Research IndicatorsGraph generated 10 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 10 March, 2017 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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: HOXC6 (cancer-related)
Zhao MY, Yu Y, Xie M, et al.Digital gene expression profiling analysis of childhood acute lymphoblastic leukemia.
Mol Med Rep. 2016; 13(5):4321-8 [PubMed
] Related Publications
Acute lymphoblastic leukemia (ALL) is the most commonly diagnosed malignancy in children. It is a heterogeneous disease, and is determined by multiple gene alterations and chromosomal rearrangements. To improve current understanding of the underlying molecular mechanisms of ALL, the present study profiled genome‑wide digital gene expression (DGE) in a population of children with ALL in China. Using second‑generation sequencing technology, the profiling revealed that 2,825 genes were upregulated and 1,952 were downregulated in the ALL group. Based on the DGE profiling data, the present study further investigated seven genes (WT1, RPS26, MSX1, CD70, HOXC4, HOXA5 and HOXC6) using reverse transcription‑quantitative polymerase chain reaction analysis. Gene Ontology analysis suggested that the differentially expressed genes were predominantly involved in immune cell differentiation, metabolic processes and programmed cell death. The results of the present study provided novel insights into the gene expression patterns in children with ALL.
Tolkach Y, Merseburger A, Herrmann T, et al.Signatures of Adverse Pathological Features, Androgen Insensitivity and Metastatic Potential in Prostate Cancer.
Anticancer Res. 2015; 35(10):5443-51 [PubMed
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BACKGROUND/AIM: The genetic characterization of prostate tumors is important for personalized therapy. The aim of the present study was to investigate the role of previously described prostate cancer-related genes in the genetic characterization of prostate tumors.
MATERIALS AND METHODS: Forty-two genes were selected for expression analysis (real time-quantitative polymerase chain reaction). One normal prostatic epithelial cell line and three standardized prostate cancer cell lines were used. Twenty-eight patients treated with radical prostatectomy were included in the study.
RESULTS: The following genes appeared to be possibly related to the metastatic potential of the tumor: ELOVL fatty acid elongase 7 (ELOVL7), enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), gastrulation brain homeobox 2 (GBX2), golgi membrane protein 1 (GOLM1), homeobox C6 (HOXC6), minichromosome maintenance complex component 6 (MCM6), marker of proliferation Ki-67 (MKI67), mucin 1, cell surface associated (MUC1), MYC binding protein 2, E3 ubiquitin protein ligase (MYCBP2), somatostatin receptor 1 (SSTR1), topoisomerase (DNA) II alpha 170 kDa (TOP2A) and exportin 6 (XPO6). Six genes were differentially expressed in patients with localized and locally advanced cancer (GOLM1, GBX2, XPO6, SSTR1, TOP2A and cell division cycle associated 5, CDCA5) and three genes (HOXC6, Cyclin-dependent kinase inhibitor 2A (CDKN2A) and MYC binding protein 2, E3 ubiquitin protein ligase, MYCBP2) in patients with a low vs. high Gleason grade/sum.
CONCLUSION: Some of the investigated genes show promising prognostic and classification features, which might be useful in a clinical setting, warranting for further validation.
Hamid AR, Hoogland AM, Smit F, et al.The role of HOXC6 in prostate cancer development.
Prostate. 2015; 75(16):1868-76 [PubMed
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BACKGROUND: Homeobox (HOX) genes, which are involved in organ development and homeostasis, have been shown to be involved in normal prostate- and PCa development. In this study, we investigate the expression levels of the HOX A-D genes in PCa. The functional relevance and potential of HOX gene as biomarkers are explored.
METHODS: We evaluated HOX gene expression in prostate tissues of different grade and stage and related the outcome to clinical parameters. We analyzed AR regulation and function of HOXC6 in PCa cell lines. We developed a urine-based HOXC6 mRNA assay for diagnostic purposes.
RESULTS: HOXC6 was one of the most upregulated HOX genes in all primary, metastasized, and castration-resistant PCa. HOXC6 upregulation was specific to the epithelial component of PCa, and HOXC6 was shown to be involved in epithelial cell proliferation. HOXC6 expression was not influenced by androgens nor by treatments targeting the AR signaling pathway. HOXC6 expression was not related to a prognosis after radical prostatectomy, that is, biochemical or local recurrence. We successfully developed an assay for HOXC6 mRNA detection in urine and confirmed that HOXC6 levels are higher in PCa patients.
CONCLUSIONS: HOXC6 has a role in all PCa stages, particularly in PCa cell proliferation. Due to its stable expression, HOXC6 is a novel candidate biomarker for PCa not only in early detection but also for monitoring of progression or response to therapy.
Tait DL, Bahrani-Mostafavi Z, Vestal CG, et al.Downregulation of HOXC6 in Serous Ovarian Cancer.
Cancer Invest. 2015; 33(7):303-11 [PubMed
] Related Publications
Homeobox (HOX) genes encode transcription factors critical to morphogenesis and cell differentiation. Although dysregulation of several HOX genes in ovarian cancer has been reported, little is known about HOXC6 expression in epithelial ovarian cancer. In this report, analysis of laser capture microdissected samples determined HOXC6 expression patterns in normal versus malignant serous ovarian carcinoma tissues. HOXC6 protein was quantified by ELISA in parallel serum samples and further validated in a larger cohort of serum samples collected from women with and without serous ovarian carcinoma. These data demonstrate significant downregulation of HOXC6 in serous ovarian cancer.
