P, Gupta N, Minna JD, Gray JW, Christman MF: Identification of frequent novel genetic alterations in small cell lung carcinoma. Cancer Res 1994;54:5086–5091.

Levin NA, Brzoska PM, Warnock ML, Gray JW, Christman MF: Identification of novel regions of altered DNA copy number in small cell lung tumors. Genes Chromosomes Cancer 1995;13:175–185.

Petersen I, Bujard M, Petersen S, Wolf G, Goeze A, Schwendel A, Langreck H, Gellert K, Reichel M, Just K, du Manoir S, Cremer T, Dietel M, Ried T: Patterns of chromosomal imbalances in adenocarcinoma and squamous cell carcinoma of the lung. Cancer Res 1997;57:2331–2335.

Petersen I, Langreck H, Wolf G, Schwendel A, Psille R, Vogt P, Reichel MB, Ried T, Dietel M: Small cell lung cancer is characterized by a high incidence of deletions on chromosomes 3p, 4q, 5q, 10q, 13q, and 17p. Br J Cancer 1997;75:79–86.

Schwendel A, Langreck H, Reichel MB, Schröck E, Ried T, Dietel M, Petersen I: Primary small cell lung carcinomas and their metastases are characterized by a recurrent pattern of genetic alterations. Int J Cancer 1997;74:86–93.

Petersen I, Petersen S: Towards a genetic-based classification of human lung cancer. Anal Cell Pathol 2001;22:111–121.

Garber ME, Troyanskaya OG, Schluens K, Petersen S, Thaesler Z, Pacyna-Gengelbach M, Riji M, Rosen GD, Perou CM, Whyte RI, Altman RB, Brown PO, Bostein D, Petersen I: Diversity of gene expression in adenocarcinoma of the lung. Proc Natl Acad Sci USA 2001;98:13784–13789.

Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, Ladd C, Beheshti J, Bueno R, Gillette M, Loda M, Weber G, Mark EJ, Lander ES, Wong W, Johnson BE, Golub TR, Sugarbaker DJ, Meyerson M: Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci USA 2001;98:13790–13795.

Petersen S, Heckert C, Rudolf J, Schlüns K, Tchernitsa OI, Schäfer R, Dietel M, Petersen I: Gene expression profiling of advanced lung cancer. Int J Cancer 2000;86:512–517.

Sambrook J, Fritsch EF, Maniatis T: Molecular Cloning. Cold Spring Harbor, Cold Spring Harbor Laboratory, 1989.

Kozak M: Mechanism of mRNA recognition by eukaryotic ribosomes during initiation of protein synthesis. Curr Top Microbiol Immunol 1981;93:81–123.

Imoto I, Pimkhaokham A, Watanabe T, Saito-Ohara F, Soeda E, Inazawa J: Amplification and overexpression of TGIF2, a novel homeobox gene of the TALE superclass, in ovarian cancer cell lines. Biochem Biophys Res Commun 2000;276:264–270.

Scott MP, Tamkun JW, Hartzell GW: The structure and function of the homeodomain. Biochim Biophys Acta 1989;989:25–48.

Mallo GV, Rechreche H, Frigerio JM, Rocha D, Zweibaum A, Lacasa M, Jordan BR, Dusetti NJ, Daghorn JC, Iovanna JL: Molecular cloning, sequencing and expression of the mRNA encoding human Cdx1 and Cdx2 homeobox. Down-regulation of Cdx1 and Cdx2 mRNA expression during colorectal carcinogenesis. Int J Cancer 1997;74:35–44.

Chawengsaksophak K, James R, Hammond VE, Kontgen F, Beck F: Homeosis and intestinal tumors in Cdx2 mutant mice. Nature 1997;386:84–87.

Raman V, Martensen SA, Reisman D, Evron E, Odenwald WF, Jaffee E, Marks J, Sukumar S: Compromised HOXA5 function can limit p53 expression in human breast tumors. Nature 2000;405:974–978.

Bowen C, Bubendorf L, Voeller HJ, Slack R, Willi N, Sauter G, Gasser TC, Koivisto P, Lack EE, Kononen J, Kallioniemi OP, Gelmann EP: Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression. Cancer Res 2000;60:6111–6115.

Costa RH, Kalinichenko VV, Lim L: Transcription factors in mouse lung development and function. Am J Physiol Lung Cell Mol Physiol 2001;280:L823–L838.

Tibero C, Barba P, Magli MC, Arvelo F, Chevalier TL, Poupon MF, Cillo C: HOX gene expression in human small-cell lung cancers xenografted into nude mice. Int J Cancer 1994;58:608–615.

Wong N, Lai P, Lee SW, Fan S, Pang E, Liew CT, Sheng Z, Lau JW, Johnson PJ: Assessment of genetic changes in hepatocellular carcinoma by comparative genomic hybridization analysis: Relationship to disease stage, tumor size, and cirrhosis. Am J Pathol 1999;154:37–43.

Koo SH, Kwon KC, Ihm CH, Jeon YM, Park JW, Sul CK: Detection of genetic alterations in bladder tumors by comparative genomic hybridization and cytogenetic analysis. Cancer Genet Cytogenet 1999;110:87–93.

Sakakura C, Hagiwara A, Taniguchi H, Yamaguchi T, Yamagishi H, Takahashi T: Chromosomal aberration in human hepatocellular carcinomas associated with hepatitis C virus infection detected by comparative genomic hybridization. Br J Cancer 1999;80:2034–2039.

Isler SG, Schenk S, Bendik I, Schraml P, Novotna H, Moch H, Sauter G, Ludwig CU: Genomic organization and chromosomal mapping of SPARC-like 1, a gene down regulated in cancer. Int J Oncol 2001;18:521–526.

Petersen S, Rudolf J, Bockmühl U, Deutschmann N, Dettel M, Petersen I: Analysis of the DMBT1 gene in carcinomas of the respiratory tract. Int J Cancer 2000;88:71–76.

Siegrist S, Féral C, Chami M, Solhonne B, Mattéi MG, Rajpert-De Meyts E, Guellaén G, Bulle F: hH-Rev107, a class II tumor suppressor gene, is expressed by post-meiotic testicular germ cells and CIS cells but not by human testicular germ cell tumors. Oncogene 2001;20:5155–5163.

Kraehn GM, Utikal J, Udart M, Greulich KM, Bezold G, Kaskel P, Leiter U, Peter RU: Extra c-myc oncogene copies in high risk cutaneous malignant melanoma and melanoma metastases. Br J Cancer 2001;84:72–79.

Calvo R, West J, Franklin W, Erickson P, Bemis L, Li E, Helfrish B, Bunn P, Roche J, Brambilla E, Rosell R, Gemmill RM, Drabkin HA: Altered HOX and WNT7A expression in human lung cancer. Proc Natl Acad Sci USA 2000;97:12776–12781.

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2003

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