HOXD10

Gene Summary

Gene:HOXD10; homeobox D10
Aliases: HOX4, HOX4D, HOX4E, Hox-4.4
Location:2q31.1
Summary:This gene is a member of the Abd-B homeobox family and encodes a protein with a homeobox DNA-binding domain. It is included in a cluster of homeobox D genes located on chromosome 2. The encoded nuclear protein functions as a sequence-specific transcription factor that is expressed in the developing limb buds and is involved in differentiation and limb development. Mutations in this gene have been associated with Wilm's tumor and congenital vertical talus (also known as "rocker-bottom foot" deformity or congenital convex pes valgus) and/or a foot deformity resembling that seen in Charcot-Marie-Tooth disease. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:homeobox protein Hox-D10
HPRD
Source:NCBIAccessed: 25 June, 2015

Ontology:

What does this gene/protein do?
Show (17)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 25 June, 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: HOXD10 (cancer-related)

Vardhini NV, Rao PJ, Murthy PB, Sudhakar G
HOXD10 expression in human breast cancer.
Tumour Biol. 2014; 35(11):10855-60 [PubMed] Related Publications
Breast cancer is the most frequent malignancy among females. In this study, we analyzed the expression pattern of a homeobox gene (HOXD10) in human invasive ductal breast cancer tissues and normal tissues. With the ACTB (β-actin) gene as a reference, HOXD10 was detected in 60 breast cancer tissues by using the quantitative real-time PCR (qPCR) method with the Relative Expression Software Tool (REST). We found that the HOXD10 expression level was significantly different between cancerous and normal tissues. Downregulation of the HOXD10 gene expression was examined in high-grade samples. Low-grade tissue showed no difference from the control group. HOXD10 expression was reduced in grade II breast carcinoma tissues. This data reveal that misexpression of the HOXD10 gene supports the development and involvement in breast cancer and may serve as a potential biomarker for the diagnosis of human ductal invasive breast carcinoma.

Hakami F, Darda L, Stafford P, et al.
The roles of HOXD10 in the development and progression of head and neck squamous cell carcinoma (HNSCC).
Br J Cancer. 2014; 111(4):807-16 [PubMed] Article available free on PMC after 12/08/2015 Related Publications
BACKGROUND: HOX gene expression is altered in many cancers; previous microarray revealed changes in HOX gene expression in head and neck squamous cell carcinoma (HNSCC), particularly HOXD10.
METHODS: HOXD10 expression was assessed by qPCR and immunoblotting in vitro and by immunohistochemistry (IHC) in tissues. Low-expressing cells were stably transfected with HOXD10 and the phenotype assessed with MTS, migration and adhesion assays and compared with the effects of siRNA knockdown in high-HOXD10-expressing cells. Novel HOXD10 targets were identified using expression microarrays, confirmed by reporter assay, and validated in tissues using IHC.
RESULTS: HOXD10 expression was low in NOKs, high in most primary tumour cells, and low in lymph node metastasis cells, a pattern confirmed using IHC in tissues. Overexpression of HOXD10 decreased cell invasion but increased proliferation, adhesion and migration, with knockdown causing reciprocal effects. There was no consistent effect on apoptosis. Microarray analysis identified several putative HOXD10-responsive genes, including angiomotin (AMOT-p80) and miR-146a. These were confirmed as HOXD10 targets by reporter assay. Manipulation of AMOT-p80 expression resulted in phenotypic changes similar to those on manipulation of HOXD10 expression.
CONCLUSIONS: HOXD10 expression varies by stage of disease and produces differential effects: high expression giving cancer cells a proliferative and migratory advantage, and low expression may support invasion/metastasis, in part, by modulating AMOT-p80 levels.

Parrella P, Barbano R, Pasculli B, et al.
Evaluation of microRNA-10b prognostic significance in a prospective cohort of breast cancer patients.
Mol Cancer. 2014; 13:142 [PubMed] Article available free on PMC after 12/08/2015 Related Publications
BACKGROUND: MicroRNA-10b (miR-10b) has a prominent role in regulating tumor invasion and metastasis by targeting the HOXD10 transcriptional repressor and has been found up-regulated in several tumor types.
METHODS: We evaluated the expression of miR-10b in paired tumor and normal specimens obtained from a prospective cohort of breast cancer patients with at least 36 months follow-up enrolled according to the REMARK guidelines (n = 150). RNA quality was measured and only samples with RNA Integrity Number (RIN) ≥7.0 were analyzed.
RESULTS: The relative expression of miR-10b in tumor as compared to its normal counterpart (RER) was determined by RT-qPCR. miR-10b RERs were higher in the subgroup of patients with synchronous metastases (n = 11, Median 0.25; IQR 0.11-1.02) as compared with patients without metastases (n = 90, Median 0.09; IQR 0.04-0.29) (p = 0.028). In the subgroup of patients without synchronous metastases (n = 90), higher miR-10b RERs were associated with increased risk of disease progression and death in both univariable (HR 1.16, p = 0.021 and HR 1.20, p = 0.015 respectively for 0.10 unitary increase of miR-10b RERs levels) and multivariable (HR1.30, p < 0.001, and HR 1.31, p = 0.003 respectively for 0.10 unitary increase of miR-10b RERs levels) Cox regression models. The addition of miR-10b RERs to the Nottingham Prognostic Index (NPI) provided an improvement in discrimination power and risk reclassification abilities for the clinical outcomes at 36 months. Survival C-indices significantly increased from 0.849 to 0.889 (p = 0.009) for OS and from 0.735 to 0.767 (p = 0.050) for DFS.
CONCLUSIONS: Our results provide evidences that the addition of miR-10b RERs to the prognostic factors used in clinical routine could improve the prediction abilities for both overall mortality and disease progression in breast cancer patients.