Leyten GH, Hessels D, Smit FP, et al.Identification of a Candidate Gene Panel for the Early Diagnosis of Prostate Cancer.
Clin Cancer Res. 2015; 21(13):3061-70 [PubMed
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PURPOSE: Serum PSA (sPSA) testing has led to the identification of patients with indolent prostate cancer, and inevitably overtreatment has become a concern. Progensa PCA3 urine testing was shown to improve the diagnosis of prostate cancer, but its diagnostic value for aggressive prostate cancer is limited. Therefore, urinary biomarkers that can be used for prediction of Gleason score ≥7 prostate cancer in biopsies are urgently needed.
EXPERIMENTAL DESIGN: Using gene expression profiling data, 39 prostate cancer biomarkers were identified. After quantitative PCR analysis on tissue specimens and urinary sediments, eight promising biomarkers for the urinary detection of prostate cancer were selected (ONECUT2, HOXC4, HOXC6, DLX1, TDRD1, NKAIN1, MS4A8B, PPFIA2). The hypothesis that biomarker combinations improve the diagnostic value for aggressive prostate cancer was tested on 358 urinary sediments of an intention-to-treat cohort.
RESULTS: A urinary three-gene panel (HOXC6, TDRD1, and DLX1) had higher accuracy [area under the curve (AUC), 0.77; 95% confidence interval (CI), 0.71-0.83] to predict Gleason score ≥7 prostate cancer in biopsies compared with Progensa PCA3 (AUC, 0.68; 95% CI, 0.62-0.75) or sPSA (AUC, 0.72; 95% CI, 0.65-0.78). Combining the three-gene panel with sPSA further improved the predictive accuracy (AUC, 0.81; 95% CI, 0.75-0.86). The accuracy of the three-gene predictive model was maintained in subgroups with low sPSA concentrations.
CONCLUSIONS: The urinary three-gene panel (HOXC6, TDRD1, and DLX1) represents a promising tool to identify patients with aggressive prostate cancer, also in those with low sPSA values. The combination of the urinary three-gene panel with sPSA bears great potential for the early diagnosis of patients with clinically significant prostate cancer.
HOXC6 is a homeobox-containing gene associated with mammary gland development and is overexpressed in variety of cancers including breast and prostate cancers. Here, we have examined the expression of HOXC6 in breast cancer tissue, investigated its transcriptional regulation via estradiol (E2) and bisphenol-A (BPA, an estrogenic endocrine disruptor) in vitro and in vivo. We observed that HOXC6 is differentially over-expressed in breast cancer tissue. E2 induces HOXC6 expression in cultured breast cancer cells and in mammary glands of Sprague Dawley rats. HOXC6 expression is also induced upon exposure to BPA both in vitro and in vivo. Estrogen-receptor-alpha (ERα) and ER-coregulators such as MLL-histone methylases are bound to the HOXC6 promoter upon exposure to E2 or BPA and that resulted in increased histone H3K4-trimethylation, histone acetylation, and recruitment of RNA polymerase II at the HOXC6 promoter. HOXC6 overexpression induces expression of tumor growth factors and facilitates growth 3D-colony formation, indicating its potential roles in tumor growth. Our studies demonstrate that HOXC6, which is a critical player in mammary gland development, is upregulated in multiple cases of breast cancer, and is transcriptionally regulated by E2 and BPA, in vitro and in vivo.
Wang DD, Xu Y, Tu YL, et al.Comparison analysis in synchronous and metachronous metastatic colorectal cancer based on microarray expression profile.
Hepatogastroenterology. 2014 Nov-Dec; 61(136):2215-8 [PubMed
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BACKGROUND/AIMS: Colorectal cancer (CRC) is one of the most common malignancies, and liver metastasis is one of the major causes of death of CRC. This study aimed to compare the genetic difference between metachronous lesions (MC) and synchronous lesions (SC) and explore the molecular pathology of CRC metastasis.
METHODOLOGY: Microarray expression profile data (GSE10961) including 8 MC and 10 SC was downloaded from Gene Expression Omnibus. The differentially expressed genes (DEGs) between the two groups were identified based on T test. Furthermore, GO enrichment analysis was performed for the down-regulated DEGs using DAVID. Finally, Classify validation of known CRC genes based on previous studies between MC and SC samples was conducted.
RESULTS: Total of 36 DEGs including 35 down-regulated DEGs and 1 up-regulated DEGs were identified. The expressional differences of the 5 informative oncogenes: EGFr, PIK3R1, PTGS2 (COX-2), PTGS1 (COX1), and ALOX5AP between SC and MC were really tiny.
CONCLUSIONS: Some DEGs, such as NFAT5, OLR1, ERAP2, HOXC6 and TWIST1 might play crucial roles in the regulation of CRC metastasis (both SC and MC) and by disrupting some pathways. However, our results indeed demand further research and experiment.
BACKGROUND: We analysed critically the potential usefulness of RNA- and DNA-based biomarkers in supporting conventional histological diagnostic tests for prostate carcinoma (PCa) detection.
