HOXA13

Gene Summary

Gene:HOXA13; homeobox A13
Aliases: HOX1, HOX1J
Location:7p15.2
Summary:In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. Expansion of a polyalanine tract in the encoded protein can cause hand-foot-uterus syndrome, also known as hand-foot-genital syndrome. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, GeneCard, Gene
Protein:homeobox protein Hox-A13
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: HOXA13 (cancer-related)

Ma RL, Shen LY, Chen KN
Coexpression of ANXA2, SOD2 and HOXA13 predicts poor prognosis of esophageal squamous cell carcinoma.
Oncol Rep. 2014; 31(5):2157-64 [PubMed] Related Publications
Esophageal squamous cell carcinoma (ESCC) is the main type of esophageal cancer, and is the sixth leading cause of cancer-related mortality among all types of cancers. Previously, we found that the homeobox A13 gene (HOXA13) plays a crucial role in the carcinogenesis of ESCC and both Annexin A2 (ANXA2) and superoxide dismutase 2 (SOD2) were its potential targets. Samples from 258 patients from two independent cohorts were collected. RT-qPCR and immunohistochemistry (IHC) were used to detect the expression levels of HOXA13, ANXA2 and SOD2. Kaplan‑Meier survival curve analysis and Cox proportional hazards regression model were employed to determine their prognostic significance. Results showed that ESCC tissues had higher ANXA2 and SOD2 mRNA and protein levels than the non-cancerous tissues. ANXA2 and SOD2 were found to be positively correlated with HOXA13 expression not only at the mRNA level but also at the protein level. In both the study cohort and the validation cohort, the median overall survival time of patients with high expression of HOXA13, ANXA2 and SOD2 was shorter than the survival time of the patients with low expression. The Cox proportional hazards model revealed that both TNM stage and coexpression of HOXA13/ANXA2/SOD2 are independent predictors of overall survival of ESCC patients. In conclusion, the present study demonstrated that ANXA2 and SOD2 are potential target genes of HOXA13 and their coexpression predicts the poor prognosis of ESCC patients.

Quagliata L, Matter MS, Piscuoglio S, et al.
Long noncoding RNA HOTTIP/HOXA13 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients.
Hepatology. 2014; 59(3):911-23 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
UNLABELLED: Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death. Despite the advances in diagnosis and management of HCC, the biology of this tumor remains poorly understood. Recent evidence highlighted long noncoding RNAs (lncRNAs) as crucial determinants of HCC development. In this study we report the lncRNA HOXA transcript at the distal tip (HOTTIP) as significantly up-regulated in HCC specimens. The HOTTIP gene is located in physical contiguity with HOXA13 and directly controls the HOXA locus gene expression by way of interaction with the WDR5/MLL complex. HOX genes encode transcription factors regulating embryonic development and cell fate. We previously described HOX genes deregulation to be involved in hepatocarcinogenesis. Indeed, we observed the marked up-regulation of HOXA13 in HCC. Here, by correlating clinicopathological and expression data, we demonstrate that the levels of HOTTIP and HOXA13 are associated with HCC patients' clinical progression and predict disease outcome. In contrast to the majority of similar studies, our data were obtained from snap-frozen needle HCC biopsies (n=52) matched with their nonneoplastic counterparts collected from patients who had not yet received any HCC-tailored therapeutic treatments at the time of biopsy. In addition, taking advantage of gain and loss of function experiments in liver cancer-derived cell lines (HuH-6 and HuH-7), we uncover a novel bidirectional regulatory loop between HOTTIP/HOXA13.
CONCLUSION: Our study highlights the key role of HOTTIP and HOXA13 in HCC development by associating their expression with metastasis and survival in HCC patients, provides novel insights on the function of lncRNA-driven hepatocarcinogenesis, and paves the way for further investigation about the possible role of HOTTIP as a predictive biomarker of HCC.

Kang JU
Characterization of amplification patterns and target genes on the short arm of chromosome 7 in early-stage lung adenocarcinoma.
Mol Med Rep. 2013; 8(5):1373-8 [PubMed] Related Publications
Chromosomal alterations are a predominant genomic force contributing to the development of lung adenocarcinoma (ADC). High density genomic arrays were conducted to identify critical genetic landmarks that may be important mediators in the formation or progression of early‑stage ADC. In this study, the most noteworthy and consistent observation was a copy number gain on the short arm of chromosome 7, which was detected in 85.7% (12/14) of cases. Notably, three distinct regions of amplification were identified between the 7p22.3 and q11.2 regions in 28.6% (4/14) of cases; at a size of 4.1 Mbp (7p22.3‑p21.1), 2.6 Mbp (7p15.2-p14.1) and 1.5 Mbp (7p12.3‑p11.2). Variations of the 7p11.2 locus that encodes EGFR are known to be oncogenic. Furthermore, potential target genes were identified that were previously not assumed to be involved in the pathogenesis of ADC, including CALM1P2 (7p11.2), HOXA4, HOXA5, HOXA6, HOXA7, HOXA9, HOXA10, HOXA11 and HOXA13 (7p15.2) and LOC442586, LOC442589, LOC442282, FAM20C and LOC442651 (7p22.3). The present study determined critical regions on the 7p arm of chromosome 7, which were implicated in ADC. The pattern of rearrangements on the 7p arm may be a consequence of the high density of potential targets and the identified genes at the 7p regions may aid in the development of therapeutic targets for ADC.

