Homeobox C6 Research Articles

Homeobox C10 Influences on the Malignant Phenotype of Gastric Cancer Cell Lines and its Elevated Expression Positively Correlates with Recurrence and Poor Survival.

The detection of molecules and mechanisms affecting the malignant phenotype of gastric cancer cells may contribute to the identification of biomarkers for metastasis and recurrence, and such molecules may serve as targets of therapy. For this purpose, in this study transcriptome analysis was performed using surgically resected specimens from patients with gastric cancer with synchronous metastasis. We identified homeobox C10 (HOXC10) as the most highly expressed gene in gastric cancer tissues compared with the adjacent noncancerous gastric mucosa. Polymerase chain reaction (PCR) array analysis was performed to identify genes coordinately expressed with HOXC10. The effects of inhibiting HOXC10 on malignant phenotype was evaluated using HOXC10 knockout gastric cancer cell lines, and antibody array analysis was performed to assess the effect of HOXC10 knockout on intracellular signaling. We used a mouse subcutaneous xenograft model to evaluate the tumorigenicity. HOXC10 expression was determined in gastric cancer tissues acquired from 300 patients with gastric cancer. PCR array analysis revealed that the levels of HOXC10 messenger RNA positively correlated with those of FGFBP1 and SOX10. The phosphorylation of ERK1/2 was decreased in HOXC10 knockout cells. HOXC10 knockout significantly suppressed proliferation by increasing apoptosis and reducing the migration and invasiveness of gastric cancer cells. Mouse xenograft models revealed that the tumorigenicity of HOXC10 knockout cells was attenuated compared with the parental cells. The relatively high expression levels of HOXC10 in gastric cancer tissues were significantly associated with hepatic and peritoneal recurrence, as well as worse prognosis. Our results indicated that HOXC10 enhances the malignant phenotype of gastric cancer cells. The expression levels of HOXC10 may therefore serve as a prognostic biomarker and the products of HOXC10 may provide targets of therapy.

Embryonic morphology observation and HOXC8 gene expression in crest cushions of Chinese Crested duck

The Chinese Crested duck (Fengtou duck) reappeared in China recently. Along with white feathers and a black bill and feet, the Fengtou duck has a high feather crest. This breed can be used for ornamental purposes or as a model organism; however, little is known about the genetic basis and development of its distinct morphological features. In this study, we observed the skull and feather crest of Fengtou duck in the embryonic stages. As a result, the protuberances of the head integument could be clearly observed at embryonic stage E9, and small perforations in the skull were first visible at E13 and were clearer at E15. Besides, intracranial fat in a small number of individuals was found starting at E15, and a small number of osteophytes was found at E18. In addition, hematoxylin–eosin (HE) and Oil Red-O staining of the crest cushion and intracranial tissue revealed fat tissue accumulation. Previous studies demonstrated that homeobox c8 (HOXC8) played a critical role in chicken crest formation. Here, we cloned the HOXC8 from Fengtou duck and determined that its transcript was highly expressed in the crest cushion; moreover, HOXC8 was detected in this tissue with a molecular weight of 38 kDa in the Fengtou duck. In conclusion, embryos of Fengtou duck have different small protuberances and perforations in the skull, including accumulation of intracranial tissue and osteophytes in some cases. Furthermore, HOXC8 may regulate the formation of the crest. These findings provide novel insight into the ontogenesis of the crest cushion in crested ducks and a basis for future studies on their evolutionary origins.

HOXC6 promotes cervical cancer progression via regulation of Bcl-2.

Homeobox C6 ( HOXC6) is a transcription factor that plays an important role in the development of several cancers. However, it is unknown whether HOXC6 regulates cervical cancer progression. In this study, we used quantitative PCR and Western blots to demonstrate that HOXC6 overexpression is associated with cervical cancer progression. These results are also supported by the public RNA-seq data showing that HOXC6 overexpression is correlated with poor patient survival. In vitro and in vivo experiments revealed that enhanced HOXC6 expression results in cervical cancer cell proliferation, cell cycle progression, anchorage colony formation, and xenograft tumor growth. Mechanistically, we show that HOXC6 up-regulates BCL2 expression through transcription regulation. Together, these results led us to conclude that overexpression of HOXC6 expression can enhance BCL2-mediated antiapoptotic effects to promote cervical cancer cell cycle progression and proliferation.-Wang, Y., Wang, C., Liu, N., Hou, J., Xiao, W., Wang, H. HOXC6 promotes cervical cancer progression via regulation of Bcl-2.