METHODS: Microarray profiling of gene expression and DNA methylation was performed on 16 benign prostatic hyperplasia (BPH) and 32 cancerous and non-cancerous prostate samples extracted by radical prostatectomy. The predictive value of the selected biomarkers was validated by qPCR-based methods using tissue samples extracted from the 58 prostates and, separately, using 227 prostate core biopsies.
RESULTS: HOXC6, AMACR and PCA3 expression showed the best discrimination between PCa and BPH. All three genes were previously reported as the most promising mRNA-based markers for distinguishing cancerous lesions from benign prostate lesions; however, none were sufficiently sensitive and specific to meet the criteria for a PCa diagnostic biomarker. By contrast, DNA methylation levels of the APC, TACC2, RARB, DGKZ and HES5 promoter regions achieved high discriminating sensitivity and specificity, with area under the curve (AUCs) reaching 0.95-1.0. Only a small overlap was detected between the DNA methylation levels of PCa-positive and PCa-negative needle biopsies, with AUCs ranging between 0.854 and 0.899.
CONCLUSIONS: DNA methylation-based biomarkers reflect the prostate malignancy and might be useful in supporting clinical decisions for suspected PCa following an initial negative prostate biopsy.
Tumor suppressor genes (TSGs) are commonly inactivated by somatic mutation and/or promoter methylation; yet, recent high-throughput genomic studies have not identified key TSGs inactivated by both mechanisms. We pursued an integrated molecular analysis based on methylation binding domain sequencing (MBD-seq), 450K Methylation arrays, whole exome sequencing, and whole genome gene expression arrays in primary head and neck squamous cell carcinoma (HNSCC) tumors and matched uvulopalatopharyngoplasty tissue samples (UPPPs). We uncovered 186 downregulated genes harboring cancer specific promoter methylation including PAX1 and PAX5 and we identified 10 key tumor suppressor genes (GABRB3, HOXC12, PARP15, SLCO4C1, CDKN2A, PAX1, PIK3AP1, HOXC6, PLCB1, and ZIC4) inactivated by both promoter methylation and/or somatic mutation. Among the novel tumor suppressor genes discovered with dual mechanisms of inactivation, we found a high frequency of genomic and epigenomic alterations in the PAX gene family of transcription factors, which selectively impact canonical NOTCH and TP53 pathways to determine cell fate, cell survival, and genome maintenance. Our results highlight the importance of assessing TSGs at the genomic and epigenomic level to identify key pathways in HNSCC, deregulated by simultaneous promoter methylation and somatic mutations.
Du YB, Dong B, Shen LY, et al.The survival predictive significance of HOXC6 and HOXC8 in esophageal squamous cell carcinoma.
J Surg Res. 2014; 188(2):442-50 [PubMed
] Related Publications
BACKGROUND & AIM: Esophageal squamous cell carcinoma (ESCC), a common disease in China, is mainly treated surgically. We established a prospective database of patients with esophageal cancer between January 2000 and December 2010, including 486 subjects with ESCC who underwent surgical treatment. In this study, we explored the prognostic significance of the expressions of HOXC6 and HOXC8, responsible for embryonic development, by studying the specimens collected from clinical subjects during strict follow-up periods.
MATERIALS & METHODS: Immunohistochemistry was used to detect the expressions of HOXC6 and HOXC8 in 274 ESCC subjects including 138 ESCC subjects treated with surgery alone and 136 ESCC subjects treated with neoadjuvant chemotherapy. Survival analysis was performed from the day of surgery to August 2013.
RESULTS: The 5-y survival rate of the 274 ESCC subjects was 44.2%, with a median survival time of 44.12 mo. For the 274 ESCC subjects involved in the investigation of HOXC6 and HOXC8 expressions, the median survival time of subjects with high-level expressions of HOXC6 and HOXC8 was shorter than that for subjects with low-level expressions (P = 0.001, P < 0.001, respectively). Similar results were obtained from the analysis of the prognostic value of HOXC6 and HOXC8 in the group treated with surgery alone and the group treated with neoadjuvant chemotherapy. Multivariate analysis demonstrated that HOXC6 and HOXC8 expressions were independent prognostic factors in patients with ESCC.
CONCLUSIONS: The HOXC6 and HOXC8 genes can be used as prognostic markers in patients with ESCC, but prospective studies are still needed to confirm.
Multiple epigenetic alterations contribute to prostate cancer progression by deregulating gene expression. Epigenetic mechanisms, especially differential DNA methylation at imprinting control regions (termed DMRs), normally ensure the exclusive expression of imprinted genes from one specific parental allele. We therefore wondered to which extent imprinted genes become deregulated in prostate cancer and, if so, whether deregulation is due to altered DNA methylation at DMRs. Therefore, we selected presumptive deregulated imprinted genes from a previously conducted in silico analysis and from the literature and analyzed their expression in prostate cancer tissues by qRT-PCR. We found significantly diminished expression of PLAGL1/ZAC1, MEG3, NDN, CDKN1C, IGF2, and H19, while LIT1 was significantly overexpressed. The PPP1R9A gene, which is imprinted in selected tissues only, was strongly overexpressed, but was expressed biallelically in benign and cancerous prostatic tissues. Expression of many of these genes was strongly correlated, suggesting co-regulation, as in an imprinted gene network (IGN) reported in mice. Deregulation of the network genes also correlated with EZH2 and HOXC6 overexpression. Pyrosequencing analysis of all relevant DMRs revealed generally stable DNA methylation between benign and cancerous prostatic tissues, but frequent hypo- and hyper-methylation was observed at the H19 DMR in both benign and cancerous tissues. Re-expression of the ZAC1 transcription factor induced H19, CDKN1C and IGF2, supporting its function as a nodal regulator of the IGN. Our results indicate that a group of imprinted genes are coordinately deregulated in prostate cancers, independently of DNA methylation changes.
