Gene Summary

Gene:HOXD11; homeobox D11
Aliases: HOX4, HOX4F
Summary:This gene belongs to the homeobox family of genes. The homeobox genes encode a highly conserved family of transcription factors that play an important role in morphogenesis in all multicellular organisms. Mammals possess four similar homeobox gene clusters, HOXA, HOXB, HOXC and HOXD, located on different chromosomes, consisting of 9 to 11 genes arranged in tandem. This gene is one of several homeobox HOXD genes located in a cluster on chromosome 2. Deletions that remove the entire HOXD gene cluster or the 5' end of this cluster have been associated with severe limb and genital abnormalities. The product of the mouse Hoxd11 gene plays a role in forelimb morphogenesis. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:homeobox protein Hox-D11
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: HOXD11 (cancer-related)

Xu W, Lu J, Zhao Q, et al.
Genome-Wide Plasma Cell-Free DNA Methylation Profiling Identifies Potential Biomarkers for Lung Cancer.
Dis Markers. 2019; 2019:4108474 [PubMed] Free Access to Full Article Related Publications
As a noninvasive blood testing, the detection of cell-free DNA (cfDNA) methylation in plasma has raised an increasing interest due to diagnostic applications. Although extensively used in cfDNA methylation analysis, bisulfite sequencing is less cost-effective. In this study, we investigated the cfDNA methylation patterns in lung cancer patients by MeDIP-seq. Compared with the healthy individuals, 330 differentially methylated regions (DMRs) at gene promoters were identified in lung cancer patients with 33 hypermethylated and 297 hypomethylated regions, respectively. Moreover, these hypermethylated genes were validated with the publicly available DNA methylation data, yielding a set of ten significant differentially methylated genes in lung cancer, including

Harada H, Miyamaoto K, Kimura M, et al.
Lung cancer risk stratification using methylation profile in the oral epithelium.
Asian Cardiovasc Thorac Ann. 2019; 27(2):87-92 [PubMed] Related Publications
BACKGROUND: Assuming that the entire airway is affected by the same inhaled carcinogen, similar molecular alterations may occur in the lung and oral cavity. Thus, we hypothesized that DNA methylation profiles in the oral epithelium may be a promising biomarker for lung cancer risk stratification.
METHODS: A methylation-specific polymerase chain reaction was performed on oral epithelium from 16 patients with lung cancer and 32 controls without lung cancer. Genes showing aberrant methylation profiles in the oral epithelium were compared between patients and controls.
RESULTS: The analysis revealed that HOXD11 and PCDHGB6 were methylated more frequently in patients than in controls ( p = 0.0055 and p = 0.0247, respectively). Combined analyses indicated that 8 of 16 (50%) patients and 3 of 32 (9.4%) controls showed DNA methylation in both genes ( p = 0.0016). Among the population limited to current and former smokers, 6 of 11 (54.5%) patients showed methylation in both genes, compared to 1 of 17 (5.9%) controls ( p = 0.0037). In a subgroup analysis limited to the population above 50-years old, 8 of 16 (50%) patients and 2 of 16 (12.5%) controls showed methylation in both genes ( p = 0.0221).
CONCLUSIONS: The results of this study indicate that specific gene methylation in the oral epithelium might be a promising biomarker for lung cancer risk assessment, especially among smokers. Risk stratification through the analysis of DNA methylation profiles in the oral epithelium may be a useful and less invasive first-step approach in an efficient two-step lung cancer screening strategy.

Hayano T, Matsui H, Nakaoka H, et al.
Germline Variants of Prostate Cancer in Japanese Families.
PLoS One. 2016; 11(10):e0164233 [PubMed] Free Access to Full Article Related Publications
Prostate cancer (PC) is the second most common cancer in men. Family history is the major risk factor for PC. Only two susceptibility genes were identified in PC, BRCA2 and HOXB13. A comprehensive search of germline variants for patients with PC has not been reported in Japanese families. In this study, we conducted exome sequencing followed by Sanger sequencing to explore responsible germline variants in 140 Japanese patients with PC from 66 families. In addition to known susceptibility genes, BRCA2 and HOXB13, we identified TRRAP variants in a mutually exclusive manner in seven large PC families (three or four patients per family). We also found shared variants of BRCA2, HOXB13, and TRRAP from 59 additional small PC families (two patients per family). We identified two deleterious HOXB13 variants (F127C and G132E). Further exploration of the shared variants in rest of the families revealed deleterious variants of the so-called cancer genes (ATP1A1, BRIP1, FANCA, FGFR3, FLT3, HOXD11, MUTYH, PDGFRA, SMARCA4, and TCF3). The germline variant profile provides a new insight to clarify the genetic etiology and heterogeneity of PC among Japanese men.