Xavier FC, Destro MF, Duarte CM, Nunes FD
Epigenetic repression of HOXB cluster in oral cancer cell lines.
Arch Oral Biol. 2014; 59(8):783-9 [PubMed] Related Publications
OBJECTIVE: Aberrant DNA methylation is a fundamental transcriptional control mechanism in carcinogenesis. The expression of homeobox genes is usually controlled by an epigenetic mechanism, such as the methylation of CpG islands in the promoter region. The aim of this study was to describe the differential methylation pattern of HOX genes in oral squamous cell carcinoma (OSCC) cell lines and transcript status in a group of hypermethylated and hypomethylated genes.
DESIGN: Quantitative analysis of DNA methylation was performed on two OSCC cell lines (SCC4 and SCC9) using a method denominated Human Homeobox Genes EpiTect Methyl qPCR Arrays, which allowed fast, precise methylation detection of 24 HOX specific genes without bisulfite conversion.
RESULTS: Methylation greater than 50% was detected in HOXA11, HOXA6, HOXA7, HOXA9, HOXB1, HOXB2, HOXB3, HOXB4, HOXB5, HOXB6, HOXC8 and HOXD10. Both cell lines demonstrated similar hypermethylation status for eight HOX genes. A similar pattern of promoter hypermethylation and hypomethylation was demonstrated for the HOXB cluster and HOXA cluster, respectively. Moreover, the hypermethylation profile of the HOXB cluster, especially HOXB4, was correlated with decreased transcript expression, which was restored following treatment with 5-aza-2'-deoxycytidine.
CONCLUSIONS: The homeobox methylation profile in OSCC cell lines is consistent with an epigenetic biomarker.

Xiao H, Li H, Yu G, et al.
MicroRNA-10b promotes migration and invasion through KLF4 and HOXD10 in human bladder cancer.
Oncol Rep. 2014; 31(4):1832-8 [PubMed] Related Publications
The present study was performed to investigate the effect of microRNA-10b (miR-10b) on cell migration and invasion in human bladder cancer (BC). Real-time PCR was performed to detect the expression of miR-10b in BC cell lines. miR-10b mimics, the negative control for mimics, miR-10b inhibitor and the negative control for inhibitor were transfected into BC cell lines and the effects of miR-10b on the migration and invasion of cells were investigated through Transwell assay. Meanwhile, protein levels of KLF4, HOXD10, E-cadherin and MMP14 were measured. Luciferase assays were also performed to validate KLF4 and HOXD10 as miR-10b targets. In vivo metastasis assay was performed to validate if miR-10b can promote BC cell line metastasis in vivo. miR-10b is significantly upregulated in BC cell lines and metastatic tissues. Increased miR-10b expression significantly enhanced BC cell migration and invasion, while decreased miR-10b expression reduced cell migration and invasion. In vivo metastasis assay demonstrated that overexpression of miR-10b markedly promoted BC metastasis. Moreover, KLF4 and HOXD10 were identified as direct targets of miR-10b in BC cells. Silencing of KLF4 or HOXD10 recapitulated the pro-metastatic function. Furthermore, we found that E-cadherin and MMP14 may be the downstream factors of KLF4 and HOXD10 in the suppression of BC metastasis by miR-10b. These data suggest that miR-10b may function as oncogenes in BC cells. Targeting these novel strategies, inhibition of miR-10b/KLF4/E-cadherin axis and miR-10b/HOXD10/MMP14 axis may be helpful as a therapeutic approach to block BC cell metastasis.

Xue M, Fang Y, Sun G, et al.
IGFBP3, a transcriptional target of homeobox D10, is correlated with the prognosis of gastric cancer.
PLoS One. 2013; 8(12):e81423 [PubMed] Article available free on PMC after 12/08/2015 Related Publications
Homeobox D10 (HoxD10) plays important roles in the differentiation of embryonic cells and progression of breast cancer. Our previous report revealed that insulin-like growth factor binding protein-3 (IGFBP3) was regulated by HoxD10 in gastric cancer cells; however, the functional roles and underlying mechanisms of IGFBP3 in gastric cancer remain unclear. Here, we found that the expression of IGFBP3 were upregulated after ectopic expression of HoxD10 in gastric cancer cells. Chromatin immunoprecipitation assay showed that HoxD10 bound to three potential regions of IGFBP3 promoter. Exogenous HoxD10 significantly enhanced the activity of luciferase reporter containing these binding regions in gastric cancer cells. Further data showed that all of these binding sites had Hox binding element "TTAT". Immunohistochemical staining results revealed that IGFBP3 expression was significantly downregulated in 86 gastric adenocarcinomas tissues relative to their adjacent non-cancerous tissues (p<0.001). Moreover, IGFBP3 expression was significantly lower in gastric tumor with lymph node metastasis compared with that without lymph node metastasis (p=0.045). Patients with high expression level of IGFBP3 showed favorable 5 year overall survival (p=0.011). Knockdown of IGFBP3 accelerated gastric cancer cell migration and invasion and induced the expression of invasive factors including MMP14, uPA and uPAR. Thus, our data suggest that HoxD10-targeted gene IGFBP3 may suppress gastric cancer cell invasion and favors the survival of gastric cancer patients.

