Deregulated HOX Genes in Ameloblastomas Are Located in Physical Contiguity to Keratin Genes Giulia Schiavo, 1 Vincenzo D’Anto `, 2 Monica Cantile, 3 Alfredo Procino, 4 Stefano Di Giovanni, 4 Rossella Valletta, 2 Luigi Terracciano, 1 Daniel Baumhoer, 1 Gernot Jundt, 1 and Clemente Cillo 4 * 1 Institute of Pathology—Molecular Pathology Division, University of Basel, Schonbeinstrasse 40, 4031 Basel, Switzerland 2 Department of Oral and Maxillofacial Sciences, Federico II University, Naples, Italy 3 Surgical Pathology Department, National Cancer Institute ‘‘G. Pascale,’’ Naples, Italy 4 Department Clinical & Experimental Medicine Federico II University Medical School Via S. Pansini 5, 80131 Naples, Italy ABSTRACT The expression of the HOX gene network in mid-stage human tooth development mostly concerns the epithelial tooth germ compartment and involves the C and D HOX loci. To further dissect the HOX gene implication with tooth epithelium differentiation we compared the expression of the whole HOX network in human ameloblastomas, as paradigm of epithelial odontogenic tumors, with tooth germs. We identified two ameloblastoma molecular types with respectively low and high number of active HOX C genes. The highly expressing HOX C gene ameloblastomas were characterized by a strong keratinized phenotype. Locus C HOX genes are located on chromosome 12q13–15 in physical contiguity with one of the two keratin gene clusters included in the human genome. The most posterior HOX C gene, HOX C13, is capable to interact with hair keratin genes located on the other keratin gene cluster in physical contiguity with the HOX B locus on chromosome 17q21– 22. Inside the HOX C locus, a 2.2 kb ncRNA (HOTAIR) able to repress transcription, in cis, along the entire HOX C locus and, in trans, at the posterior region of the HOX D locus has recently been identified. Interestingly both loci are deregulated in ameloblastomas. Our finding support an important role of the HOX network in characterizing the epithelial tooth compartment. Furthermore, the physical contiguity between locus C HOX and keratin genes in normal tooth epithelium and their deregulation in the neoplastic counterparts suggest they may act on the same mechanism potentially involved with epithelial tumorigenesis. J. Cell. Biochem. 112: 3206–3215, 2011. ß 2011 Wiley Periodicals, Inc. KEY WORDS: HOX GENES; HOX AND AMELOBLASTOMAS; HOX AND KERATINS O dontogenic tumors of the jawbones are lesions arising from epithelial, ectomesenchymal, and/or mesenchymal tissues representing parts of the tooth-forming apparatus [Philipsen and Reichart, 2006]. Solid/multicystic ameloblastomas are epithelial and locally invasive tumors that represent the second most common tumor type of all odontogenic tumors [Jundt and Reichart, 2008]. They typically grow slowly and often recur after incomplete excision but virtually never metastasize [Gardner, 1996]. Most of the ameloblastomas develop in the posterior region of the mandible and display heterogeneous gene expression patterns compared with human tooth germs [Carinci et al., 2004; Ruhin-Poncet et al., 2009]. Ameloblastomas show two distinct histopathological patterns without clinical importance. Whereas the follicular subtype demonstrates islands of odontogenic epithelium resembling the enamel organ within a fibrous stroma, the plexiform subtype shows anastomosing strands of primarily basal cells with an inconspicuous stellate reticulum [Gardner, 1996]. The expression of different keratins (CK8, CK19, AE1/AE3) has been described in distinct Journal of Cellular Biochemistry ARTICLE Journal of Cellular Biochemistry 112:3206–3215 (2011) 3206 Potential conflict of interest: Nothing to report. Reference Register of the German-Austria-Swiss working group of tumours of the jaws (DOESAK). Grant sponsor: Oncosuisse (Krebsliga Schweiz) KLS; Grant number: 02005-02-2007; Grant sponsor: Krebsliga Beider Basel; Grant number: KLBB 06/2006; Grant sponsor: PRIN (Italy); Grant number: 2006069951_003. *Correspondence to: Clemente Cillo, Via S. Pansini 5, Naples 80131, Italy. E-mail: clecillo@unina.it Received 17 May 2011; Accepted 22 June 2011  DOI 10.1002/jcb.23248  ß 2011 Wiley Periodicals, Inc. Published online 5 July 2011 in Wiley Online Library (wileyonlinelibrary.com).