de Barros E Lima Bueno R, Ramão A, Pinheiro DG, et al.
HOX genes: potential candidates for the progression of laryngeal squamous cell carcinoma.
Tumour Biol. 2016; 37(11):15087-15096 [PubMed] Related Publications
Laryngeal squamous cell carcinoma (LSCC) is a very aggressive cancer, considered to be a subtype of the head and neck squamous cell carcinoma (HNSCC). Despite significant advances in the understanding and treatment of cancer, prognosis of patients with LSCC has not improved recently. In the present study, we sought to understand better the genetic mechanisms underlying LSCC development. Thirty-two tumor samples were collected from patients undergoing surgical resection of LSCC. The samples were submitted to whole-genome cDNA microarray analysis aiming to identify genetic targets in LSCC. We also employed bioinformatic approaches to expand our findings using the TCGA database and further performed functional assays, using human HNSCC cell lines, to evaluate viability, cell proliferation, and cell migration after silencing of selected genes. Eight members of the homeobox gene family (HOX) were identified to be overexpressed in LSCC samples when compared to normal larynx tissue. Quantitative RT-PCR analysis validated the overexpression of HOX gene family members in LSCC. Receiver operating characteristic (ROC) statistical method curve showed that the expression level of seven members of HOX gene family can distinguish tumor from nontumor tissue. Correlation analysis of clinical and gene expression data revealed that HOXC8 and HOXD11 genes were associated with the differentiation degree of tumors and regional lymph node metastases, respectively. Additionally, siRNA assays confirmed that HOXC8, HOXD10, and HOXD11 genes might be critical for cell colony proliferation and cell migration. According to our findings, several members of the HOX genes were overexpressed in LSCC samples and seem to be required in biological processes involved in tumor development. This suggests that HOX genes might play a critical role in the physiopathology of LSCC tumors.

Knight JM, Kim E, Ivanov I, et al.
Comprehensive site-specific whole genome profiling of stromal and epithelial colonic gene signatures in human sigmoid colon and rectal tissue.
Physiol Genomics. 2016; 48(9):651-9 [PubMed] Free Access to Full Article Related Publications
The strength of associations between various exposures (e.g., diet, tobacco, chemopreventive agents) and colorectal cancer risk may partially depend on the complex interaction between epithelium and stroma across anatomic subsites. Currently, baseline data describing genome-wide coding and long noncoding gene expression profiles in the healthy colon specific to tissue type and location are lacking. Therefore, colonic mucosal biopsies from 10 healthy participants who were enrolled in a clinical study to evaluate effects of lignan supplementation on gut resiliency were used to characterize the site-specific global gene expression signatures associated with stromal vs. epithelial cells in the sigmoid colon and rectum. Using RNA-seq, we demonstrate that tissue type and location patterns of gene expression and upstream regulatory pathways are distinct. For example, consistent with a key role of stroma in the crypt niche, mRNAs associated with immunoregulatory and inflammatory processes (i.e., CXCL14, ANTXR1), smooth muscle contraction (CALD1), proliferation and apoptosis (GLP2R, IGFBP3), and modulation of extracellular matrix (MMP2, COL3A1, MFAP4) were all highly expressed in the stroma. In comparison, HOX genes (HOXA3, HOXD9, HOXD10, HOXD11, and HOXD-AS2, a HOXD cluster antisense RNA 2), and WNT5B expression were also significantly higher in sigmoid colon compared with the rectum. These findings provide strong impetus for considering colorectal tissue subtypes and location in future observational studies and clinical trials designed to evaluate the effects of exposures on colonic health.