Li Q, Ding C, Chen C, et al.
miR-224 promotion of cell migration and invasion by targeting Homeobox D 10 gene in human hepatocellular carcinoma.
J Gastroenterol Hepatol. 2014; 29(4):835-42 [PubMed] Related Publications
BACKGROUND AND AIM: MicroRNAs (miRNAs) are small noncoding RNA molecules that control target gene expression and are implicated in the regulation of diverse cellular pathways. In our previous research, we have demonstrated that miR-224 was overexpressed in liver cancer cells and tissues, which was an important factor in the regulation of cell migration and invasion. This study aimed to further explore the regulatory mechanism of miR-224 in the migration and invasion in liver cancer cells.
METHODS: A luciferase reporter assay was used to confirm that the HOXD10 gene was a direct target of miR-224. Quantitative reverse transcriptase-polymerase chain reaction, Western blotting, Transwell migration, and Matrigel invasion assays were performed to clarify the molecular mechanism of miR-224 in the regulation of cell migration and invasion in human hepatocellular carcinoma (HCC).
RESULTS: (i) The expression of miR-224 was strongly upregulated in MHHC97H and MHCC97L cells, and its expression level was significantly associated with cell invasive potential. (ii) The HOXD10 gene was confirmed to be a direct target of miR-224. Compared with normal liver tissues and cells, HOXD10 had lower expression in HCC tissues and cells and inversely regulated HCC cell invasion. (iii) miR-224 promoted expression of the tumor invasion-associated proteins p-PAK4 and MMP-9 by directly targeting HOXD10.
CONCLUSION: Our findings suggest a previously undescribed regulatory pathway in which the miR-224/HOXD10/p-PAK4/MMP-9 signaling pathway contributes to the regulation of cell migration and invasion and provides a new biotarget for HCC treatment.

Bhatlekar S, Addya S, Salunek M, et al.
Identification of a developmental gene expression signature, including HOX genes, for the normal human colonic crypt stem cell niche: overexpression of the signature parallels stem cell overpopulation during colon tumorigenesis.
Stem Cells Dev. 2014; 23(2):167-79 [PubMed] Article available free on PMC after 12/08/2015 Related Publications
Our goal was to identify a unique gene expression signature for human colonic stem cells (SCs). Accordingly, we determined the gene expression pattern for a known SC-enriched region--the crypt bottom. Colonic crypts and isolated crypt subsections (top, middle, and bottom) were purified from fresh, normal, human, surgical specimens. We then used an innovative strategy that used two-color microarrays (∼18,500 genes) to compare gene expression in the crypt bottom with expression in the other crypt subsections (middle or top). Array results were validated by PCR and immunostaining. About 25% of genes analyzed were expressed in crypts: 88 preferentially in the bottom, 68 in the middle, and 131 in the top. Among genes upregulated in the bottom, ∼30% were classified as growth and/or developmental genes including several in the PI3 kinase pathway, a six-transmembrane protein STAMP1, and two homeobox (HOXA4, HOXD10) genes. qPCR and immunostaining validated that HOXA4 and HOXD10 are selectively expressed in the normal crypt bottom and are overexpressed in colon carcinomas (CRCs). Immunostaining showed that HOXA4 and HOXD10 are co-expressed with the SC markers CD166 and ALDH1 in cells at the normal crypt bottom, and the number of these co-expressing cells is increased in CRCs. Thus, our findings show that these two HOX genes are selectively expressed in colonic SCs and that HOX overexpression in CRCs parallels the SC overpopulation that occurs during CRC development. Our study suggests that developmental genes play key roles in the maintenance of normal SCs and crypt renewal, and contribute to the SC overpopulation that drives colon tumorigenesis.

Nakayama I, Shibazaki M, Yashima-Abo A, et al.
Loss of HOXD10 expression induced by upregulation of miR-10b accelerates the migration and invasion activities of ovarian cancer cells.
Int J Oncol. 2013; 43(1):63-71 [PubMed] Related Publications
Small and large non-coding RNAs (ncRNAs) contribute to the acquisition of aggressive tumor behavior in diverse human malignancies. Two types of ncRNAs, miRNA‑10b (miR-10b) and homemobox (HOX) transcript antisense RNA (HOTAIR), can suppress the translation of the HOXD10 gene, an mRNA encoding a transcriptional repressor that inhibits the expression of cell migration/invasion-associated genes. Using epithelial ovarian cancer cell lines and primary tumors, we investigated whether miR‑10b and/or HOTAIR can regulate the expression of HOXD10, and whether it permits gain of pro‑metastatic gene products, matrix metallopeptidase 14 (MMP14) and ras homolog family member C (RHOC). Overexpression of miR-10b induced a decrease in HOXD10 protein expression, and upregulated the migration and invasion abilities in ovarian cancer cell lines (P<0.05). In these cells, a significant increase of MMP14 and RHOC protein was observed. No significant upregulation of the HOXD10 protein was observed in cells with the treatment of HOTAIR-siRNA. Positive signals for HOXD10 and MMP14 proteins were observed in 47 (69%) and 25 (37%) of 68 patients with epithelial ovarian cancers. An inverse correlation between HOXD10 and MMP14 immunoreactivities was observed (P<0.05), and miR-10b expression was also inversely correlated with HOXD10 protein expression (P<0.05). These results suggested that downregulation of HOXD10 expression by miR-10b overexpression may induce an increase of pro-metastatic gene products, such as MMP14 and RHOC, and contribute to the acquisition of metastatic phenotypes in epithelial ovarian cancer cells.