Shiba N, Ichikawa H, Taki T, et al.
NUP98-NSD1 gene fusion and its related gene expression signature are strongly associated with a poor prognosis in pediatric acute myeloid leukemia.
Genes Chromosomes Cancer. 2013; 52(7):683-93 [PubMed] Related Publications
The cryptic t(5;11)(q35;p15.5) creates a fusion gene between the NUP98 and NSD1 genes. To ascertain the significance of this gene fusion, we explored its frequency, clinical impact, and gene expression pattern using DNA microarray in pediatric acute myeloid leukemia (AML) patients. NUP98-NSD1 fusion transcripts were detected in 6 (4.8%) of 124 pediatric AML patients. Supervised hierarchical clustering analyses using probe sets that were differentially expressed in these patients detected a characteristic gene expression pattern, including 18 NUP98-NSD1-negative patients (NUP98-NSD1-like patients). In total, a NUP98-NSD1-related gene expression signature (NUP98-NSD1 signature) was found in 19% (24/124) and in 58% (15/26) of cytogenetically normal cases. Their 4-year overall survival (OS) and event-free survival (EFS) were poor (33.3% in NUP98-NSD1-positive and 38.9% in NUP98-NSD1-like patients) compared with 100 NUP98-NSD1 signature-negative patients (4-year OS: 86.0%, 4-year EFS: 72.0%). Interestingly, t(7;11)(p15;p15)/NUP98-HOXA13, t(6;11)(q27;q23)/MLL-MLLT4 and t(6;9)(p22;q34)/DEK-NUP214, which are known as poor prognostic markers, were found in NUP98-NSD1-like patients. Furthermore, another type of NUP98-NSD1 fusion transcript was identified by additional RT-PCR analyses using other primers in a NUP98-NSD1-like patient, revealing the significance of this signature to detect NUP98-NSD1 gene fusions and to identify a new poor prognostic subgroup in AML.

Han Y, Tu WW, Wen YG, et al.
Identification and validation that up-expression of HOXA13 is a novel independent prognostic marker of a worse outcome in gastric cancer based on immunohistochemistry.
Med Oncol. 2013; 30(2):564 [PubMed] Related Publications
Homeobox (HOX) gene family is known to be classic examples of the intimate relationship between embryogenesis and tumorigenesis. However, less is known about the involvement of HOX gene family with gastric cancerogenesis. Here, we screened the expression of HOX gene family in gastric cancers and explored the relationships between them by cDNA microarray. We found several differentially expressed HOX genes in gastric cancers, especially HOXA10 (11/12) and HOXA13 (11/12) with significantly higher expression in the cancerous tissues. Furthermore, we validated HOXA13 as a novel prognostic marker in gastric cancer based on immunohistochemistry and statistical analysis. HOXA13 expression was significantly up-regulated in cancerous tissues compared with the corresponding non-cancerous mucosa (P < 0.001). Up-expression of HOXA13 was significantly correlated with T stage (P = 0.002), M stage (P = 0.024), advanced UICC stage (P < 0.001), histological differentiation (P = 0.005), and relapse (P = 0.001). Patients with positive HOXA13 expression had a obviously lower overall survival (OS) and disease-free survival (DFS) rate than patients with negative HOXA13 expression (HR 3.331, 95 % CI 1.722-6.442, P < 0.001; HR 3.289, 95 % CI 1.703-6.351, P < 0.001, respectively). Univariate and multivariate Cox analysis confirmed that HOXA13 could serve as a significant independent prognostic factor for DFS and OS. Therefore, our results indicated that several HOX genes might be closely involved in the process of the gastric tumorigenesis. Furthermore, up-expression of HOXA13 might be associated with highly aggressive phenotype of gastric cancer. HOXA13 was a significant independent prognostic factor and could serve as a putative biomarker for diagnosis and prognosis of gastric cancer.

Halldórsdóttir AM, Kanduri M, Marincevic M, et al.
Mantle cell lymphoma displays a homogenous methylation profile: a comparative analysis with chronic lymphocytic leukemia.
Am J Hematol. 2012; 87(4):361-7 [PubMed] Related Publications
Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are mature CD5(+) B-cell malignancies with different biological/clinical characteristics. We recently reported an association between different prognostic subgroups of CLL (i.e., IGHV mutated and unmutated) and genomic methylation pattern. However, the relationship between DNA methylation and prognostic markers, such as the proliferation gene expression signature, has not been investigated in MCL. We applied high-resolution methylation microarrays (27,578 CpG sites) to assess the global DNA methylation profiles in 20 MCL (10 each with high/low proliferation signature) and 30 CLL (15 poor-prognostic IGHV unmutated subset #1 and 15 good-prognostic IGHV mutated subset #4) samples. Notably, MCL and each CLL subset displayed distinct genomic methylation profiles. After unsupervised hierarchical clustering, 17/20 MCL cases formed a cluster separate from CLL, while CLL subsets #1 and #4 formed subclusters. Surprisingly, few differentially methylated genes (n = 6) were identified between high vs. low proliferation MCL. In contrast, distinct methylation profiles were demonstrated for MCL and CLL. Importantly, certain functional classes of genes were preferentially methylated in either disease. For instance, developmental genes, in particular homeobox transcription factor genes (e.g., HLXB9, HOXA13), were more highly methylated in MCL, whereas apoptosis-related genes were enriched among targets methylated in CLL (e.g., CYFIP2, NR4A1). Results were validated using pyrosequencing, RQ-PCR and reexpression of specific genes. In summary, the methylation profile of MCL was homogeneous and no correlation with the proliferation signature was observed. Compared to CLL, however, marked differences were discovered such as the preferential methylation of homeobox genes in MCL.