von Heyking K, Roth L, Ertl M, et al.
The posterior HOXD locus: Its contribution to phenotype and malignancy of Ewing sarcoma.
Oncotarget. 2016; 7(27):41767-41780 [PubMed] Free Access to Full Article Related Publications
Microarray analysis revealed genes of the posterior HOXD locus normally involved in bone formation to be over-expressed in primary Ewing sarcoma (ES). The expression of posterior HOXD genes was not influenced via ES pathognomonic EWS/ETS translocations. However, knock down of the dickkopf WNT signaling pathway inhibitor 2 (DKK2) resulted in a significant suppression of HOXD10, HOXD11 and HOXD13 while over-expression of DKK2 and stimulation with factors of the WNT signaling pathway such as WNT3a, WNT5a or WNT11 increased their expression. RNA interference demonstrated that individual HOXD genes promoted chondrogenic differentiation potential, and enhanced expression of the bone-associated gene RUNX2. Furthermore, HOXD genes increased the level of the osteoblast- and osteoclast-specific genes, osteocalcin (BGLAP) and platelet-derived growth factor beta polypeptide (PDGFB), and may further regulate endochondral bone development via induction of parathyroid hormone-like hormone (PTHLH). Additionally, HOXD11 and HOXD13 promoted contact independent growth of ES, while in vitro invasiveness of ES lines was enhanced by all 3 HOXD genes investigated and seemed mediated via matrix metallopeptidase 1 (MMP1). Consequently, knock down of HOXD11 or HOXD13 significantly suppressed lung metastasis in a xeno-transplant model in immune deficient mice, providing overall evidence that posterior HOXD genes promote clonogenicity and metastatic potential of ES.

Mehrian-Shai R, Yalon M, Moshe I, et al.
Identification of genomic aberrations in hemangioblastoma by droplet digital PCR and SNP microarray highlights novel candidate genes and pathways for pathogenesis.
BMC Genomics. 2016; 17:56 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The genetic mechanisms underlying hemangioblastoma development are still largely unknown. We used high-resolution single nucleotide polymorphism microarrays and droplet digital PCR analysis to detect copy number variations (CNVs) in total of 45 hemangioblastoma tumors.
RESULTS: We identified 94 CNVs with a median of 18 CNVs per sample. The most frequently gained regions were on chromosomes 1 (p36.32) and 7 (p11.2). These regions contain the EGFR and PRDM16 genes. Recurrent losses were located at chromosome 12 (q24.13), which includes the gene PTPN11.
CONCLUSIONS: Our findings provide the first high-resolution genome-wide view of chromosomal changes in hemangioblastoma and identify 23 candidate genes: EGFR, PRDM16, PTPN11, HOXD11, HOXD13, FLT3, PTCH, FGFR1, FOXP1, GPC3, HOXC13, HOXC11, MKL1, CHEK2, IRF4, GPHN, IKZF1, RB1, HOXA9, and micro RNA, such as hsa-mir-196a-2 for hemangioblastoma pathogenesis. Furthermore, our data implicate that cell proliferation and angiogenesis promoting pathways may be involved in the molecular pathogenesis of hemangioblastoma.

Svoboda LK, Harris A, Bailey NJ, et al.
Overexpression of HOX genes is prevalent in Ewing sarcoma and is associated with altered epigenetic regulation of developmental transcription programs.
Epigenetics. 2014; 9(12):1613-25 [PubMed] Free Access to Full Article Related Publications
The polycomb proteins BMI-1 and EZH2 are highly overexpressed by Ewing sarcoma (ES), a tumor of stem cell origin that is driven by EWS-ETS fusion oncogenes, most commonly EWS-FLI1. In the current study we analyzed expression of transcription programs that are controlled by polycomb proteins during embryonic development to determine if they are abnormal in ES. Our results show that polycomb target gene expression in ES deviates from normal tissues and stem cells and that, as expected, most targets are relatively repressed. However, we also discovered a paradoxical up regulation of numerous polycomb targets and these were highly enriched for homeobox (HOX) genes. Comparison of HOX profiles between malignant and non-malignant tissues revealed a distinctive HOX profile in ES, which was characterized by overexpression of posterior HOXD genes. In addition, ectopic expression of EWS-FLI1 during stem cell differentiation led to aberrant up regulation of posterior HOXD genes. Mechanistically, this up regulation was associated with altered epigenetic regulation. Specifically, ES and EWS-FLI1+ stem cells displayed a relative loss of polycomb-dependent H3K27me3 and gain of trithorax-dependent H3K4me3 at the promoters of posterior HOXD genes and also at the HOXD11.12 polycomb response element. In addition, a striking correlation was evident between HOXD13 and other genes whose regulation is coordinately regulated during embryonic development by distal enhancer elements. Together, these studies demonstrate that epigenetic regulation of polycomb target genes, in particular HOXD genes, is altered in ES and that these changes are mediated downstream of EWS-FLI1.