Qu Y, Dang S, Hou P
Gene methylation in gastric cancer.
Clin Chim Acta. 2013; 424:53-65 [PubMed] Related Publications
Gastric cancer is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur in developing countries. In the early years of the molecular biology revolution, cancer research mainly focuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer, including DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation in the promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-related genes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages of gene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as serum and gastric washes have led to many studies of application in gastric cancer. This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, in gastric cancer and illustrates the impact epigenetics has had on this field.

Lin J, Teo S, Lam DH, et al.
MicroRNA-10b pleiotropically regulates invasion, angiogenicity and apoptosis of tumor cells resembling mesenchymal subtype of glioblastoma multiforme.
Cell Death Dis. 2012; 3:e398 [PubMed] Article available free on PMC after 12/08/2015 Related Publications
Glioblastoma multiforme (GBM) is a heterogeneous disease despite its seemingly uniform pathology. Deconvolution of The Cancer Genome Atlas's GBM gene expression data has unveiled the existence of distinct gene expression signature underlying discrete GBM subtypes. Recent conflicting findings proposed that microRNA (miRNA)-10b exclusively regulates glioma growth or invasion but not both. We showed that silencing of miRNA-10b by baculoviral decoy vectors in a glioma cell line resembling the mesenchymal subtype of GBM reduces its growth, invasion and angiogenesis while promoting apoptosis in vitro. In an orthotopic human glioma mouse model, inhibition of miRNA-10b diminishes the invasiveness, angiogenicity and growth of the mesenchymal subtype-like glioma cells in the brain and significantly prolonged survival of glioma-bearing mice. We demonstrated that the pleiotropic nature of miRNA-10b was due to its suppression of multiple tumor suppressors, including TP53, FOXO3, CYLD, PAX6, PTCH1, HOXD10 and NOTCH1. In particular, siRNA-mediated knockdown experiments identified TP53, PAX6, NOTCH1 and HOXD10 as invasion regulatory genes in our mesenchymal subtype-like glioma cells. By interrogating the REMBRANDT, we noted that dysregulation of many direct targets of miRNA-10b was associated with significantly poorer patient survival. Thus, our study uncovers a novel role for miRNA-10b in regulating angiogenesis and suggests that miRNA-10b may be a pleiotropic regulator of gliomagenesis.

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] Article available free on PMC after 12/08/2015 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.

Dong CG, Wu WK, Feng SY, et al.
Co-inhibition of microRNA-10b and microRNA-21 exerts synergistic inhibition on the proliferation and invasion of human glioma cells.
Int J Oncol. 2012; 41(3):1005-12 [PubMed] Related Publications
MicroRNAs (miRNAs) are small non-coding RNAs that function as negative gene regulators. Alterations in the expression of miRNAs have been implicated in the pathogenesis and development of most human malignancies. Recent data indicate that microRNA-21 and microRNA-10b are significantly elevated in glioblastoma multiforme (GBM) suggesting their role in the regulation of multiple genes associated with cancer. In this study, U87MG human glioblastoma cells were treated with miRNA inhibitors targeting miR-10b and miR-21, alone or in combination. The results showed that the miR-21 inhibitor additively interacted with miR-10b inhibitor on U87MG cells. The 50% inhibitory concentration values were dramatically decreased in cells treated with the combination of miR-10b and miR-21 inhibitors. Furthermore, inhibitors synergistically combined, enhanced apoptosis significantly and reduced invasion ability assessed by flow cytometry and Transwell migration assay. Thus, the miR-21 inhibitor may interrupt the activity of EGFR pathways, increasing PDCD4 and TPM1 expression and reducing MMP activities, independently of PTEN status. Meanwhile, miR-10b inhibitor reduced by Twist proceeds to inhibit translation of the mRNA encoding HOXD10 leading to the increase of the expression of the well-characterized pro-metastatic gene RHOC. Taken together, these data strongly suggest that a combination of miR-21 inhibitor and miR-10b inhibitor could be an effective therapeutic strategy for controlling the growth of GBM by inhibiting oncogene expression and overexpressing tumor suppressor genes. Moreover, a regulatory strategy based on the combination of miRNA inhibitors may provide insights into the mechanisms of the modulation of signaling genes involved in tumor cell apoptosis and invasiveness.