Greenblatt S, Li L, Slape C, et al.
Knock-in of a FLT3/ITD mutation cooperates with a NUP98-HOXD13 fusion to generate acute myeloid leukemia in a mouse model.
Blood. 2012; 119(12):2883-94 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Constitutive activation of FLT3 by internal tandem duplication (ITD) is one of the most common molecular alterations in acute myeloid leukemia (AML). FLT3/ITD mutations have also been observed in myelodysplastic syndrome patients both before and during progression to AML. Previous work has shown that insertion of an FLT3/ITD mutation into the murine Flt3 gene induces a myeloproliferative neoplasm, but not progression to acute leukemia, suggesting that additional cooperating events are required. We therefore combined the FLT3/ITD mutation with a model of myelodysplastic syndrome involving transgenic expression of the Nup98-HoxD13 (NHD13) fusion gene. Mice expressing both the FLT3/ITD and NHD13 transgene developed AML with 100% penetrance and short latency. These leukemias were driven by mutant FLT3 expression and were susceptible to treatment with FLT3 tyrosine kinase inhibitors. We also observed a spontaneous loss of the wild-type Flt3 allele in these AMLs, further modeling the loss of the heterozygosity phenomenon that is seen in human AML with FLT3-activating mutations. Because resistance to FLT3 inhibitors remains an important clinical issue, this model may help identify new molecular targets in collaborative signaling pathways.

Shen LY, Chen KN
Exploration of target genes of HOXA13 in esophageal squamous cell carcinoma cell line.
Cancer Lett. 2011; 312(1):18-23 [PubMed] Related Publications
Homeobox genes encode transcriptional factors which regulate cell proliferation and differentiation and have been found to be deregulated in many tumors. Previously, we found that the median survival time of patients with ESCC (Esophageal squamous cell carcinoma) expressing HOXA13 was significantly shorter than those with HOXA13-negative ESCC and we also demonstrated that knockdown of HOXA13 blocked cell proliferation in vitro and in vivo. In this study, we examined the protein expression changes after HOXA13 knockdown by 2-dimentional electrophoresis. Forty-five spots were significantly different, among which 24 were down-regulated and 21 were up-regulated after HOXA13 knockdown. The proteins from 14 gel-spots were further characterized by MALDI-TOF MS, among which, AnnexinA2, MnSOD and ERAB, are validated by Western Blot analysis. Transcriptional target analysis revealed that HOXA13 regulated several cell signaling pathways that are critically involved in cell proliferation, survival and migration. These results provide an additional support to a hypothesis that HOXA13 might participate in the carcinogenesis of ESCC.

Cillo C, Schiavo G, Cantile M, et al.
The HOX gene network in hepatocellular carcinoma.
Int J Cancer. 2011; 129(11):2577-87 [PubMed] Related Publications
Liver organogenesis and cancerogenesis share common mechanisms. HOX genes control normal development, primary cellular processes and are characterized by a unique genomic network organization. Less is known about the involvement of HOX genes with liver cancerogenesis. The comparison of the HOX gene network expression between nontumorous livers and hepatocellular carcinomas (HCCs) highlights significant differences in the locus A HOX genes, located on chromosome 7, with a consistent overexpression of HOXA13 mRNA thus validating this gene deregulation as a feature of HCC. HOXA13 is a determinant of gut primordia and posterior body structures. Transcriptome analysis of HCC/nontumorous liver mRNAs, selected on the basis of HOXA13 overexpression, recognizes a set of deregulated genes. The matching of these genes with previously reported HCC transcriptome analysis identifies cell-cycle and nuclear pore-related HCC phenotype displaying poor prognosis. HOXA13 and HOXA7 homeoproteins share a consensus sequence that physically links eIF4E nuclear bodies acting on the export of specific mRNAs (c-myc, FGF-2, vascular endothelial growth factor (VEGF), ornithine decarboxylase (ODC) and cyclin D1). We report the protein-protein interaction between HOXA13 and eIF4E in liver cancer cells and the deregulation of eIF4E mRNA and protein in cell cycle/nuclear pore HCC group phenotype and in T4 stage HCCs, respectively. Thus, transcriptional and post-transcriptional HOXA13 deregulation is involved in HCC possibly through the mRNA nuclear export of eIF4E-dependent transcripts.