Mengual L, Ars E, Lozano JJ, et al.Gene expression profiles in prostate cancer: identification of candidate non-invasive diagnostic markers.
Actas Urol Esp. 2014; 38(3):143-9 [PubMed
] Related Publications
OBJECTIVE: To analyze gene expression profiles of prostate cancer (PCa) with the aim of determining the relevant differentially expressed genes and subsequently ascertain whether this differential expression is maintained in post-prostatic massage (PPM) urine samples.
MATERIAL AND METHODS: Forty-six tissue specimens (36 from PCa patients and 10 controls) and 158 urine PPM-urines (113 from PCa patients and 45 controls) were collected between December 2003 and May 2007. DNA microarrays were used to identify genes differentially expressed between tumour and control samples. Ten genes were technically validated in the same tissue samples by quantitative RT-PCR (RT-qPCR). Forty two selected differentially expressed genes were validated in an independent set of PPM-urines by qRT-PCR.
RESULTS: Multidimensional scaling plot according to the expression of all the microarray genes showed a clear distinction between control and tumour samples. A total of 1047 differentially expressed genes (FDR≤.1) were indentified between both groups of samples. We found a high correlation in the comparison of microarray and RT-qPCR gene expression levels (r=.928, P<.001). Thirteen genes maintained the same fold change direction when analyzed in PPM-urine samples and in four of them (HOXC6, PCA3, PDK4 and TMPRSS2-ERG), these differences were statistically significant (P<.05).
CONCLUSION: The analysis of PCa by DNA microarrays provides new putative mRNA markers for PCa diagnosis that, with caution, can be extrapolated to PPM-urines.
DeInnocentes P, Perry AL, Graff EC, et al.Characterization of HOX gene expression in canine mammary tumour cell lines from spontaneous tumours.
Vet Comp Oncol. 2015; 13(3):322-36 [PubMed
] Related Publications
Spatial/temporal controls of development are regulated by the homeotic (HOX) gene complex and require integration with oncogenes and tumour suppressors regulating cell cycle exit. Spontaneously derived neoplastic canine mammary carcinoma cell models were investigated to determine if HOX expression profiles were associated with neoplasia as HOX genes promote neoplastic potential in human cancers. Comparative assessment of human and canine breast cancer expression profiles revealed remarkable similarity for all four paralogous HOX gene clusters and several unlinked HOX genes. Five canine HOX genes were overexpressed with expression profiles consistent with oncogene-like character (HOXA1, HOXA13, HOXD4, HOXD9 and SIX1) and three HOX genes with underexpressed profiles (HOXA11, HOXC8 and HOXC9) were also identified as was an apparent nonsense mutation in HOXC6. This data, as well as a comparative analysis of similar data from human breast cancers suggested expression of selected HOX genes in canine mammary carcinoma could be contributing to the neoplastic phenotype.
Chen EY, Dobrinski KP, Brown KH, et al.Cross-species array comparative genomic hybridization identifies novel oncogenic events in zebrafish and human embryonal rhabdomyosarcoma.
PLoS Genet. 2013; 9(8):e1003727 [PubMed
] Free Access to Full Article Related Publications
Human cancer genomes are highly complex, making it challenging to identify specific drivers of cancer growth, progression, and tumor maintenance. To bypass this obstacle, we have applied array comparative genomic hybridization (array CGH) to zebrafish embryonal rhabdomyosaroma (ERMS) and utilized cross-species comparison to rapidly identify genomic copy number aberrations and novel candidate oncogenes in human disease. Zebrafish ERMS contain small, focal regions of low-copy amplification. These same regions were commonly amplified in human disease. For example, 16 of 19 chromosomal gains identified in zebrafish ERMS also exhibited focal, low-copy gains in human disease. Genes found in amplified genomic regions were assessed for functional roles in promoting continued tumor growth in human and zebrafish ERMS--identifying critical genes associated with tumor maintenance. Knockdown studies identified important roles for Cyclin D2 (CCND2), Homeobox Protein C6 (HOXC6) and PlexinA1 (PLXNA1) in human ERMS cell proliferation. PLXNA1 knockdown also enhanced differentiation, reduced migration, and altered anchorage-independent growth. By contrast, chemical inhibition of vascular endothelial growth factor (VEGF) signaling reduced angiogenesis and tumor size in ERMS-bearing zebrafish. Importantly, VEGFA expression correlated with poor clinical outcome in patients with ERMS, implicating inhibitors of the VEGF pathway as a promising therapy for improving patient survival. Our results demonstrate the utility of array CGH and cross-species comparisons to identify candidate oncogenes essential for the pathogenesis of human cancer.
Zhang Q, Jin XS, Yang ZY, et al.Upregulated Hoxc6 expression is associated with poor survival in gastric cancer patients.