Liu Z, Zhu J, Cao H, et al.
miR-10b promotes cell invasion through RhoC-AKT signaling pathway by targeting HOXD10 in gastric cancer.
Int J Oncol. 2012; 40(5):1553-60 [PubMed] Related Publications
MicroRNAs play critical roles in tumorigenesis as either oncogenes or tumor suppressors. As a microRNA induced by Twist, miR-10b function as a metastasis driver in different types of cancer, in which the downstream target gene HOXD10 is the main mediator. In gastric tumor species, miR-10b levels were dramatically elevated in lymphoma node metastasis-positive tumor tissues compared with lymphoma node metastasis-free tumor tissues, and were correlated to dowregulation of HOXD10 expression. In gastric cell lines with distinct degrees of differentiation, miR-10b was highly expressed in the cell line with strong metastatic ability. In MNK45 cells, inhibition of miR-10b led to abrogation of cell invasion. While in GES-1 cells, miR-10 overexpression resulted in enhancement of invasiveness through translational inhibition of HOXD10, and constitutive expression of HOXD10 reversed the effects of miR-10b on cell invasion. Furthermore, either knockdown of RhoC or inhibition of AKT activation interfered miR-10-induced invasiveness in GES-1 cells. In summary, these observations suggest that miR-10b can stimulate the upregulation of RhoC and AKT phosphorylation through targeting HOXD10, thus promoting cell invasion in gastric tumors.

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] Article available free on PMC after 12/08/2015 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.

Wang L, Chen S, Xue M, et al.
Homeobox D10 gene, a candidate tumor suppressor, is downregulated through promoter hypermethylation and associated with gastric carcinogenesis.
Mol Med. 2012; 18:389-400 [PubMed] Article available free on PMC after 12/08/2015 Related Publications
Homeobox D10 (HoxD10 ) gene plays a critical role in cell differentiation and morphogenesis during development. However, the function of HoxD10 in tumor progression remains largely unknown. We demonstrate that the expression of HoxD10 is commonly downregulated in gastric cancer tissues (n = 33) and cell lines (n = 8) relative to normal stomach tissues. Functionally, reexpression of HoxD10 results in significant inhibition of cell survival, induction of cell apoptosis, and impairment of cell migration and invasion. Moreover, ectopic expression of HoxD10 suppresses gastric tumor growth in a mouse xenograft model. To identify target candidates of HoxD10, we performed cDNA microarray and showed that HoxD10 regulates multiple downstream genes including IGFBP3. Reintroduction of HoxD10 transcriptionally upregulates IGFBP3, activates caspase 3 and caspase 8, and subsequently induces cell apoptosis. Methylation specific PCR revealed that HoxD10 promoter DNA was hypermethylated in gastric cancer cell lines. Additionally, 5-aza demethylation treatment could transiently reactivate the expression of HoxD10 in gastric cancer cells. HoxD10 promoter methylation frequently was detected in gastric cancer tissues obtained from endoscopic biopsies (85.7%, 24/28) and surgically resected samples (82.6%, 57/69). Intestinal metaplasia tissues showed a 60% methylation rate (18/30), but no detectable methylation in normal stomach tissues (0%, 0/10). Taken together, our results suggest that HoxD10 functions as a candidate tumor suppressor in gastric cancer, which is inactivated through promoter hypermethylation.

Gabriely G, Teplyuk NM, Krichevsky AM
Context effect: microRNA-10b in cancer cell proliferation, spread and death.
Autophagy. 2011; 7(11):1384-6 [PubMed] Related Publications
Single microRNA (miRNA) can regulate expression of several or multiple principal targets in a specific microenvironment. In different cellular contexts, the same miRNA may exhibit diverse functions, depending on the repertoire and stoichiometry of its direct mRNA targets. For instance, in breast cancer, microRNA-10b (miR-10b) promotes invasion and metastasis of tumor cells through post-transcriptional regulation of HOXD10. In contrast, in glioblastoma (GBM), the most common and malignant primary brain tumor, miR-10b promotes proliferation and prevents death of cancer cells by targeting cell cycle inhibitors and pro-apoptotic genes. Here, we discuss a unique role of miR-10b in cancer cell survival, in diverse tumor microenvironments.

Sun L, Yan W, Wang Y, et al.
MicroRNA-10b induces glioma cell invasion by modulating MMP-14 and uPAR expression via HOXD10.
Brain Res. 2011; 1389:9-18 [PubMed] Related Publications
MicroRNAs are small endogenous noncoding RNAs, which modulate target gene expression by binding with target mRNA sequences in the 3'untranslated region (UTR) with an imperfect complementarity that inhibits the mRNA translation. Many microRNAs have been reported to function as tumor oncogenes or anti-oncogenes. Recently, more and more microRNAs have been reported to contribute to a tumor's invasive potential. Here, we show that microRNA-10b (miR-10b) was over-expressed in glioma samples and directly associated with the glioma's pathological grade and malignancy. We also found that miR-10b induced glioma cell invasion by modulating tumor invasion factors MMP-14 and uPAR expression via the direct target HOXD10. The miR-10b/HOXD10/MMP-14/uPAR signaling pathway might contribute to the invasion of glioma. Accordingly, glioma cells lost their invasive ability when treated with specific antisense oligonucleotides (miR-10b inhibitors), suggesting that miR-10b could be used as a new bio-target to cure glioma.