HOXC8: a predictive glioma biomarker that induces epithelia-mesenchymal transition

BackgroundThe transcription factor Homeobox C8 (HOXC8) is overexpressed and regulates many important genes involved in the proliferation and invasion of many malignant tumors. However, the function of HOXC8 in gliomas remains unclear.MethodBased on the Chinese Glioma Genome Atlas (CGGA) set, HOXC8 expression is negatively correlated with overall survival (OS). Small interfering RNA (si-HOXC8) was used to downregulate the mRNA and protein expression levels of HOXC8 to assess glioma cell proliferation, migration and invasion.ResultsPatients with higher HOXC8 levels showed poorer prognosis. DAVID analysis results indicated that HOXC8 was related to cell cycle, cell adhesion and immune response. In U251 and LN229 glioma cells treated with small interfering RNA for HOXC8 (si-HOXC8) for gene knockdown, significantly lower cell capacity of growth, migration and invasion was observed. Moreover, HOXC8 knockdown could reduce the protein expression of classical epithelial mesenchymal transition (EMT) related markers.ConclusionHOXC8 may play an important role in glioma proliferation, migration and invasion. These findings indicated that HOXC8 may constitute a novel target for glioma treatment.

Upregulated expression of HOXC8 is associated with poor prognosis of cervical cancer.

Homeobox C8 (HOXC8) is a transcription factor that has been reported to regulate numerous genes associated with tumor progression. However, its function in cervical cancer (CC) remains to be elucidated. In the present study, the expression level of HOXC8 was examined in CC tissues and cell lines using reverse transcription-quantitative polymerase chain reaction and western blot analysis. Additionally, CC cell lines were transfected with small interfering RNAs (siRNAs) to downregulate the expression of HOX8 and assess cell proliferation using Cell Counting Kit-8. The results demonstrated a significantly increased expression of HOXC8 in CC tissues and cell lines compared with non-tumor tissues, and a normal cervical cell line, respectively. Additionally, the downregulation of HOXC8, which was achieved by siRNA transfection, significantly inhibited the proliferation rate of CC cell lines. Kaplan-Meier curves demonstrated that the increased expression of HOXC8 was associated with poor prognosis of patients with CC. Additionally, univariate and multivariate analysis revealed that HOXC8 was a significant and independent predictor for overall survival of patients with CC. In conclusion, the results of the present study suggest that HOXC8 may be involved in the progression of CC and may serve as a therapeutic target for CC.

Evaluation of prostate cancer risk in men with PSA < 1.5.

64 Background: Prostate Specific Antigen (PSA) screening remains controversial primarily because of over detection and treatment. There is an unmet clinical need to identify patients at increased risk for high-grade (HG – Gleason Score ≥7) prostate cancer (PCa) since PSA has low sensitivity. Combining PSA with well-validated prostate cancer biomarkers (PCM) can improve risk assessment. We investigated the performance of three PCMs (phi – prostate health index, 4KScore, and SelectMDx) on patients with PSA levels < 1.5 ng/mL that represent a “safe zone” where risk of any PCa is rare Methods: 652 men were screened for PCa during the annual Prostate Cancer Awareness Week at the University of Colorado Hospital. This study was supported by Prostate Condition Education Council and the Schramm Foundation. phi is evaluated using p2PSA, total PSA, and free PSA in serum. Phi < 52.7 suggests absence of HG PCa. 4KScore incorporates four kallikrein protein biomarkers: total PSA, free PSA, intact PSA, human kallikrein protein, and clinical information. A 4KScore < 20% suggests absence of HG PCa. The SelectMDx post-DRE urine test measures mRNA levels of the homeobox C6 and distal-less homeobox 1 biomarkers. SelectMDx score of 0% indicates absence of HG PCa. Results: No patients with a PSA < 1.5 had SelectMDx > 0% and/or phi > 52.7. One patient had a 4KScore of 27%, indicating a risk for HG PCa. For patients with PSA between 1.5-3.99, 2.9% (4/135), 7.4% (4/54), and 2.3% (2/85) had positive phi, 4KScore, and SelectMDx results, respectively. Conclusions: Men with PSA <1.5 ng/mL are at very low risk for HG PCa. Men with PSA between 1.5-3.99 with positive PCM results may be referred for further evaluation. [Table: see text]

Overexpression of HOXC10 promotes angiogenesis in human glioma via interaction with PRMT5 and upregulation of VEGFA expression.