Neoplasma. 2013; 60(4):439-45 [PubMed
] Related Publications
Human Hox genes (Homeobox) have crucial roles in development and differentiation, regulating numerous processes including apoptosis, receptor signalling, differentiation, motility and angiogenesis. Aberrant expression of Hoxc6 gene has been reported in several tumor tissues and cancer cell lines. The prognostic significance of Hoxc6 in gastric cancer remains largely unknown.This study was aimed to investigate the clinical significance of Hoxc6 in gastric cancer.Total RNA of paired tissue samples (n=25) and a tissue microarray containing 161 paired tissues from patients with gastric cancers at different stages were collected. Quantitative real-time PCR and immunochemistry assay were carried out to investigate the expression of Hoxc6. Hoxc6 mRNA was increased in gastric cancer tissues ( 16 of 25) compared with the adjacent normal mucosa (P<0.05). Immunohistochemical detection showed that expression of Hoxc6 was associated with the depth of tumor invasion (P<0.05). Patients with higher expression levels of Hoxc6 had a shorter overall survival rate (P<0.05).Hoxc6 might contribute to the progression of gastric carcinogenesis and may be a significant predictor of poor survival in patients with gastric cancer after curative operations.
Homeobox C6 (HOXC6) genes belong to the homeoprotein family of transcription factors, which play an important role in morphogenesis and cellular differentiation during embryonic development. The aim of this study was to explore the role of HOXC6 in the regulation of Bcl-2 in human head and neck squamous cell carcinoma (HNSCC). The HOXC6 and Bcl-2 gene were identified as being overexpressed in HNSCC tissue and cell lines. Transfection assays demonstrated that HOXC6 increased the levels of Bcl-2 mRNA and protein. A luciferase reporter assay suggested that HOXC6 induced activity of the Bcl-2 promoter. A series of Bcl-2 promoter deletion mutants were examined and the minimal HOXC6-responsive region was identified to be in the TAAT motif (-420 bp) of the Bcl-2 promoter. Interestingly, the inhibition of HOXC6 using siRNA led to the repression of Bcl-2 expression and induced caspase-3-dependent apoptosis; overexpression of HOXC6 in HNSCC cells increased the resistance to paclitaxel-induced apoptosis. Together, our findings suggest that HOXC6 is an important mechanism of the anti-apoptotic pathway via regulation of Bcl-2 expression.
Androgens are essential for the development of the prostate and prostate cancer. We examined androgen-regulated gene expression in the human prostate. Samples from benign and malignant prostate tissue and samples containing prostate tissue obtained from prostate cancer patients three days after surgical castration were further processed as probes for a GeneChip array. The comparison of gene expression profiles in castrated samples and in benign or malignant prostate tissue samples revealed androgen-regulated genes. We further evaluated the genes which were differentially expressed in benign and malignant prostate samples. The androgen-regulated expression of dual specificity phosphatase 1 (DUSP1) was confirmed in the LNCaP prostate cancer cell line, as the expression of DUSP1 increased with androgen treatment over the course of time. The expression of the genes CRISP3, PCA3, OR51E2, HOXC6, AGR3, AMACR and SLC14A1 was affected by castration in addition to differential expression in the benign and malignant prostate. These sample results require further investigation for the role of AGR3 and SLC14A1 in prostate cancer as these associations have not been reported previously.
BACKGROUND & AIMS: The molecular alterations that underlie carcinoid tumor pathogenesis remain poorly defined. The homeobox gene HOXC6 was highly up-regulated in human gastrointestinal carcinoid tumors, and we sought to define its pathogenic role.
METHODS: The functional and physical properties of Hoxc6 were investigated by establishing carcinoid cells that stably overexpressed Hoxc6 or were deficient in Hoxc6. Cellular proliferation assays, luciferase reporter assays, Western blotting, immunoprecipitation, DNA affinity precipitation, and DNA microarray studies were performed.
RESULTS: Expression of Hoxc6 in cultured human BON1 carcinoid cells enhanced their proliferation, and knock-down of Hoxc6 inhibited their growth. Hoxc6 activated the oncogenic activator protein-1 signaling pathway through a physical interaction with JunD. Mutations in the homeodomain of Hoxc6 blocked this interaction and inhibited proliferation of carcinoid cells. Of note, Hoxc6 induced the expression of genes that characteristically are up-regulated in carcinoid tumors, including neurotensin and connective tissue growth factor.
CONCLUSIONS: A novel molecular pathway has been identified that links Hoxc6 with oncogenic signaling through the activator protein-1 pathway in carcinoid tumorigenesis.
Homeobox transcription factors are developmentally regulated genes that play crucial roles in tissue patterning. Homeobox C6 (HOXC6) is overexpressed in prostate cancers and correlated with cancer progression, but the downstream targets of HOXC6 are largely unknown. We have performed genome-wide localization analysis to identify promoters bound by HOXC6 in prostate cancer cells. This analysis identified 468 reproducibly bound promoters whose associated genes are involved in functions such as cell proliferation and apoptosis. We have complemented these data with expression profiling of prostates from mice with homozygous disruption of the Hoxc6 gene to identify 31 direct regulatory target genes of HOXC6. We show that HOXC6 directly regulates expression of bone morphogenic protein 7, fibroblast growth factor receptor 2, insulin-like growth factor binding protein 3, and platelet-derived growth factor receptor alpha (PDGFRA) in prostate cells and indirectly influences the Notch and Wnt signaling pathways in vivo. We further show that inhibition of PDGFRA reduces proliferation of prostate cancer cells, and that overexpression of HOXC6 can overcome the effects of PDGFRA inhibition. HOXC6 regulates genes with both oncogenic and tumor suppressor activities as well as several genes such as CD44 that are important for prostate branching morphogenesis and metastasis to the bone microenvironment.