Starkova J, Zamostna B, Mejstrikova E, et al.
HOX gene expression in phenotypic and genotypic subgroups and low HOXA gene expression as an adverse prognostic factor in pediatric ALL.
Pediatr Blood Cancer. 2010; 55(6):1072-82 [PubMed] Related Publications
BACKGROUND: HOX genes play an important role in both normal lymphopoiesis and leukemogenesis. However, HOX expression patterns in leukemia cells compared to normal lymphoid progenitors have not been systematically studied in acute lymphoblastic leukemia (ALL) subtypes.
PROCEDURE: The RNA expression levels of HOXA, HOXB, and CDX1/2 genes were analyzed by qRT-PCR in a cohort of 61 diagnostic pediatric ALL samples and FACS-sorted subpopulations of normal lymphoid progenitors.
RESULTS: The RNA expression of HOXA7-10, HOXA13, and HOXB2-4 genes was exclusively detected in leukemic cells and immature progenitors. The RNA expression of HOXB6 and CDX2 genes was exclusively detected in leukemic cells but not in B-lineage cells at any of the studied developmental stages. HOXA3-4, HOXA7, and HOXB3-4 genes were differentially expressed between BCP-ALL and T-ALL subgroups, and among genotypically defined MLL/AF4, TEL/AML1, BCR/ABL, hyperdiploid and normal karyotype subgroups. However, this differential expression did not define specific clusters in hierarchical cluster analysis. HOXA7 gene was low expressed at the RNA level in patients with hyperdiploid leukemia, whereas HOXB7 and CDX2 genes were low expressed in TEL/AML1-positive and BCR/ABL-positive cases, respectively. In contrast to previous findings in acute myeloid leukemia, high HOXA RNA expression was associated with an excellent prognosis in Cox's regression model (P = 0.03). In MLL/AF4-positive ALL, lower HOXA RNA expression correlated with the methylation status of their promoters.
CONCLUSIONS: HOX gene RNA expression cannot discriminate leukemia subgroups or relative maturity of leukemic cells. However, HOXA RNA expression correlates with prognosis, and particular HOX genes are expressed in specific genotypically characterized subgroups.

Bach C, Buhl S, Mueller D, et al.
Leukemogenic transformation by HOXA cluster genes.
Blood. 2010; 115(14):2910-8 [PubMed] Related Publications
HOX homeobox genes are important regulators of normal and malignant hematopoiesis. Abdominal-type HOXA genes like HOXA9 are highly leukemogenic. However, little is known about transformation by anterior HOXA genes. Here we performed a comprehensive assessment of the oncogenic potential of every HOXA gene in primary hematopoietic cells. With exception of HOXA2 and HOXA5, all HOXA genes caused a block or delay of hematopoietic differentiation and cooperated with Meis1. No evidence for the alleged tumor-suppressor function of HOXA5 could be found. Whereas all active HOXA genes immortalized mixed granulocytic/monocytic populations, HOXA13 preferentially specified monocytoid development. The anterior HOXA genes HOXA1, HOXA4, and HOXA6 transformed cells, generating permanent cell lines, although they did so less potently than HOXA9. Upon transplantation these lines induced myeloproliferation and acute myeloid leukemia in recipient animals. Kinetic studies with inducible HOX derivatives demonstrated that anterior HOXA genes autonomously contributed to cellular transformation. This function was not mediated by endogenous Hoxa9, which was persistently expressed in cells transformed by anterior HOX genes. In summary our results demonstrate a hitherto unexpected role of anterior HOXA genes in hematopoietic malignancy.

Falaschi A, Abdurashidova G, Biamonti G
DNA replication, development and cancer: a homeotic connection?
Crit Rev Biochem Mol Biol. 2010; 45(1):14-22 [PubMed] Related Publications
The homeotic proteins are transcription factors, highly conserved in metazoan organisms, exerting a pivotal role in development and differentiation. They individually display a loose specificity for the DNA sequence they can bind, but operate mainly in multi-molecular associations that assure their target and function specificity. Homeotic proteins are known to play a role in the positive or negative regulation of cell proliferation. Furthermore, many homeotic proteins are actually proto-oncogenes, since different translocations involving their genes cause tumors, particularly in the hematopoietic system. A one-hybrid screen to detect proteins with affinity for the lamin B2 replication origin identified three homeotic proteins, namely HoxA13, HoxC10 and HoxC13. Recent data demonstrate that the HoxC13 oncoprotein specifically associates with replication foci and binds in vitro and in vivo to several human DNA replication origins. Moreover, Hox proteins interact with geminin, a regulator of cell cycle progression, and control the interaction of this protein with the DNA replication licensing factor Ctd1. Thus, the homeotic proteins, by participating directly in the function of DNA replication origins, may provide a direct link between the accurate regulation of DNA replication required by the morphogenetic program and the deregulation of this process typical of cancer.