High levels of angiogenesis are associated with poor prognosis in patients with gliomas. However, the molecular mechanisms underlying tumor angiogenesis remain unclear.Methods: The effect of homeobox C10 (HOXC10) on tube formation, migration, and proliferation of human umbilical vein endothelial cells (HUVECs) and on chicken chorioallantoic membranes (CAMs) was examined. An animal xenograft model was used to examine the effect of HOXC10 on xenograft angiogenesis or the effect of bevacizumab, a monoclonal antibody against vascular endothelial growth factor A (VEGFA), on HOXC10-overexpressing xenografts. A chromatin immunoprecipitation assay was applied to investigate the mechanism in which HOXC10 regulated VEGFA expression.Results: Overexpressing HOXC10 enhanced the capacity of glioma cells to induce tube formation, migration and proliferation of HUVECs, and neovascularization in CAMs, while silencing HOXC10 had the opposite result. We observed that CD31 staining was significantly increased in tumors formed by HOXC10-overexpressing U251MG cells but reduced in HOXC10-silenced tumors. Mechanistically, HOXC10 could transcriptionally upregulate VEGFA expression by binding to its promoter. Strikingly, treatment with bevacizumab, a monoclonal antibody against VEGFA, significantly inhibited the growth of HOXC10-overexpressing tumors and efficiently impaired angiogenesis. Protein arginine methyltransferase 5 (PRMT5) and WD repeat domain 5 (WDR5), both of which regulate histone post-translational modifications, were required for HOXC10-mediated VEGFA upregulation. Importantly, a significant correlation between HOXC10 levels and VEGFA expression was observed in a cohort of human gliomas.Conclusions: This study suggests that HOXC10 induces glioma angiogenesis by transcriptionally upregulating VEGFA expression, and may represent a potential target for antiangiogenic therapy in gliomas.

Homeobox C10 knockdown suppresses cell proliferation and promotes cell apoptosis in osteosarcoma cells through regulating caspase 3.

AimHomeobox (HOX) genes and their protein products have been found to function as oncogenes in the progression of many cancers. But the role of Homeobox C10 (HOXC10) in osteosarcoma (OS) still remains less understood. In this study, we firstly determine the biologic functions of HOXC10 in OS.Materials and methodsWe examined the expression of HOXC10 in OS tissues by quantitative real-time polymerase chain reaction and Western blot assays. We investigated the effects of HOXC10 on cell proliferation, apoptosis and caspase 3 activity in three OS cell lines by RNA interference, Cell Counting Kit-8, flow cytometry and colorimetric assays.ResultsWe found that HOXC10 was elevated in OS tissues. Silencing HOXC10 significantly inhibited cell proliferation, induced cell apoptosis and increased the expression and activity of caspase 3. The resistance assay further suggested that HOXC10 affected cell growth and apoptosis through regulating the expression and activity of caspase 3.ConclusionHOXC10 might function as an oncogene in OS by regulating the expression and activity of caspase 3.

Interleukin enhancer-binding factor 3 and HOXC8 co-activate cadherin 11 transcription to promote breast cancer cells proliferation and migration.