Fassan M, Baffa R, Palazzo JP, et al.
MicroRNA expression profiling of male breast cancer.
Breast Cancer Res. 2009; 11(4):R58 [PubMed] Article available free on PMC after 12/08/2015 Related Publications
INTRODUCTION: MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. Their aberrant expression may be involved in human diseases, including cancer. To test the hypothesis that there is a specific miRNA expression signature which characterizes male breast cancers, we performed miRNA microarray analysis in a series of male breast cancers and compared them with cases of male gynecomastia and female breast cancers.
METHODS: Paraffin blocks were obtained at the Department of Pathology of Thomas Jefferson University from 28 male patients including 23 breast cancers and five cases of male gynecomastia, and from 10 female ductal breast carcinomas. The RNA harvested was hybridized to miRNA microarrays (~1,100 miRNA probes, including 326 human and 249 mouse miRNA genes, spotted in duplicate). To further support the microarray data, an immunohistochemical analysis for two specific miRNA gene targets (HOXD10 and VEGF) was performed in a small series of male breast carcinoma and gynecomastia samples.
RESULTS: We identified a male breast cancer miRNA signature composed of a large portion of underexpressed miRNAs. In particular, 17 miRNAs with increased expression and 26 miRNAs with decreased expression were identified in male breast cancer compared with gynecomastia. Among these miRNAs, some had well-characterized cancer development association and some showed a deregulation in cancer specimens similar to the one previously observed in the published signatures of female breast cancer. Comparing male with female breast cancer miRNA expression signatures, 17 significantly deregulated miRNAs were observed (four overexpressed and 13 underexpressed in male breast cancers). The HOXD10 and VEGF gene immunohistochemical expression significantly follows the corresponding miRNA deregulation.
CONCLUSIONS: Our results suggest that specific miRNAs may be directly involved in male breast cancer development and that they may represent a novel diagnostic tool in the characterization of specific cancer gene targets.

Chen A, Cuevas I, Kenny PA, et al.
Endothelial cell migration and vascular endothelial growth factor expression are the result of loss of breast tissue polarity.
Cancer Res. 2009; 69(16):6721-9 [PubMed] Article available free on PMC after 12/08/2015 Related Publications
Recruiting a new blood supply is a rate-limiting step in tumor progression. In a three-dimensional model of breast carcinogenesis, disorganized, proliferative transformed breast epithelial cells express significantly higher expression of angiogenic genes compared with their polarized, growth-arrested nonmalignant counterparts. Elevated vascular endothelial growth factor (VEGF) secretion by malignant cells enhanced recruitment of endothelial cells (EC) in heterotypic cocultures. Significantly, phenotypic reversion of malignant cells via reexpression of HoxD10, which is lost in malignant progression, significantly attenuated VEGF expression in a hypoxia-inducible factor 1alpha-independent fashion and reduced EC migration. This was due primarily to restoring polarity: forced proliferation of polarized, nonmalignant cells did not induce VEGF expression and EC recruitment, whereas disrupting the architecture of growth-arrested, reverted cells did. These data show that disrupting cytostructure activates the angiogenic switch even in the absence of proliferation and/or hypoxia and restoring organization of malignant clusters reduces VEGF expression and EC activation to levels found in quiescent nonmalignant epithelium. These data confirm the importance of tissue architecture and polarity in malignant progression.

Baffa R, Fassan M, Volinia S, et al.
MicroRNA expression profiling of human metastatic cancers identifies cancer gene targets.
J Pathol. 2009; 219(2):214-21 [PubMed] Related Publications
Small non-coding microRNAs (miRNAs) contribute to cancer development and progression, and are differentially expressed in normal tissues and cancers. However, the specific role of miRNAs in the metastatic process is still unknown. To seek a specific miRNA expression signature characterizing the metastatic phenotype of solid tumours, we performed a miRNA microarray analysis on 43 paired primary tumours (ten colon, ten bladder, 13 breast, and ten lung cancers) and one of their related metastatic lymph nodes. We identified a metastatic cancer miRNA signature comprising 15 overexpressed and 17 underexpressed miRNAs. Our results were confirmed by qRT-PCR analysis. Among the miRNAs identified, some have a well-characterized association with cancer progression, eg miR-10b, miR-21, miR-30a, miR-30e, miR-125b, miR-141, miR-200b, miR-200c, and miR-205. To further support our data, we performed an immunohistochemical analysis for three well-defined miRNA gene targets (PDCD4, DHFR, and HOXD10 genes) on a small series of paired colon, breast, and bladder cancers, and one of their metastatic lymph nodes. We found that the immunohistochemical expression of these targets significantly follows the corresponding miRNA deregulation. Our results suggest that specific miRNAs may be directly involved in cancer metastasis and that they may represent a novel diagnostic tool in the characterization of metastatic cancer gene targets.

