HOX D13 expression across 79 tumor tissue types

Abstract

HOX genes control normal development, primary cellular processes and are characterized by a unique genomic network organization. Locus D HOX genes play an important role in limb generation and mesenchymal condensation. Dysregulated HOXD13 expression has been detected in breast cancer, melanoma, cervical cancer and astrocytomas. We have investigated the epidemiology of HOXD13 expression in human tissues and its potential deregulation in the carcinogenesis of specific tumors. HOXD13 homeoprotein expression has been detected using microarray technology comprising more than 4,000 normal and neoplastic tissue samples including 79 different tumor categories. Validation of HOXD13 expression has been performed, at mRNA level, for selected tumor types. Significant differences are detectable between specific normal tissues and corresponding tumor types with the majority of cancers showing an increase in HOXD13 expression (16.1% normal vs. 57.7% cancers). In contrast, pancreas and stomach tumor subtypes display the opposite trend. Interestingly, detection of the HOXD13 homeoprotein in pancreas-tissue microarrays shows that its negative expression has a significant and adverse effect on the prognosis of patients with pancreatic cancer independent of the T or N stage at the time of diagnosis. Our study provides, for the first time, an overview of a HOX protein expression in a large series of normal and neoplastic tissue types, identifies pancreatic cancer as one of the most affected by the HOXD13 hoemoprotein and underlines the way homeoproteins can be associated to human cancerogenesis. ' UICCKey words: HOXD13; HOX and multitumor tissue microarray; HOXD13 and pancreas Class I Homeobox genes (Hox, mice; HOX, human) are transcription factors mostly involved in embryonic development. 1 They display an unique genomic network organization: 4 compact chromosomal loci (HOXA at 7p15.3, HOXB at 17q21.3, HOXC at 12q13.3 and HOXD at 2q31 2 ) where 39 sequence corresponding genes can be aligned with each other into 13 antero-posterior paralogous groups. The HOX gene network, the most repeat-poor regions in the human genome, 3 is also expressed in normal adult human organs. 4 HOX genes appear to regulate phenotype cell identity, 5,6 cell differentiation 7,8 and control primary cellular processes, as proven by the description of congenital, 9 somatic 10 and metabolic 11 diseases involving these genes. Furthermore, besides the already established role of the HOX network in hematopoiesis and leukemogenesis, 12 HOX genes are implicated in the neoplastic alterations of human solid tissues and organs such as kidney, colon, lung, skin, bladder, liver, breast and prostate. 13,14 New crucial functions have recently been ascribed to HOX genes and homeoproteins mostly related to their interaction with miRNAs and ncRNAs to guarantee transcription and export of specific mRNAs. 15,16 Locus D HOX genes are localized on chromosome 2q31-32 and play a role, with its posterior paralogous genes, in limb and digit generation during embryonic development 1...

Deregulation of HOX B13 Expression in Urinary Bladder Cancer Progression

“…It is very interesting to show the good overlap between the gene and protein expression of HOX B13, as previously demonstrated for other genes of the HOX network [8,13].…”

“…The posterior genes of the network, in particular those belonging to the paralogous group 13, are responsible, during normal development, of the correct formation of limbs and urogenital structures, and their alteration is often associated with tumor evolution [8,9,13,16].…”

“…There are numerous studies that associate abnormal expression of HOX genes to the development of various human cancers [12][13][14][15]. In particular it was largely investigated the role of HOX B13 in tumor progression [16][17][18][19][20].…”

Hox B4 as potential marker of non-differentiated cells in human cervical cancer cells

“…On the other hand, several reports have shown altered HOX gene expression in human cancer, suggesting that it plays an important role in cancerogenesis (Cantile et al 2009). In this context, we have previously reported the altered expression of the HOXB gene family in CC (López et al 2006a, b).…”

Spatiotemporal Proteomic Analyses during Pancreas Cancer Progression Identifies Serine/Threonine Stress Kinase 4 (STK4) as a Novel Candidate Biomarker for Early Stage Disease

“…These markers include up-regulation of claudin 18 (31), matrix metalloproteinase 7 (32), and the secreted kallikrein-related peptidase 6 (33,34), as well as markers previously reported as downregulated, including E-cadherin and the homeobox transcription factor HOXD13 (35). The panel of seven proteins whose increased expression we validated and monitored during PDA progression included some novel (DSC2, RFC4, and STK4) and some previously identified (p19ARF, FN1, BSG, and SMAD2) putative markers.…”