Zhang X, Hamada J, Nishimoto A, et al.HOXC6 and HOXC11 increase transcription of S100beta gene in BrdU-induced in vitro differentiation of GOTO neuroblastoma cells into Schwannian cells.
J Cell Mol Med. 2007 Mar-Apr; 11(2):299-306 [PubMed
] Free Access to Full Article Related Publications
HOX genes encode transcription factors that play a key role in morphogenesis and cell differentiation during embryogenesis of animals. Human neuroblastoma cells are known to be chemically induced to differentiate into neuronal or Schwannian cells. In the present study, we investigated the roles of HOX genes in differentiation of GOTO neuroblastoma cells into Schwannian cells. When GOTO cells were grown in the presence of 5-bromo-2'-deoxyuridine (BrdU), they increased the expressions of two HOX genes (HOXC6 and HOXC11) and marker genes for Schwannian cells (S100beta and myelin basic protein). Forced expression of HOXC11 alone or both HOXC6 isoform 1 and HOXC11 induced the expression of S100beta in GOTO cells. In transient transfection experiments, the overexpression of HOXC6 and HOXC11 transactivated the S100beta promoter-reporter construct. Taken together, our results suggest that HOXC6 and HOXC11 are associated with differentiation of GOTO cells into Schwannian cells through the transcriptional activation of S100beta gene.
Hassan NM, Hamada J, Murai T, et al.Aberrant expression of HOX genes in oral dysplasia and squamous cell carcinoma tissues.
Oncol Res. 2006; 16(5):217-24 [PubMed
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Human HOX genes consist of 39 genes and encode transcription factors that function as master developmental regulators. We hypothesized that the misexpression of HOX genes was associated with carcinogenesis and malignant progression. The expression levels of 39 HOX genes in 31 human oral squamous cell carcinoma (SCC), 11 dysplasia, and 10 normal mucosa tissues were quantified by the real-time RT-PCR method. The expression levels of 18 HOX genes in the SCC tissues were significantly higher than those in the normal mucosa tissues. The dysplasia tissues showed higher expression of HOXA2, A3, B3, and D10 than normal mucosa tissues whereas they showed lower expression of HOXA1, B7, B9, and C8 than SCC. The SCC with lymph node metastasis showed high expression of HOXC6 compared to the SCC without it. These results suggest that misexpressions of particular HOX genes are implicated in the development of oral dysplasia and SCC.
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.
Thompson MA, Stumph J, Henrickson SE, et al.Differential gene expression in anaplastic lymphoma kinase-positive and anaplastic lymphoma kinase-negative anaplastic large cell lymphomas.
Hum Pathol. 2005; 36(5):494-504 [PubMed
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Anaplastic large cell lymphoma (ALCL) is an aggressive large T- or null-cell lymphoma. Most ALCLs arising in children and young adults express a constitutively active receptor tyrosine kinase, anaplastic lymphoma kinase (ALK). Anaplastic large cell lymphomas lacking ALK are clinically heterogeneous and their pathogenesis is unknown. This study is the first complementary DNA (cDNA) microarray analysis using RNA extracted from tumor tissue (7 ALK+ ALCLs and 7 ALK- ALCLs) to identify genes differentially expressed or shared between the ALK+ and ALK- tumors. Unsupervised hierarchical clustering using the top 11 most statistically significant discriminator cDNAs correctly grouped all ALK+ and ALK- tumors. Hierarchical clustering analysis using the 44 cDNAs with the greatest differential expression between ALK+ and ALK- RNAs grouped 6 of 7 ALK+ ALCLs together and 1 ALK+ ALCL with the ALK- group. In general, ALK+ tumors overexpress genes encoding signal transduction molecules (SYK , LYN , CDC37) and underexpress transcription factor genes (including HOXC6 and HOX A3 ) compared with the ALK- group. Cyclin D3 was overexpressed in the ALK+ group and the cell cycle inhibitor p19INK4D was decreased in the ALK- group, suggesting different mechanisms of promoting G 1 /S transition. Both groups had similar proliferation rates. Genes highly expressed in both ALK- and ALK+ ALCLs included kinases (LCK, protein kinase C, vav2, and NKIAMRE) and antiapoptotic molecules, suggesting possible common pathogenetic mechanisms as well.
Chen KN, Gu ZD, Ke Y, et al.Expression of 11 HOX genes is deregulated in esophageal squamous cell carcinoma.
Clin Cancer Res. 2005; 11(3):1044-9 [PubMed
] Related Publications
PURPOSE: HOX genes are vital for all aspects of mammalian growth and differentiation, and recent data have shown that their deregulated expression is related to carcinogenesis. To date, there has been no systemic study on expression of HOX genes in esophageal carcinoma. We investigated the expression pattern of 39 known HOX genes in cancerous and noncancerous tissue from 36 patients with esophageal squamous cell carcinoma to determine whether their expression is altered in esophageal cancer.