Cadherin 11 (CDH11) expression is detected only in invasive breast cancer cells and aggressive breast cancer specimens. However, little is known about the molecular mechanisms of CDH11 transcriptional regulation. Here, we report that interleukin enhancer binding factor 3 (ILF3) interacts with Homeobox C8 (HOXC8) to activate CDH11 transcription in breast cancer cells. Using co-immunoprecipitation and mass spectrometry analyses, ILF3 is shown to interact with HOXC8 in breast cancer cells. We demonstrate that ILF3 binds to the CDH11 promoter on nucleotides –2982 ~ –2978 and –2602 ~ 2598 and interacts with HOXC8 to co-activate CDH11 transcription. We further show that ILF3 promotes proliferation and migration, at least partially, by facilitating CDH11 expression in breast cancer cells. Moreover, immunohistochemistry (IHC) shows that expression of CDH11, ILF3 and HOXC8 are all upregulated in breast cancer specimens compared to normal breast tissues. Importantly, the expression levels of CDH11, ILF3 and HOXC8 are elevated in the advanced stages of breast cancer, and high expression of CDH11, ILF3 and HOXC8 is associated with poor distant metastasis-free survival (DMFS) for breast cancer patients.

Increased HOXC6 expression predicts chemotherapy sensitivity in patients with esophageal squamous cell carcinoma.

Increased expression of homeobox C6 (HOXC6) predicts poor prognosis of patients with esophageal squamous cell carcinoma (ESCC) and promotes ESCC cell proliferation. Additionally, the expression of HOXC6 was upregulated in chemosensitive ESCC cell lines. Therefore, it was hypothesized that HOXC6 may be associated with chemosensitivity of ESCC. Patients with ESCC who underwent neoadjuvant chemotherapy followed by surgery by a single-surgeon team between January 2000 and December 2012 were enrolled in the present study. Pretreatment biopsy specimens and postoperative resection samples were collected. Immunohistochemistry was performed to examine HOXC6 expression, and the association between HOXC6 expression and tumor regression grade (TRG) was analyzed. In cell lines exhibiting stable knockdown of HOXC6, Cell Counting Kit-8 assays were used to evaluate the chemosensitivity of cells to various concentrations of cisplatin and paclitaxel. A total of 51 pretreatment biopsy specimens were assessed, and patients with increased expression of HOXC6 in pretreatment biopsy specimens exhibited higher TRGs. A total of 186 surgical samples were evaluated; HOXC6 was expressed at a decreased level in patients with higher TRG and at a high level in patients with lower TRG. In addition, downregulation of HOXC6 decreased the sensitivity of ESCC cell lines to cisplatin and paclitaxel, resulting in an increased half-maximal inhibitory concentration. Increased expression of HOXC6 prior to treatment was associated with chemosensitivity in ESCC tissues.

Homeobox C10 inhibits the osteogenic differentiation potential of mesenchymal stem cells

ABSTRACTPurpose: Mesenchymal stem cells (MSCs) are a reliable cell source for tissue regeneration. However, the molecular mechanisms underlying the directed differentiation of MSCs remain unclear which impedes potential clinical applications. Recent studies have discovered that Homeobox (HOX) genes are involved in the differentiation regulation of MSCs and bone formation. In this study, we investigate the HOXC10 function in the osteogenic differentiation potential of MSCs. Materials and Methods: Stem cells from apical papilla (SCAPs) and adipose-derived stem cells (ADSCs) were used in this study. Alkaline phosphatase (ALP) activity assays, ALP staining, Alizarin red staining, quantitative calcium analysis, osteogenesis-associated gene expression, and in vivo transplantation experiments were used to study osteogenic differentiation potential. Results: Our results showed that overexpression of HOXC10 in SCAPs inhibited ALP activity and mineralization in vitro and decreased the mRNA expression of collagen alpha-1 (I) chain, bone sialoprotein, osteocalcin, and a key transcription factor, runt-related transcription factor 2, in SCAPs. Depletion of HOXC10 promoted osteogenic differentiation in SCAPs in vitro. In addition, in vivo transplantation experiments in nude mice confirmed that SCAPs osteogenesis was triggered when HOXC10 was downregulated. Furthermore, depletion of HOXC10 also enhanced osteogenic differentiation in ADSCs. Conclusions: Taken together, these results indicated that HOXC10 decreased the MSC osteogenic differentiation potential. Thus, inhibition of HOXC10 in MSCs might have the potential to improve tissue regeneration and provide insight into the mechanism underlying the directed differentiation of MSCs.