Sharpe DJ, Orr KS, Moran M, et al.
POU2F1 activity regulates HOXD10 and HOXD11 promoting a proliferative and invasive phenotype in head and neck cancer.
Oncotarget. 2014; 5(18):8803-15 [PubMed] Free Access to Full Article Related Publications
HOX genes are master regulators of organ morphogenesis and cell differentiation during embryonic development, and continue to be expressed throughout post-natal life. To test the hypothesis that HOX genes are dysregulated in head and neck squamous cell carcinoma (HNSCC) we defined their expression profile, and investigated the function, transcriptional regulation and clinical relevance of a subset of highly expressed HOXD genes. Two HOXD genes, D10 and D11, showed strikingly high levels in HNSCC cell lines, patient tumor samples and publicly available datasets. Knockdown of HOXD10 in HNSCC cells caused decreased proliferation and invasion, whereas knockdown of HOXD11 reduced only invasion. POU2F1 consensus sequences were identified in the 5' DNA of HOXD10 and D11. Knockdown of POU2F1 significantly reduced expression of HOXD10 and D11 and inhibited HNSCC proliferation. Luciferase reporter constructs of the HOXD10 and D11 promoters confirmed that POU2F1 consensus binding sites are required for optimal promoter activity. Utilizing patient tumor samples a significant association was found between immunohistochemical staining of HOXD10 and both the overall and the disease-specific survival, adding further support that HOXD10 is dysregulated in head and neck cancer. Additional studies are now warranted to fully evaluate HOXD10 as a prognostic tool in head and neck cancers.

Zha Y, Ding E, Yang L, et al.
Functional dissection of HOXD cluster genes in regulation of neuroblastoma cell proliferation and differentiation.
PLoS One. 2012; 7(8):e40728 [PubMed] Free Access to Full Article Related Publications
Retinoic acid (RA) can induce growth arrest and neuronal differentiation of neuroblastoma cells and has been used in clinic for treatment of neuroblastoma. It has been reported that RA induces the expression of several HOXD genes in human neuroblastoma cell lines, but their roles in RA action are largely unknown. The HOXD cluster contains nine genes (HOXD1, HOXD3, HOXD4, and HOXD8-13) that are positioned sequentially from 3' to 5', with HOXD1 at the 3' end and HOXD13 the 5' end. Here we show that all HOXD genes are induced by RA in the human neuroblastoma BE(2)-C cells, with the genes located at the 3' end being activated generally earlier than those positioned more 5' within the cluster. Individual induction of HOXD8, HOXD9, HOXD10 or HOXD12 is sufficient to induce both growth arrest and neuronal differentiation, which is associated with downregulation of cell cycle-promoting genes and upregulation of neuronal differentiation genes. However, induction of other HOXD genes either has no effect (HOXD1) or has partial effects (HOXD3, HOXD4, HOXD11 and HOXD13) on BE(2)-C cell proliferation or differentiation. We further show that knockdown of HOXD8 expression, but not that of HOXD9 expression, significantly inhibits the differentiation-inducing activity of RA. HOXD8 directly activates the transcription of HOXC9, a key effector of RA action in neuroblastoma cells. These findings highlight the distinct functions of HOXD genes in RA induction of neuroblastoma cell differentiation.

Rodini CO, Xavier FC, Paiva KB, et al.
Homeobox gene expression profile indicates HOXA5 as a candidate prognostic marker in oral squamous cell carcinoma.
Int J Oncol. 2012; 40(4):1180-8 [PubMed] Free Access to Full Article Related Publications
The search for molecular markers to improve diagnosis, individualize treatment and predict behavior of tumors has been the focus of several studies. This study aimed to analyze homeobox gene expression profile in oral squamous cell carcinoma (OSCC) as well as to investigate whether some of these genes are relevant molecular markers of prognosis and/or tumor aggressiveness. Homeobox gene expression levels were assessed by microarrays and qRT-PCR in OSCC tissues and adjacent non-cancerous matched tissues (margin), as well as in OSCC cell lines. Analysis of microarray data revealed the expression of 147 homeobox genes, including one set of six at least 2-fold up-regulated, and another set of 34 at least 2-fold down-regulated homeobox genes in OSCC. After qRT-PCR assays, the three most up-regulated homeobox genes (HOXA5, HOXD10 and HOXD11) revealed higher and statistically significant expression levels in OSCC samples when compared to margins. Patients presenting lower expression of HOXA5 had poorer prognosis compared to those with higher expression (P=0.03). Additionally, the status of HOXA5, HOXD10 and HOXD11 expression levels in OSCC cell lines also showed a significant up-regulation when compared to normal oral keratinocytes. Results confirm the presence of three significantly upregulated (>4-fold) homeobox genes (HOXA5, HOXD10 and HOXD11) in OSCC that may play a significant role in the pathogenesis of these tumors. Moreover, since lower levels of HOXA5 predict poor prognosis, this gene may be a novel candidate for development of therapeutic strategies in OSCC.