Gu ZD, Shen LY, Wang H, et al.
HOXA13 promotes cancer cell growth and predicts poor survival of patients with esophageal squamous cell carcinoma.
Cancer Res. 2009; 69(12):4969-73 [PubMed] Related Publications
Homeobox genes are known to be classic examples of the intimate relationship between embryogenesis and tumorigenesis. Here, we investigated whether inhibition of HOXA13, a member of the homeobox genes, was sufficient to affect the proliferation of esophageal cancer cells in vitro and in vivo, and studied the association between HOXA13 expression and survival of patients with esophageal squamous cell carcinoma (ESCC). HOXA13 expression was permanently knocked down using an RNA interference technique, and cell strain with stable knockdown of HOXA13 protein was established. Colony formation assay showed that the number of colonies in HOXA13 protein-deficient cells was significantly less than that of control cells (P < 0.01). Tumor growth in nude mice showed that the weight and volume of tumors from the HOXA13 knockdown cells was significantly less than that from the control cells (P < 0.01). Then, HOXA13 expression in ESCC specimens and paired noncancerous mucosa was detected by immunohistochemistry, and overexpression of HOXA13 was found to be more pronounced in ESCCs than paired noncancerous mucosa (P < 0.05). Furthermore, the association of HOXA13 expression and disease-free survival time was analyzed in 155 ESCC cases. The median survival time of patients expressing HOXA13 was significantly shorter than HOXA13-negative patients (P = 0.0006). Multivariate analysis indicated that tumor-node-metastasis (TNM) stage and HOXA13 expression were independent predictors of disease-free survival time of patients with ESCC. Our results showed that HOXA13 expression enhanced tumor growth in vitro and in vivo, and was a negative independent predictor of disease-free survival of patients with ESCC.

Yang YC, Wang SW, Wu IC, et al.
A tumorigenic homeobox (HOX) gene expressing human gastric cell line derived from putative gastric stem cell.
Eur J Gastroenterol Hepatol. 2009; 21(9):1016-23 [PubMed] Related Publications
GOAL: Study the mechanism of gastric tumor development.
BACKGROUND: We have generated and characterized a novel human gastric cell line, KMU-CS12 (CS12), from an immortal cell line, KMU-CSN (CSN; formerly named as GI2CS) which was derived from putative human gastric stem cell/progenitor cell clone, KMU-GI2.
STUDY: The characterization of the CS12 cell line includes gene expression by immunocytochemical staining, cell proliferation and differentiation potential, cyotogenetic analysis by Giemsa banding and spectral karyotype analysis (SKY), and tumorigenicity in immune-deficient congenic inbred, nude mice (BALB/cAnN-Foxn1nu/CrlNarl). The Agilent Human 1A oligo-array and RT-PCR were also employed to analyze the expression of homeobox (HOX) genes.
RESULTS: The CS12 gastric cell line showed cancer cell phenotypes, i.e. the ability of anchorage-independent growth high frequency (44%) and to the expression of Oct-4, a transcription factor expressed in embryonic stem cells and many types of cancer cells, and tumor development in immune deficient mice. SKY analysis indicated a characteristic duplication of the short arm of chromosome 7 to chromosome 12. Agilent Human 1A oligo-array analysis showed that the expression of 1145 genes was upregulated while that of 890 genes was downregulated in CS12 cells. RT-PCR revealed that homeobox genes (HOXA4, HOXA5, HOXA7, HOXA9, and HOXA13) were highly expressed in CS12 cells in culture, as well as tumor tissues developed by CS12 cells in immunodeficient mice for six to eight weeks.
CONCLUSION: Except for the duplication of the short arm of Chromosome 7 on Chromosome12, the karyotype of the tumorigenic CS12 cells is similar to the parental GI2 cells which are non-tumorigenic and normal in karyotype. This chromosomal change could be the cause for the high expression of HOXA genes and tumorigenicity of these cells found in this study. Thus HOXA genes might play an important role in gastric carcinogenesis.

Holyoake A, O'Sullivan P, Pollock R, et al.
Development of a multiplex RNA urine test for the detection and stratification of transitional cell carcinoma of the bladder.
Clin Cancer Res. 2008; 14(3):742-9 [PubMed] Related Publications
PURPOSE: New markers that enable the percentage of transitional cell carcinomas (TCC) of the bladder that are diagnosed before invasion of the bladder muscle layers to be increased would reduce the morbidity and mortality associated with this disease. The purpose of this study was to develop a simple, accurate urine test based on mRNA markers and simple gene signatures that (a) could detect TCC before muscle invasion while maintaining high specificity in patients with hematuria or urinary tract infections and (b) identify patients most likely to have grade 3 or stage > or =T1 disease.
EXPERIMENTAL DESIGN: RNA markers with high overexpression in stage Ta tumors and/or T1 to T4 tumors but low expression in blood or inflammatory cells were characterized by quantitative reverse transcription-PCR using 2 mL of voided urine from 75 TCC patients and 77 control patients with other urological diseases.
RESULTS: A combination of the RNAs CDC2, MDK, IGFBP5, and HOXA13 detected 48%, 90%, and 100% of stage Ta, T1, and >T1 TCCs, respectively, at a specificity of 85%. Detection of Ta tumors increased to 60% for primary (non-recurrent) Ta tumors and 76% for Ta tumors > or =1 cm in diameter. Test specificity was 80% for the 20 control patients with urinary tract infections. The combination of CDC2 and HOXA13 distinguished between grade 1 to 2 TCCs and grade 3 or stage > or =T1 TCCs with approximately 80% specificity and sensitivity.
CONCLUSIONS: Simple gene expression signatures can be used as urine markers for the accurate detection and characterization of bladder cancer.