Analytical validation of an mRNA-based urine test to predict the presence of high-grade prostate cancer

BackgroundThe challenge for prostate cancer (PCa) diagnosis is to improve the ability to distinguish indolent from aggressive PCa. Increased urinary levels of Distal-less Homeobox 1 (DLX1) and Homeobox C6 (HOXC6) mRNA have been associated with high-grade PCa (Gleason Score ≥7). Reverse transcriptase PCR (RT-PCR)-assays for the quantification of DLX1 and HOXC6 mRNA levels were developed, and clinical validation showed that these urinary markers can significantly improve accuracy for detection of high-grade PCa at biopsy. The aim of this study was to validate the analytical performance of these mRNA-based assays, including specimen stability and analytical sensitivity, specificity, precision, repeatability and reproducibility.MethodsAnalytical validation of the RT-PCR assays for DLX1, HOXC6 and KLK3 was performed using in vitro transcribed (IVT) specimens of the target genes, covering all aspects of the analytical method including assay sensitivity, specificity, linearity, precision, repeatability and reproducibility using pre-specified acceptance criteria. To confirm that the mRNA assays are sufficient robust for use in clinical routine laboratories, the performance characteristics were verified in an independent laboratory using post-DRE collected urine samples from 101 men scheduled for prostate biopsy.ResultsA stabilization buffer, developed for urine preservation under standard pre-processing conditions, makes sample shipment from clinics to laboratories easily feasible. The mRNA in urine samples, preserved in this stabilization buffer, is stable at room temperature up to 5 days from collection, resulting in 100% evaluable rate. The long term stability of the mRNAs in the buffer was shown by similar clinical performances using RNA values obtained immediately after urine collection (area under curve (AUC) 0.72(95% CI: 0.61–0.83)) and after 1-year storage (AUC 0.71 (95% CI: 0.60–0.81)). Test performance was not compromised by most common inhibitors and bacterial strains found in urine. However, an inhibitory effect of hemoglobin was observed.All precision, reproducibility, instrument and inter-laboratory variation data obtained for the mRNA-based assays met the pre-specified acceptance criteria of a standard deviation less than or equal to 0.5 crossing point. The analysis of 99 whole urine samples at two laboratories indicated a very strong positive correlation (r = 0.997, P < 0.001). The test outcome in terms of absolute difference in likelihood for high-grade PCa upon biopsy was less than 2% between the two sites.ConclusionsThis study illustrates the robustness of the mRNA assays, enabling testing in clinical routine laboratories and molecular pathology laboratories where the here described automated RNA extraction and PCR platforms are available.

The predictive potential and oncogenic effects of HOXC8 expression on osteosarcoma.

Homeobox C8 (HOXC8) has been implicated in cell growth, migration, and metastasis of various cancers, yet its role in osteosarcoma remains to be explored. In the present study, resected osteosarcoma specimens from 50 patients were enrolled to evaluate the expression of HOXC8 protein by immunohistochemistry (IHC). In vitro and in vivo assays were used to determine the effect of HOXC8 on cell growth, migration, and tumor growth. HOXC8 expression was observed in 31 (62.0%) of the 50 primary tumors and significantly associated with poorly or un-differentiated specimens (P=0.031) and larger tumor size (P=0.049). Survival analysis demonstrated that HOXC8 is a candidate predictive factor in predicting patients' outcome and chemotherapeutic effect. HOXC8 knockdown led to inhibition of tumor cell proliferation and migration in vitro by inhibiting MMP-9 expression and tumor growth in vivo. Our results strongly suggest that HOXC8 is involved in the tumorigenesis of osteosarcoma and might serve as a novel predictor for patients' outcome.

Long Noncoding RNA HOXC-AS1 Suppresses Ox-LDL-Induced Cholesterol Accumulation Through Promoting HOXC6 Expression in THP-1 Macrophages.

Atherosclerosis is a common pathological basis of cardiovascular disease, which remains the leading cause of mortality. Long noncoding RNAs (lncRNAs) are newly studied non-protein-coding RNAs involved in gene regulation, but how lncRNAs exert regulatory effect on atherosclerosis remains unclear. In this study, we found that lncRNA HOXC cluster antisense RNA 1 (HOXC-AS1) and homeobox C6 (HOXC6) were downregulated in carotid atherosclerosis by performing microarray analysis. The results were verified in atherosclerotic plaques and normal arterial intima tissues by quantitative reverse transcription PCR and western blot analysis. Lentivirus-mediated overexpression of HOXC-AS1 induced HOXC6 expression at mRNA and protein levels in THP-1 macrophages. Besides, oxidized low-density lipoprotein (Ox-LDL) decreased expression of HOXC-AS1 and HOXC6 in a time-dependent manner. Induction of cholesterol accumulation by Ox-LDL could be partly suppressed by overexpression of HOXC-AS1.