Morgan R, Plowright L, Harrington KJ, et al.
Targeting HOX and PBX transcription factors in ovarian cancer.
BMC Cancer. 2010; 10:89 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ovarian cancer still has a relatively poor prognosis due to the frequent occurrence of drug resistance, making the identification of new therapeutic targets an important goal. We have studied the role of HOX genes in the survival and proliferation of ovarian cancer cells. These are a family of homeodomain-containing transcription factors that determine cell and tissue identity in the early embryo, and have an anti-apoptotic role in a number of malignancies including lung and renal cancer.
METHODS: We used QPCR to determine HOX gene expression in normal ovary and in the ovarian cancer cell lines SK-OV3 and OV-90. We used a short peptide, HXR9, to disrupt the formation of HOX/PBX dimers and alter transcriptional regulation by HOX proteins.
RESULTS: In this study we show that the ovarian cancer derived line SK-OV3, but not OV-90, exhibits highly dysregulated expression of members of the HOX gene family. Disrupting the interaction between HOX proteins and their co-factor PBX induces apoptosis in SK-OV3 cells and retards tumour growth in vivo.
CONCLUSION: HOX/PBX binding is a potential target in ovarian cancer.

Rossi Degl'Innocenti D, Castiglione F, Buccoliero AM, et al.
Quantitative expression of the homeobox and integrin genes in human gastric carcinoma.
Int J Mol Med. 2007; 20(4):621-9 [PubMed] Related Publications
The homeobox (HOX) genes are a large family of regulator genes involved in the control of developmental processes and cell differentiation. The HOX genes encode transcription factors, and an increasing number of studies have shown that these genes may be implicated in the growth and the progression of many types of tumours. The present study investigated the expression of the HOX and integrin genes and their relationships in gastric carcinoma. We analyzed the RNA expression of 13 HOX genes from HOXA, C and D clusters and alphaV, alpha5 and alpha8 integrin genes in 24 gastric cancer samples by quantitative real-time PCR. The results showed that the HOXA2 gene and the alpha8 integrin gene had a lower expression in tumour samples than in normal gastric mucosas. The comparison between the HOX and integrin genes showed that HOXA2 and alphaV integrin expression presented the same trend in 83% of the samples. Moreover, in cancer samples that expressed the HOXD11 gene, the expression of alphaV integrin was lower with respect to normal mucosas. The different roles of HOX and integrin genes in gastric carcinoma remain to be fully elucidated. These findings suggest that the HOX genes may play a critical role in the genesis, maintenance and diffusion of gastric carcinoma.

Cai LY, Abe M, Izumi S, et al.
Identification of PRTFDC1 silencing and aberrant promoter methylation of GPR150, ITGA8 and HOXD11 in ovarian cancers.
Life Sci. 2007; 80(16):1458-65 [PubMed] Related Publications
Methylated promoter CpG islands (CGIs) can be used to find novel tumor-suppressor genes and disease markers. In this study, to identify promoter CGIs aberrantly methylated in human ovarian cancers, we performed a genome-wide screening for differentially methylated DNA fragments using methylation-sensitive-representational difference analysis (MS-RDA). MS-RDA isolated 185 DNA fragments specifically methylated in an ovarian cancer cell line (ES-2), compared with a normal human ovarian surface epithelial cell line (HOSE6-3), and 33 of them were derived from putative promoter CGIs. Ten ovarian cancer cell lines were analyzed by methylation-specific PCR, and seven (GPR150, LOC222171, PRTFDC1, LOC339210, ITGA8, C9orf64 and HOXD11) of the 33 CGIs were methylated in one or more of the cell lines. Their downstream genes were barely expressed in cell lines without unmethylated DNA molecules by quantitative reverse-transcription-PCR. Demethylation of methylated cell lines with 5-aza-2'-deoxycytidine restored expression of two genes (PRTFDC1 and C9orf64). In primary ovarian cancers, CGIs of GPR150 (in 4 of 15 cancers), ITGA8 (2/15), PRTFDC1 (1/15), and HOXD11 (1/15) were methylated. Silencing of PRTFDC1 was revealed here for the first time, and aberrant methylation of GPR150, ITGA8 and HOXD11 could be candidate tumor markers.