Hidaka E, Tanaka M, Matsuda K, et al.
A complex karyotype, including a three-way translocation generating a NUP98-HOXD13 transcript, in an infant with acute myeloid leukemia.
Cancer Genet Cytogenet. 2007; 176(2):137-43 [PubMed] Related Publications
We report the case of an infant with acute myeloblastic leukemia who had the abnormal karyotype 46,XX,t(2;11;9)(q31;p15;q22),t(6;11;15)(q21;q23;q22),t(8;10)(q13;q22). At relapse, a different three-way translocation emerged. Fluorescence in situ hybridization and a reverse transcription-polymerase chain reaction assay detected the NUP98-HOXD13 fusion gene in bone marrow cells of the patient at diagnosis and at relapse. Sequence analysis showed that exon 12 of NUP98 was fused in-frame with exon 2 of HOXD13. The patient had neither a rearrangement of the MLL gene nor aberrations for FLT3, KIT, NRAS, KRAS, or PTPN11. The NUP98-HOXD13 fusion transcript created by t(2;11;9)(q31;p15;q22) may play an important role in the leukemogenesis in this case.

Su X, Drabkin H, Clappier E, et al.
Transforming potential of the T-cell acute lymphoblastic leukemia-associated homeobox genes HOXA13, TLX1, and TLX3.
Genes Chromosomes Cancer. 2006; 45(9):846-55 [PubMed] Related Publications
The importance of HOXA genes in T-cell acute lymphoblastic leukemia (T-ALL) has recently been recognized. We report a novel chromosomal translocation in a T-ALL patient that maps upstream of the HOXA13 gene and downstream of the BCL11B/CTIP2 locus. Analysis of HOXA gene transcription demonstrated massive expression of HOXA13, whereas the other HOXA genes were unaffected. A genomic rearrangement of the HOXA locus associated with exclusive expression of HOXA13 was observed in a second patient. This situation resembles chromosomal translocations activating genes of the TLX/HOX11 family in T-ALLs. To compare the leukemogenic properties of HOXA13 to that of TLX proteins, cohorts of lethally irradiated mice were transplanted with bone marrow transduced with a retroviral vector expressing TLX3 or HOXA13. Cells transduced with TLX3 or HOXA13 could not be detected in the peripheral blood of mice post-transplantation and none of the mice developed malignancies. Cotransduction of the HOX cofactor MEIS1 with TLX3 or HOXA13 did not alter this outcome. However, in a myeloid clonogenic assay HOXA13 and TLX3 extended the proliferation of progenitors similarly to what was observed for TLX1. Altogether, our results strongly suggest the absolute requirement for cooperative events in association with homeobox gene up-regulation to induce T-cell leukemogenesis.

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.

Chow KU, Nowak D, Kim SZ, et al.
In vivo drug-response in patients with leukemic non-Hodgkin's lymphomas is associated with in vitro chemosensitivity and gene expression profiling.
Pharmacol Res. 2006; 53(1):49-61 [PubMed] Related Publications
Only a few approaches are available to address the mechanisms of cell death in vivo which are induced by anticancer treatment in patients with malignancies. In this study in vitro chemosensitivity testing of primary peripheral blood leukemic cells of five patients suffering from different leukemic non-Hodgkin's lymphomas was combined with the analysis of the in vivo rate of apoptosis by flow-cytometry (Annexin V and depolarisation of mitochondrial membrane potential (MMP) by JC-1). Furthermore, changes in expression patterns of apoptosis related proteins during chemotherapeutic treatment were detected by Western Blot. Gene expression profiling (HG-U133A, Affymetrix, Santa Clara, CA) was employed to identify common marker genes of in vivo drug response. In vitro chemosensitivity was tested using the cytotoxic agents which the patients were scheduled to receive and was strongly correlated with effective reduction of leukemic lymphoma cells in patients resulting in complete remissions in all five cases. Due to the rapid clearance of apoptotic tumor cells in vivo neither the analysis of the in vivo rate of apoptosis and depolarisation of MMP nor the assessment of expression of regulators of apoptosis showed concordant results concerning the drug response. However, assessment of gene expression during therapy could identify a set of 30 genes to significantly discriminate between samples from patients before treatment compared to samples from the same patients after receiving cytotoxic therapy. Among these 30 genes we found a high proportion of genes associated with apoptotic cell death, cell proliferation and cell cycle signalling including complement lysis inhibitor (clusterin/CLU), beta-catenin interacting protein (ICAT), peroxisome proliferator activated receptor alpha (PPARalpha), TNF alpha converting enzyme (ADAM17/TACE), homeo box A3 (HOX1), inositol polyphosphatase 5-phosphatase type IV (PPI5PIV) and inhibitor of p53 induced apoptosis alpha (IPIA-Alpha/NM23-H6). These results indicate that in vitro chemosensitivity testing and gene expression profiling can successfully be utilised to analyse in vivo drug response in patients with leukemic NHL's and can be used to explore new pathway models of drug-induced cell death in vivo which are independent of different lymphoma subtypes and different treatment regimens.