Sasayama T, Nishihara M, Kondoh T, et al.
MicroRNA-10b is overexpressed in malignant glioma and associated with tumor invasive factors, uPAR and RhoC.
Int J Cancer. 2009; 125(6):1407-13 [PubMed] Related Publications
MicroRNAs (miRNAs) are effective post-transcriptional regulators of gene expression and are important in many biological processes. Although the oncogenic and tumor suppressive functions of several miRNAs have been characterized, the role of miRNAs in mediating tumor invasion and migration remains largely unexplored. Recently, miR-10b was identified as an miRNA highly expressed in metastatic breast cancer, promoting cell migration and invasion. Here, we performed real-time reverse transcriptase polymerase chain reaction (RT-PCR) assays on 43 glioma samples (17 glioblastoma, 6 anaplastic astrocytoma, 10 low-grade astrocytoma, 6 oligodendroglioma and 4 ependymoma) and 6 glioma cell lines. We found that miR-10b expression was upregulated in all glioma samples compared to non-neoplastic brain tissues. The expression levels of miR-10b were associated with higher grade glioma. In addition, mRNA expressions of RhoC and urokinase-type plasminogen activator receptor (uPAR), which were thought to be regulated by miR-10b via HOXD10, were statistically significantly correlated with the expression of miR-10b (p < 0.001, p = 0.001, respectively). Also, protein expression levels of RhoC and uPAR were associated with expression levels of miR-10b (p = 0.009, p = 0.014, respectively). Finally, multifocal lesions on enhanced MRI of 7 malignant gliomas were associated with higher expression levels of miR-10b (p = 0.02). Our data indicated that miR-10b might play some role in the invasion of glioma cells.

Bennett LB, Schnabel JL, Kelchen JM, et al.
DNA hypermethylation accompanied by transcriptional repression in follicular lymphoma.
Genes Chromosomes Cancer. 2009; 48(9):828-41 [PubMed] Article available free on PMC after 12/08/2015 Related Publications
High-throughput microarray technologies were used to study DNA methylation accompanied by transcriptional changes in follicular lymphoma (FL). Using Methylated CpG Island Amplification with Microarrays to study CpG Island DNA methylation in FL, we discovered widespread hypermethylation of homeobox genes and previously identified targets of polycomb repressive complex 2 (PRC2) in cell lines and primary tumors, but not in benign follicular hyperplasia (BFH). DNA methylation for HOXA11, HOXD10, HOXB7, HOXC12, PAX6, LHX9, SFMBT2, EN2, and PAX7 was independently validated in the RL cell line and HOXA11, HOXD10, PAX6, and EN2 in primary tumors. Combined Bisulfite Restriction Analysis (COBRA) also established DNA methylation for the previously identified PRC2 targets DCC, DES, GAD2, AQP5, GPR61, GRIA4, GJD2, and AMPH in FL but not in BFH. Gene expression analyses revealed 411 genes that were hypermethylated and transcriptionally repressed in RL, 74% of which were reactivated by the demethylating agent 5-aza-2'-deoxycytidine (5-azaD) plus or minus the histone deacetylase inhibitor trichostatin A (TSA). Forty genes were also downregulated in primary FL. Our results suggest that extensive hypermethylation in promoters of polycomb target genes is a characteristic of FL and that loss of expression of certain SUZ12 target genes could be functionally relevant for lymphomagenesis.

Reddy SD, Ohshiro K, Rayala SK, Kumar R
MicroRNA-7, a homeobox D10 target, inhibits p21-activated kinase 1 and regulates its functions.
Cancer Res. 2008; 68(20):8195-200 [PubMed] Article available free on PMC after 12/08/2015 Related Publications
MicroRNAs are noncoding RNAs that inhibit the expression of their targets in a sequence-specific manner and play crucial roles during oncogenesis. Here we show that microRNA-7 (miR-7) inhibits p21-activated kinase 1 (Pak1) expression, a widely up-regulated signaling kinase in multiple human cancers, by targeting the 3'-untranslated region (UTR) of Pak1 mRNA. We noticed an inverse correlation between the levels of endogenous miR-7 and Pak1 expression in human cancer cells. We discovered that endogenous miR-7 expression is positively regulated by a homeodomain transcription factor, HoxD10, the loss of which leads to an increased invasiveness. HoxD10 directly interacts with the miR-7 chromatin. Accordingly, the levels of Pak1 protein are progressively up-regulated whereas those of miR-7 and its upstream activator HoxD10 are progressively down-regulated in a cellular model of breast cancer progression from low to highly invasive phenotypes. Furthermore, HoxD10 expression in highly invasive breast cancer cells resulted in an increased miR-7 expression but reduced Pak1 3'-UTR-luciferase activity and reduced Pak1 protein. Finally, we show that miR-7 introduction inhibits the motility, invasiveness, anchorage-independent growth, and tumorigenic potential of highly invasive breast cancer cells. Collectively, these findings establish for the first time that Pak1 is a target of miR-7 and that HoxD10 plays a regulatory role in modifying the expression of miR-7 and, consequently, the functions of the miR-7-Pak1 pathway in human cancer cells.

Schmittgen TD, Livak KJ
Analyzing real-time PCR data by the comparative C(T) method.
Nat Protoc. 2008; 3(6):1101-8 [PubMed] Related Publications
Two different methods of presenting quantitative gene expression exist: absolute and relative quantification. Absolute quantification calculates the copy number of the gene usually by relating the PCR signal to a standard curve. Relative gene expression presents the data of the gene of interest relative to some calibrator or internal control gene. A widely used method to present relative gene expression is the comparative C(T) method also referred to as the 2 (-DeltaDeltaC(T)) method. This protocol provides an overview of the comparative C(T) method for quantitative gene expression studies. Also presented here are various examples to present quantitative gene expression data using this method.