Furuta J, Nobeyama Y, Umebayashi Y, et al.
Silencing of Peroxiredoxin 2 and aberrant methylation of 33 CpG islands in putative promoter regions in human malignant melanomas.
Cancer Res. 2006; 66(12):6080-6 [PubMed] Related Publications
Aberrant methylation of promoter CpG islands (CGI) is involved in silencing of tumor suppressor genes and is also a potential cancer biomarker. Here, to identify CGIs aberrantly methylated in human melanomas, we did a genome-wide search using methylation-sensitive representational difference analysis. CGIs in putative promoter regions of 34 genes (ABHD9, BARHL1, CLIC5, CNNM1, COL2A1, CPT1C, DDIT4L, DERL3, DHRS3, DPYS, EFEMP2, FAM62C, FAM78A, FLJ33790, GBX2, GPR10, GPRASP1, HOXA9, HOXD11, HOXD12, HOXD13, p14ARF, PAX6, PRDX2, PTPRG, RASD1, RAX, REC8L1, SLC27A3, TGFB2, TLX2, TMEM22, TMEM30B, and UNC5C) were found to be methylated in at least 1 of 13 melanoma cell lines but not in two cultured normal melanocytes. Among these genes, Peroxiredoxin 2 (PRDX2) was expressed in normal melanocytes, and its expression was lost in melanomas with methylation. The loss of expression was restored by treatment of melanomas with a demethylating agent 5-aza-2'-deoxycytidine. In surgical melanoma specimens, methylation of PRDX2 was detected in 3 of 36 (8%). Furthermore, immunohistochemical analysis of PRDX2 showed that disappearance of immunoreactivity tends to associate with its methylation. PRDX2 was recently reported to be a negative regulator of platelet-derived growth factor signaling, and its silencing was suggested to be involved in melanomas. On the other hand, 12 CGIs were methylated in >or=9 of the 13 melanoma cell lines and are considered as candidate melanoma biomarkers.

Yamashita T, Tazawa S, Yawei Z, et al.
Suppression of invasive characteristics by antisense introduction of overexpressed HOX genes in ovarian cancer cells.
Int J Oncol. 2006; 28(4):931-8 [PubMed] Related Publications
HOX genes encode transcription factors that function to establish basic body pattern during embryogenesis and maintain the function of specific organs in the adult. Recent studies have demonstrated that HOX genes are also involved in oncogenesis in a range of malignancies. To elucidate whether HOX genes contribute to ovarian carcinogenesis, we created an expression profile of HOX genes using ovarian derived materials from surgical samples and epithelial ovarian cancer cells derived from five different cell lines. Real-time quantitative RT-PCR assay indicated overexpression of 14 HOX genes in clusters A and B but only 2 genes in clusters C and D. Of the 16 HOX genes, overexpression of paralogs of HOX3, HOX4 and HOX7 is seen in cluster A and B, and of HOX13 in all paralogs. In addition, HOXB7, HOXA13 and HOXB13 showed high levels of overexpression in cancer cells and tissues whereas no or little expression was observed in normal controls. To examine whether overexpressed HOX genes regulate invasion of ovarian cancer cells directly, we introduced an antisense DNA fragment of overexpressed HOXB7 and HOXB13, and HOXC5 that did not show overexpression into SKOV3 cells by electroporation. Antisense introduction followed by chemoinvasion assay using matrigel chamber demonstrated that SKOV3 cells introduced an antisense of each HOXB7 and HOXB13 showed 85% and 50% reduction of invasion ability compared to the parental SKOV3 cells, respectively. In contrast, antisense of HOXC5 introduced cells showed no significant difference of the invasion ability. These results suggest an important role of overexpressed HOX genes, especially for invasive characteristics of ovarian cancer cells.