EXPERIMENTAL DESIGN: Thirty-six patients with resectable esophageal squamous cell carcinoma (ESCC) were enrolled in this study. Specific primers were designed for each of 39 HOX genes, and reverse transcription-PCR was done in cancerous and noncancerous samples of these 36 patients. Furthermore, the expression of HOXA9 protein was subjected to Western blot analysis in all 36 paired tissue samples.
RESULTS: Eight of 39 HOX genes were expressed in cancerous but not in noncancerous tissue. Five of 39 HOX genes were expressed both in cancerous and noncancerous tissue. Of the latter, expression of HOXA7, HOXA9, and HOXC6 was significantly higher in cancerous tissue (P < 0.05). The remaining 26 HOX genes were not detected in either types of tissue. HOXA9 protein was expressed in both kinds of tissue (cancer tissue versus noncancerous mucosa: 0.34 +/- 0.32 versus 0.24 +/- 0.27, P = 0.121).
CONCLUSIONS: This is the first comprehensive survey of 39 HOX gene expression in ESCC and noncancerous mucosa. Five of the 39 HOX genes were expressed in both types of tissue indicating their possible role in maintaining normal structure and function of adult esophageal mucosa. Eleven of the 39 HOX genes were deregulated in cancer tissue. These genes possibly participate in the carcinogenesis of ESCC.
Ramachandran S, Liu P, Young AN, et al.Loss of HOXC6 expression induces apoptosis in prostate cancer cells.
Oncogene. 2005; 24(1):188-98 [PubMed
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We have performed whole genome expression profiling of 28 patient prostate tumor samples and 12 normal prostate samples and identified 55 upregulated and 60 downregulated genes significantly changed in prostate tumor samples compared to normal prostate tissues. Among the members of the upregulated gene set was the developmental transcription factor Homeobox C6 (HOXC6). Silencing of HOXC6 expression using small-interfering RNA (siRNA) resulted in decreased proliferation rates for both androgen-dependent LnCaP cells and the LnCaP-derived androgen-independent C4-2 cell line. Flow cytometry and immunoblotting for the caspase-cleaved form of poly-ADP ribose polymerase (PARP) determined that the decrease in cell numbers was due to increased apoptosis. To validate the specificity of the siRNA-induced apoptosis, LnCaP cells were cotransfected with siRNA specific to the HOXC6 3'UTR and a mammalian expression vector containing the HOXC6 open reading frame, but lacking the 3'UTR. Overexpression of HOXC6 rescued the LnCaP cells from HOXC6 siRNA-induced apoptosis, and increased growth of control GFP siRNA-transfected cells. Expression profiling of HOXC6 siRNA transfections and HOXC6 overexpression identified neutral endopeptidase (NEP) and insulin-like growth factor binding protein-3 (IGFBP-3) as potential proapoptotic repression targets of HOXC6. Our data suggest that HOXC6 may be a novel potential therapeutic target for prostate cancer.
Bertrand FE, Spengeman JD, Shah N, LeBien TWB-cell development in the presence of the MLL/AF4 oncoprotein proceeds in the absence of HOX A7 and HOX A9 expression.
Leukemia. 2003; 17(12):2454-9 [PubMed
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Infant acute lymphoblastic leukemia (ALL) is frequently characterized by the t(4;11)(q21;q23) cytogenetic abnormality encoding the MLL/AF4 oncogene, increased HOX gene expression and a pro-B/monocytoid phenotype. We have previously established a novel MLL/AF4-positive cell line, B-lineage 3 (BLIN-3), which retains several features of normal B-lineage development (functional Ig gene rearrangement and apoptotic sensitivity to stromal cell withdrawal) not generally observed in infant ALL. We now use microarray analysis to identify patterns of gene expression in BLIN-3 that may modulate MLL/AF4 oncogenesis and contribute to the retention of normal B-lineage developmental characteristics. Comparison of 6815 expressed genes in BLIN-3 with published microarray data on leukemic blasts from t(4;11) patients indicated that BLIN-3 was unique in lacking the expression of certain HOX-A cluster genes. These results were validated by RT-PCR showing no expression of HOX A7 or HOX A9 in BLIN-3. A HOX C8 promoter reporter was active in BLIN-3, indicating that lack of HOX gene expression in BLIN-3 was not due to a nonfunctional MLL/AF4. Our results suggest that B-lineage development can proceed in t(4;11) leukemic blasts in the absence of HOX-A gene expression.
Miller GJ, Miller HL, van Bokhoven A, et al.Aberrant HOXC expression accompanies the malignant phenotype in human prostate.
Cancer Res. 2003; 63(18):5879-88 [PubMed
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Dysregulation of HOX gene expression has been implicated as a factor in malignancies for a number of years. However, no consensus has emerged regarding specific causative genes. Using a degenerate reverse transcription-PCR technique, we show up-regulation of genes from the HOXC cluster in malignant prostate cell lines and lymph node metastases. When relative expression levels of the four HOX clusters were examined, lymph node metastases and cell lines derived from lymph node metastases exhibited very similar patterns, patterns distinct from those in benign cells or malignant cell lines derived from other tumor sites. Specific reverse transcription-PCR for HOXC4, HOXC5, HOXC6, and HOXC8 confirmed overexpression of these genes in malignant cell lines and lymph node metastases. Laser capture microdissection and examination of paired tumor/normal prostate epithelial cells also indicated overexpression of these HOXC genes in primary tumor cells. Our data indicate a possible link between expression of HOXC genes and malignancy in prostate cells. Overexpression of HOXC8 in LNCaP prostate cancer cells suppressed transactivation by androgen receptors. We speculate that HOXC overexpression may predispose tumor cells to androgen independence by necessitating adaptation to diminished androgen signaling.