Grier DG, Thompson A, Kwasniewska A, et al.
The pathophysiology of HOX genes and their role in cancer.
J Pathol. 2005; 205(2):154-71 [PubMed] Related Publications
The HOM-C clustered prototype homeobox genes of Drosophila, and their counterparts, the HOX genes in humans, are highly conserved at the genomic level. These master regulators of development continue to be expressed throughout adulthood in various tissues and organs. The physiological and patho-physiological functions of this network of genes are being avidly pursued within the scientific community, but defined roles for them remain elusive. The order of expression of HOX genes within a cluster is co-ordinated during development, so that the 3' genes are expressed more anteriorly and earlier than the 5' genes. Mutations in HOXA13 and HOXD13 are associated with disorders of limb formation such as hand-foot-genital syndrome (HFGS), synpolydactyly (SPD), and brachydactyly. Haematopoietic progenitors express HOX genes in a pattern characteristic of the lineage and stage of differentiation of the cells. In leukaemia, dysregulated HOX gene expression can occur due to chromosomal translocations involving upstream regulators such as the MLL gene, or the fusion of a HOX gene to another gene such as the nucleoporin, NUP98. Recent investigations of HOX gene expression in leukaemia are providing important insights into disease classification and prediction of clinical outcome. Whereas the oncogenic potential of certain HOX genes in leukaemia has already been defined, their role in other neoplasms is currently being studied. Progress has been hampered by the experimental approach used in many studies in which the expression of small subsets of HOX genes was analysed, and complicated by the functional redundancy implicit in the HOX gene system. Attempts to elucidate the function of HOX genes in malignant transformation will be enhanced by a better understanding of their upstream regulators and downstream target genes.

Hung YC, Ueda M, Terai Y, et al.
Homeobox gene expression and mutation in cervical carcinoma cells.
Cancer Sci. 2003; 94(5):437-41 [PubMed] Related Publications
An association between deregulation of homeobox (HOX) gene expression and oncogenic transformation has been recently reported in human tumors. In this study, we investigated HOX gene expression and mutation in cervical carcinoma cells. Using reverse transcription-PCR, 11 human cervical carcinoma cell lines and 14 normal cervical tissue samples were examined for mRNA expression of the 39 class I HOX genes. DNA samples from 11 cell lines were tested for mutations in exons 1 and 2 of the HOXA10 and A13 genes using overlapping primer pairs which also cover intron 1 of these genes. HOXA1, B2, B4, C5, C10 and D13 genes were expressed in 8, 7, 9, 9, 9 and 11 of 11 cervical carcinoma cell lines, respectively, but not in any of the normal cervical tissues. HOXA9, A11, A13, B5, C4, D3 and D9 genes were expressed in all cell lines and normal tissues. In contrast, 13 of 39 HOX genes were silent in all materials examined. Single-strand conformational polymorphism and sequence analysis revealed a C insertion after base 1042 and/or a G to C substitution at base 1113 in intron 1 of the HOXA13 gene in 4 of 11 cell lines, however, neither deletions nor mutations were detected in exons 1 and 2 of the HOX A10 and A13 genes. Our data suggest that the expression of HOXA1, B2, B4, C5, C10 and D13 genes might be involved in the process leading to the transformation of normal cervical cells.

Pineault N, Buske C, Feuring-Buske M, et al.
Induction of acute myeloid leukemia in mice by the human leukemia-specific fusion gene NUP98-HOXD13 in concert with Meis1.
Blood. 2003; 101(11):4529-38 [PubMed] Related Publications
HOX genes, notably members of the HOXA cluster, and HOX cofactors have increasingly been linked to human leukemia. Intriguingly, HOXD13, a member of the HOXD cluster not normally expressed in hematopoietic cells, was recently identified as a partner of NUP98 in a t(2;11) translocation associated with t-AML/MDS. We have now tested directly the leukemogenic potential of the NUP98-HOXD13 t(2; 11) fusion gene in the murine hematopoietic model. NUP98-HOXD13 strongly promoted growth and impaired differentiation of early hematopoietic progenitor cells in vitro; this effect was dependent on the NUP98 portion and an intact HOXD13 homeodomain. Expression of the NUP98-HOXD13 fusion gene in vivo resulted in a partial impairment of lymphopoiesis but did not induce evident hematologic disease until late after transplantation (more than 5 months), when some mice developed a myeloproliferative-like disease. In contrast, mice transplanted with bone marrow (BM) cells cotransduced with NUP98-HOXD13 and the HOX cofactor Meis1 rapidly developed lethal and transplantable acute myeloid leukemia (AML), with a median disease onset of 75 days. In summary, this study demonstrates that NUP98-HOXD13 can be directly implicated in the molecular process leading to leukemic transformation, and it supports a model in which the transforming properties of NUP98-HOXD13 are mediated through HOX-dependent pathways.

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, Ono R, et al.
The chromosome translocation t(7;11)(p15;p15) in acute myeloid leukemia results in fusion of the NUP98 gene with a HOXA cluster gene, HOXA13, but not HOXA9.
Genes Chromosomes Cancer. 2002; 34(4):437-43 [PubMed] Related Publications
The nucleoporin gene NUP98 has been reported to be fused to 9 partner genes in hematologic malignancies with 11p15 translocations. The NUP98-HOXA9 fusion gene has been identified in acute myeloid leukemia (AML) and chronic myelogenous leukemia with t(7;11)(p15;p15). We report here a novel NUP98 partner gene, HOXA13, in a patient with de novo AML having t(7;11)(p15;p15). The HOXA13 gene is part of the HOXA cluster genes and contains 2 exons, encoding a protein of 338 amino acids with a homeodomain. The NUP98-HOXA13 fusion protein consists of the N-terminal phenylalanine-glycine repeat motif of NUP98 and the C-terminal homeodomain of HOXA13, similar to the NUP98-HOXA9 fusion protein. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis in various leukemic cell lines showed that the HOXA13 gene was expressed significantly more frequently in acute monocytic leukemic cell lines than in other leukemic cell lines (P = 0.039). HOXA13 and three HOXA cluster genes (A9, A10, A11) located at the 5' end of the HOXA9 gene were frequently expressed in myeloid leukemic cell lines. Our results revealed that t(7;11)(p15;p15) was not a single chromosomal abnormality at the molecular level. The protein encoded by the NUP98-HOXA13 fusion gene is similar to that encoded by NUP98-HOXA9, and the expression pattern of the HOXA13 gene in leukemic cell lines is similar to that of the HOXA9 gene, suggesting that the NUP98-HOXA13 fusion protein may play a role in leukemogenesis through a mechanism similar to that of the NUP98-HOXA9 fusion protein.