Miyamoto K, Fukutomi T, Akashi-Tanaka S, et al.
Identification of 20 genes aberrantly methylated in human breast cancers.
Int J Cancer. 2005; 116(3):407-14 [PubMed] Related Publications
Aberrant methylation of CpG islands (CGI) not only plays a role in gene silencing, but is also a potential cancer biomarker. To identify more CGI aberrantly methylated in human breast cancers, we carried out a genome-wide search for aberrant methylation, using methylation-sensitive-representational difference analysis. CGI in 5' upstream regions of 20 genes, TSPAN-2, AK5, LOC284999, HOXD11, FLJ25161, XT3, PCDH10, PCDHGB6, SIM1, LOC346978, COE2, TDH (FLJ25033), LOC346419, FLJ33790, GJB2, AMN, LOC201164, DLX4, DCC and FOXA2, were found to be methylated in at least one of 8 breast cancer cell lines. Fifteen of the 20 genes were methylated in more than one of 21 primary breast cancers in Stages I or II, and especially, those of LOC346978, HOXD11, SIM1, PCDHGB6 and FLJ25161 were methylated in more than 10 cancers. All the breast cancers had some aberrant methylation. Among the 13 genes whose CGI were completely methylated in one or more cell lines, FOXA2 and XT3 were expressed in normal human mammary epithelial cells (HMEC) and were not expressed in cancer cell lines with complete methylation. The other 11 genes examined were barely expressed, or not expressed even in HMEC. Our results showed that breast cancer cells accumulate aberrant methylation of the CGI identified here. This may serve as markers for early-stage breast cancers and suggests that aberrant methylation targets transcriptionally inactive genes in vivo.

Terui K, Kitazawa J, Takahashi Y, et al.
Successful treatment of acute myelomonocytic leukaemia with NUP98-HOXD11 fusion transcripts and monitoring of minimal residual disease.
Br J Haematol. 2003; 120(2):274-6 [PubMed] Related Publications
Patients with haematological malignancies involving the NUP98 gene have been reported to have an aggressive clinical course and a poor outcome. We report successful treatment of a 15-year-old Japanese boy with acute myelomonocytic leukaemia having t(2;11)(q31;p15) and a novel fusion transcript, NUP98-HOXD11. He achieved complete remission by combined chemotherapy, and underwent unrelated cord blood transplantation 4 months after diagnosis. He is in complete remission 24 months after diagnosis. Monitoring of minimal residual disease (MRD) showed the absence of fusion transcript 12 months after transplantation. This is the first report of monitoring MRD in a patient with haematological malignancy involving NUP98 fusion transcripts.

Panagopoulos I, Isaksson M, Billström R, et al.
Fusion of the NUP98 gene and the homeobox gene HOXC13 in acute myeloid leukemia with t(11;12)(p15;q13).
Genes Chromosomes Cancer. 2003; 36(1):107-12 [PubMed] Related Publications
The NUP98 gene at 11p15 is known to be fused to DDX10, HOXA9, HOXA11, HOXA13, HOXD11, HOXD13, LEDGF, NSD1, NSD3, PMX1, RAP1GDS1, and TOP1 in various hematologic malignancies. The common theme in all NUP98 chimeras is a transcript consisting of the 5' part of NUP98 and the 3' portion of the partner gene; however, apart from the frequent fusion to different homeobox genes, there is no apparent similarity among the other partners. We here report a de novo acute myeloid leukemia with a t(11;12)(p15;q13), resulting in a novel NUP98/HOXC13 fusion. Fluorescence in situ hybridization analyses, by the use of probes covering NUP98 and the HOXC gene cluster at 12q13, revealed a fusion signal at the der(11)t(11;12), indicating a NUP98/HOXC chimera, whereas no fusion was found on the der(12)t(11;12), suggesting that the translocation was accompanied by a deletion of the reciprocal fusion gene. Reverse transcription-PCR and sequence analyses showed that exon 16 (nucleotide 2290) of NUP98 was fused in-frame with exon 2 (nucleotide 852) of HOXC13. Neither the HOXC13/NUP98 transcript nor the normal HOXC13 was expressed. The present results, together with previous studies of NUP98/homeobox gene fusions, strongly indicate that NUP98/HOXC13 is of pathogenetic importance in t(11;12)-positive acute myeloid leukemia.