Amesse LS, Moulton R, Zhang YM, Pfaff-Amesse TExpression of HOX gene products in normal and abnormal trophoblastic tissue.
Gynecol Oncol. 2003; 90(3):512-8 [PubMed
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OBJECTIVE: The expression pattern of three homeobox genes products, HOX A11, HOX B6, and HOX C6, was examined in normal human placental tissue and abnormal trophoblastic tissue derived from complete hydatidiform moles and choriocarcinoma tumors. We sought to determine whether expression of these gene products during different states of trophoblastic differentiation and proliferation is constant or demonstrates variation. Variation in expression of these respective homeobox genes may provide insight into predicting which molar tissues are likely to develop into choriocarcinoma tumors.
METHODS: Tissue sections from a total of 12 samples were studied. Among these, six full-term human placentas, three complete hydatidiform moles, and three choriocarcinoma tumors were examined for expression of the homeobox HOX A11, HOX B6, and HOX C6 gene products, using immunohistochemistry staining methods.
RESULTS: Expression of HOX homeobox gene products, HOX A11, HOX B6, and HOX C6, was detected in full-term human placenta and tissue from complete hydatiform moles. Abnormal trophoblasts from complete moles demonstrated an immunoreactivity expression pattern comparable to that of normal trophoblasts from term pregnancies. However, definitive expression of these respective homeobox genes was not identified in tissue obtained from choriocarcinoma tumors.
CONCLUSION: Variation in expression of HOX homeobox gene products, HOX A11, HOX B6, and HOX C6, was established in trophoblast tissue obtained from full-term human placentas, complete hydatiform moles, and choriocarcinoma tumors. This finding indicates that normal full-term trophoblasts and abnormal molar trophoblasts may share similar fundamental regulatory control mechanisms. The absence of definitive expression of these HOX gene products in trophoblastic cells derived from choriocarcinoma tumors indicates that while HOX A11, HOX B6, and HOX C6 genes may be involved in maintenance of some trophoblastic cell states, they may be either downregulated or have alterations in their expression in trophoblasts from choriocarcinoma tumors.
Ferrando AA, Armstrong SA, Neuberg DS, et al.Gene expression signatures in MLL-rearranged T-lineage and B-precursor acute leukemias: dominance of HOX dysregulation.
Blood. 2003; 102(1):262-8 [PubMed
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Rearrangements of the MLL locus, located on human chromosome 11q23, are frequent in both infant and therapy-related leukemias. Gene expression analysis of MLL-rearranged B-precursor acute lymphoblastic leukemias (MLL B-ALLs) has identified these cases as a unique subtype of leukemia, characterized by the expression of genes associated with both lymphoid and myeloid hematopoietic lineages. Here we show that MLL fusions also generate a distinct genetic subtype of T-lineage ALL (MLL T-ALL), in which leukemic cells are characterized by an early arrest in thymocyte differentiation, with suggestive evidence of commitment to the gammadelta lineage. Interestingly, multiple genes linked to cell proliferation (eg, PCNA, MYC, CDK2, and POLA) were down-regulated in MLL-fusion samples, relative to those transformed by other T-ALL oncogenes (P <.000 001, Fisher exact test). Overall, MLL T-ALL cases consistently demonstrated increased levels of expression of a subset of major HOX genes--HOXA9, HOXA10, and HOXC6--and the MEIS1 HOX coregulator (P <.008, one-sided Wilcoxon test), a pattern of gene expression that was reiterated in MLL B-ALLs. However, expression of myeloid lineage genes, previously reported in MLL B-ALLs, was not identified in T-lineage cases with this abnormality, suggesting that myeloid gene dysregulation is dispensable in leukemic transformation mediated by MLL fusion proteins. Our findings implicate dysregulation of HOX gene family members as a dominant mechanism of leukemic transformation induced by chimeric MLL oncogenes.
Zhang YM, Xu B, Rote N, et al.Expression of homeobox gene transcripts in trophoblastic cells.
Am J Obstet Gynecol. 2002; 187(1):24-32 [PubMed
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OBJECTIVE: This study was conducted to examine the dynamics of homeobox gene expression in the differentiation of trophoblasts as a key to the understanding of the regulatory mechanisms that are involved in placental development.
STUDY DESIGN: Expression of homeobox genes was examined in primary trophoblastic cells and in the BeWo choriocarcinoma model cell lines by molecular and immunocytochemistry techniques.
RESULTS: We demonstrated the expression of 3 homeobox genes (HOX B6, HOX C6, and HOX A11) in primary trophoblastic cells. BeWo cells showed an expression pattern similar to that of the primary cell lines. In both primary trophoblasts and BeWo cells, the HOX A11 gene, but not the HOX B6 or HOX C6 genes, were found to down-regulate with differentiation from single- to multinucleate giant cells.
CONCLUSION: This study demonstrates a novel expression pattern for HOX A11 gene in trophoblastic differentiation and suggests that the down-regulation of HOX A11 may be necessary for the differentiation of cytotrophoblasts into syncytiotrophoblasts.