Fujino T, Suzuki A, Ito Y, et al.
Single-translocation and double-chimeric transcripts: detection of NUP98-HOXA9 in myeloid leukemias with HOXA11 or HOXA13 breaks of the chromosomal translocation t(7;11)(p15;p15).
Blood. 2002; 99(4):1428-33 [PubMed] Related Publications
It has been demonstrated that the chromosomal translocation t(7;11)(p15;p15) in patients with human acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) invariably involves fusion of the nucleoporin gene, NUP98, on chromosome 11 and the class 1 HOX gene, HOXA9, on chromosome 7, and that the fusion gene NUP98-HOXA9 is an important gene in myeloid leukemogenesis. Here are reported 2 novel chromosome 7p15 targets of the t(7;11)(p15;p15) chromosomal translocation in 2 patients with CML and myelodysplastic syndrome (MDS). Southern blot and polymerase chain reaction (PCR) analyses of leukemia cell DNA failed to show rearrangement of HOXA9, whereas NUP98 was found to be rearranged in both cases. Reverse transcription-PCR analysis using a NUP98 primer and a degenerate primer corresponding to the third helix of the homeodomain of HOXA demonstrated that NUP98 was fused in-frame to HOXA11 in the patient with CML and to HOXA13 in the patient with MDS. The chromosomal breakpoints on 7p15 were located within introns of HOXA11 or HOXA13 genes. In both patients chimeric NUP98-HOXA9 transcripts were also observed. These findings suggest that AbdB-type HOXA genes are common targets of t(7;11)(p15;p15) chromosomal translocations and that a single translocation can produce more than one NUP98-HOXA fusion gene, presumably because of altered splicing.

Huang T, Chesnokov V, Yokoyama KK, et al.
Expression of the Hoxa-13 gene correlates to hepatitis B and C virus associated HCC.
Biochem Biophys Res Commun. 2001; 281(4):1041-4 [PubMed] Related Publications
To study the Hoxa-13 gene in the liver, we examined its expression by RT-PCR in various liver cell lines, rat livers under different conditions, and human primary hepatocellular carcinomas (HCCs). The gene was found to be expressed in cell lines originating from liver stem-like cells, but not in cell lines originating from hepatocytes and bile duct epithelia. Expression was induced in rat livers after treatment with d-galactosamine, which is known to induce oval cell proliferation, but not after a two-thirds partial hepatectomy (2/3 PH) where induction of oval cell proliferation is thought not to occur. Expression of the gene correlated with human HCC samples associated with Hepatitis B or C virus infection in this small series. These results suggest that the Hoxa-13 gene may provide a potentially useful tool for elucidation of mechanisms involved in lineage-specific differentiation and carcinogenesis of liver stem cells.

Iwai SA, Nishina Y, Kosaka M, et al.
The kinetics of induction of Hox1.6 and C-jun mRNA during three different ways of inducing differentiation in teratocarcinoma F9 cells.
In Vitro Cell Dev Biol Anim. 1995; 31(6):462-6 [PubMed] Related Publications
Changes in Hox1.6 and c-jun gene expression were examined upon F9 cell differentiation that was induced by three independent methods: a drug treatment with retinoic acid (RA), that with sodium butyrate (NaB), and a genetic approach using the ts mutant. To obtain further information on the mechanism of teratocarcinoma cell differentiation we have examined the kinetics of the induction of Hox1.6 and c-jun mRNA whose gene products have been demonstrated to have specific roles in gene regulation. Expression of Hox1.6 mRNA was induced more rapidly than c-jun mRNA by all the above three inducing methods. Furthermore, protein synthesis was not required for the induction of Hox1.6 mRNA as well as of c-jun mRNA synthesis in all three methods. The data suggested that the transcriptional increase in the Hox1.6 mRNA was a primary response and could play an important role in F9 cell differentiation.

Duboule D, Baron A, Mähl P, Galliot B
A new homeo-box is present in overlapping cosmid clones which define the mouse Hox-1 locus.
EMBO J. 1986; 5(8):1973-80 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
A new murine homeo-box (Hox1-3) has been isolated and studied with respect to its structure and transcriptional pattern. This homeo-box is part of a gene which is specifically regulated during mouse prenatal development and expressed in a restricted number of teratocarcinoma tumours as well as in adult testis. Hox1-3 is shown to be a member of a cluster of at least four homeo-boxes lying within a 75-kb segment of DNA on mouse chromosome 6. The structure of the whole cluster, the Hox-1 locus is presented.

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