Taketani T, Taki T, Shibuya N, et al.
The HOXD11 gene is fused to the NUP98 gene in acute myeloid leukemia with t(2;11)(q31;p15).
Cancer Res. 2002; 62(1):33-7 [PubMed] Related Publications
The nucleoporin gene, NUP98, has been reported to be fused to seven partner genes in hematological malignancies with 11p15 translocations. We report here a novel NUP98 partner gene, HOXD11, not HOXD13, in a pediatric patient with de novo AML having t(2;11)(q31;p15), using a cDNA panhandle PCR. The HOXD11 gene is one of the HOXD cluster genes and contains 2 exons, encoding a protein of 338 amino acids with a homeodomain. Reverse transcription (RT)-PCR analysis showed that two alternatively spliced 5'-NUP98 transcripts were fused in frame to the HOXD11 gene. Both proteins consist of an NH(2)-terminal phenylalanine-glycine repeat motif of NUP98 and COOH-terminal homeodomain of HOXD11. RT-PCR analysis in various leukemic cell lines showed that expression of the HOXD11 gene was significantly more frequent in BCR-ABL-positive than in BCR-ABL-negative leukemic cell lines (P = 0.028). Our results revealed that t(2;11)(q31;p15) was not a single chromosomal abnormality and that the NUP98-HOXD fusion genes encode similar fusion proteins, which suggests that the NUP98-HOXD11 as well as NUP98-HOXD13 fusion protein play a role in leukemogenesis through similar mechanisms.

Meazza R, Faiella A, Corsetti MT, et al.
Expression of HOXC4 homeoprotein in the nucleus of activated human lymphocytes.
Blood. 1995; 85(8):2084-90 [PubMed] Related Publications
We have analyzed the expression of homeoproteins of the HOX family in resting and activated lymphoid cells and in neoplastic lymphoid cell lines by the use of monoclonal antibodies (MoAbs) already shown to react with the homeoproteins HOXA10, HOXC6, and HOXD4, respectively. Anti-HOXA10 and C6 MoAbs DIDi not show any reactivity with the lymphoid cells tested, whereas anti-HOXD4 MoAb stained few resting peripheral blood lymphocytes (PBLs) and most phytohemagglutinin (PHA)-stimulated PBLs as early as 6 hours after stimulation. The pattern of staining of PHA-activated PBLs is reminiscent of the stages of nucleolar fragmentation in different phases of the cell cycle. The MoAb reacted also with activated or Epstein-Barr virus-transformed B cells, with clonal or polyclonal T and natural killer (NK) cells, with leukemic T-cell lines, and with a Burkitt's lymphoma cell line. RNAse protection experiments, per formed with probes specific for HOXD4 or for the highly homologous HOXA4, HOXB4, and HOXC4, belonging to the same paralogy group, indicated that only HOXC4 mRNA is present in resting or activated PBLs. Northern blot analysis on polyA+ RNA from activated PBLs or Raji cells showed the presence of two different HOXC4 transcripts of 2.8 and 1.9 kb. Gel retardation and Southwestern blot assays showed the presence of a 32-kD homeoprotein with DNA-binding properties typical of a HOX4 homeoprotein in nucleolar extracts of PHA-activated, but not of resting, lymphocytes. Taken together, these data indicate that the HOXC4 homeoprotein is expressed in activated and/or proliferating lymphocytes of the T-, B-, or NK-cell lineage, whereas it is weakly expressed in a minority of resting cells. The early expression and the nucleolar localization suggest an involvement of HOXC4 in the regulation of genes controlling lymphocyte activation and/or proliferation.

Magli MC, Barba P, Celetti A, et al.
Coordinate regulation of HOX genes in human hematopoietic cells.
Proc Natl Acad Sci U S A. 1991; 88(14):6348-52 [PubMed] Free Access to Full Article Related Publications
Hematopoiesis is a continuous process in which precursor cells proliferate and differentiate throughout life. However, the molecular mechanisms that govern this process are not clearly defined. Homeobox-containing genes, encoding DNA-binding homeodomains, are a network of genes highly conserved throughout evolution. They are organized in clusters expressed in the developing embryo with a positional hierarchy. We have analyzed expression of the four human HOX loci in erythroleukemic, promyelocytic, and monocytic cell lines to investigate whether the physical organization of human HOX genes reflects a regulatory hierarchy involved in the differentiation process of hematopoietic cells. Our results demonstrate that cells representing various stages of hematopoietic differentiation display differential patterns of HOX gene expression and that HOX genes are coordinately switched on or off in blocks that may include entire loci. The entire HOX4 locus is silent in all lines analyzed and almost all the HOX2 genes are active in erythroleukemic cells and turned off in myeloid-restricted cells. Our observations provide information about the regulation of HOX genes and suggest that the coordinate regulation of these genes may play an important role in lineage determination during early steps of hematopoiesis.

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