Negrini M, Calin GA
Breast cancer metastasis: a microRNA story.
Breast Cancer Res. 2008; 10(2):203 [PubMed] Article available free on PMC after 12/08/2015 Related Publications
MicroRNAs (miRNAs) are small noncoding RNAs with regulatory functions, which play an important role in breast cancer. Several studies have shown that miRNAs can act either as tumor suppressors or as oncogenes, and that measurement of miRNA expression in malignancies may have diagnostic and prognostic implications. This article highlights a series of three recent studies that prove the involvement of miRNAs in breast cancer metastases. The first proves that miR-10b indirectly activates the pro-metastatic gene RHOC by suppressing HOXD10, thus leading to tumor invasion and metastasis. The second proves that miR-373 and miR-520c can also promote tumor invasion and metastasis, at least in part by regulating the gene CD44. The third identifies miR-335, miR-206, and miR-126 as suppressors of breast cancer metastasis. Loss of miR-335 leads to the activation of SOX4 and TNC (encoding tenascin C), which are responsible for the acquisition of metastatic properties. Altogether, these remarkable findings are important for our understanding of malignant transformation in the breast and may have implications for the management of patients with advanced breast cancer. The use of miRNAs as anticancer therapeutic agents is promising, and such fine molecular studies certainly help in bringing miRNAs closer to clinical practice.

Ma L, Teruya-Feldstein J, Weinberg RA
Tumour invasion and metastasis initiated by microRNA-10b in breast cancer.
Nature. 2007; 449(7163):682-8 [PubMed] Related Publications
MicroRNAs have been implicated in regulating diverse cellular pathways. Although there is emerging evidence that some microRNAs can function as oncogenes or tumour suppressors, the role of microRNAs in mediating cancer metastasis remains unexplored. Here we show, using a combination of mouse and human cells, that microRNA-10b (miR-10b) is highly expressed in metastatic breast cancer cells and positively regulates cell migration and invasion. Overexpression of miR-10b in otherwise non-metastatic breast tumours initiates robust invasion and metastasis. Expression of miR-10b is induced by the transcription factor Twist, which binds directly to the putative promoter of mir-10b (MIRN10B). The miR-10b induced by Twist proceeds to inhibit translation of the messenger RNA encoding homeobox D10, resulting in increased expression of a well-characterized pro-metastatic gene, RHOC. Significantly, the level of miR-10b expression in primary breast carcinomas correlates with clinical progression. These findings suggest the workings of an undescribed regulatory pathway, in which a pleiotropic transcription factor induces expression of a specific microRNA, which suppresses its direct target and in turn activates another pro-metastatic gene, leading to tumour cell invasion and metastasis.

Han L, Witmer PD, Casey E, et al.
DNA methylation regulates MicroRNA expression.
Cancer Biol Ther. 2007; 6(8):1284-8 [PubMed] Related Publications
MicroRNAs (miRNAs), an important class of small regulatory molecules for gene expression, are transcribed by RNA polymerase II. But little is known about the mechanisms that control miRNA expression. Comparing miRNA expression profiles between colon cancer cell line HCT 116 and its derivative, DNA methyltransferase 1 and 3b (DNMT1 and DNMT3b) double knockout cell line, we found that the expression of about 10% miRNAs was regulated by DNA methylation. In addition, neither 5-aza-2'-deoxycytidine treatment nor deletion of DNMT1 alone recapitulated miRNA expression profile seen in the double knockout cell line, suggesting that miRNA expression was tightly controlled by DNA methylation and partial methylation reduction was not sufficient for miRNA reexpression. We also found that HOXA3 and HOXD10 were putative targets of mir-10a, one of the differentially expressed miRNAs that is located in HOX gene cluster.

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.

Carrio M, Arderiu G, Myers C, Boudreau NJ
Homeobox D10 induces phenotypic reversion of breast tumor cells in a three-dimensional culture model.
Cancer Res. 2005; 65(16):7177-85 [PubMed] Related Publications
Homeobox (Hox) genes are master regulatory genes that direct organogenesis and maintain differentiated tissue function. We previously reported that HoxD10 helps to maintain a quiescent, differentiated phenotype in endothelial cells by suppressing expression of genes involved in remodeling the extracellular matrix and cell migration. Here we investigated whether HoxD10 could also promote or maintain a differentiated phenotype in epithelial cells. We observed that HoxD10 expression is progressively reduced in epithelial cells as malignancy increases in both breast and endometrial tumors. Retroviral gene transfer to restore expression of HoxD10 in the malignant breast tumor cells MDA-MB-231 significantly impaired migration, and when these cells were cultured in a three-dimensional laminin-rich basement membrane (3DlrBM) model, they formed polarized, acinar structures. This phenotypic reversion was accompanied by decreased alpha3 integrin expression and reduced proliferation. Importantly, expression of HoxD10 in the MDA-MB-231 cells inhibited their ability to form tumors in mouse xenografts. Taken together, our results suggest that HoxD10 has tumor-suppressive functions for mammary epithelial cells.

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