Overexpression of HOXC8 is Associated With Poor Prognosis in Epithelial Ovarian Cancer.

Homeobox C8 (HOXC8) is a transcription factor that has been reported as a potential driver oncogene in several tumors and involved in the regulation of many cancer-related proteins. In this study, we investigated the expression and role of HOXC8 in ovarian cancer. Western blot and immunohistochemistry analyses were performed to detect the expression of HOXC8. Kaplan-Meier curve showed that high expression of HOXC8 was related to poor prognosis of patients with epithelial ovarian cancer (EOC). Starvation and refeeding assay were used to assess cell cycle, suggesting that HOXC8 played a critical role in EOC cell proliferation. HOXC8 depletion by small interfering RNA inhibited cell proliferation, migration, and induced apoptosis in EOC cells. Moreover, HOXC8 knockdown increased the expression of ZAC1. Owing to the overexpression of HOXC8, our findings implied that HOXC8 is involved in the progression of EOC and could be a potential therapeutical approach of EOC.

Identification of Differential Genes Expression Profiles and Pathways of Bone Marrow Mesenchymal Stem Cells of Adolescent Idiopathic Scoliosis Patients by Microarray and Integrated Gene Network Analysis

Microarray approach and integrated gene network analysis. To explore the differential genetic expression profile, gene ontology terms, and Kyoto Encyclopedia of Genes and Genomes pathways in bone marrow mesenchymal stem cells (BM-MSCs) of idiopathic scoliosis (AIS) and non-AIS controls. The pathogenesis of adolescent AIS and the accompanying generalized osteopenia remain unclear. Our previous study suggested increased proliferation ability and decreased osteogenic differentiation ability of BM-MSCs of AIS. Therefore, we hypothesized that MSCs may play a significant role in the etiology and pathogenesis of AIS. In this study, microarray analysis was used to identify differentially expressed genes (DEGs) of BM-MSCs from AIS patients compared with those from healthy individuals. Comprehensive bioinformatics analyses were then used to enrich datasets for gene ontology and pathway. Based on the gene signal transduction network analysis of DEGs contained in significant pathways, 24 potential crucial genes were selected for validation by reverse transcription polymerase chain reaction. There are 1027 previously unrecognized DEGs in BM-MSCs from AIS patients. Pathway analysis revealed dysregulated mitogen-activated protein kinase (MAPK) signaling pathway, PI3K-Akt signaling pathway, calcium signaling pathway, peroxisome proliferator-activated receptor (PPAR) signaling pathway, ubiquitin-mediated proteolysis, and Notch signaling pathway, all of which have been reported to play an important role in regulating the osteogenic or adipogenic differentiation of MSCs. Furthermore, gene signal transduction networks analysis indicated that mitogen-activated protein kinase kinase 1 (MAP2K1), SMAD family member 3 (SMAD3), homeobox C6 (HOXC6), heat shock 70kDa protein 6 (HSPA6), general transcription factor IIi (GTF2I), CREB binding protein (CREBBP), phosphoinositide-3-kinase, regulatory subunit 2 (PIK3R2), and dual specificity phosphatase 2 (DUSP2) may play essential roles in AIS pathogenesis and accompanied osteopenia. This study reports the differential genes expression profiles of BM-MSCs from AIS patients and related potential pathways for the first time. These previously unrecognized genes and molecular pathways might play a significant role in not only the causal mechanism of osteopenia in AIS, but also the AIS initiation and development. The identification of these candidate genes provides novel insight into the underlying etiological mechanisms of AIS. N/A.

Silencing homeobox C6 inhibits colorectal cancer cell proliferation.

Homeobox C6 (HOXC6), a member of the homeobox family that encodes highly conserved transcription factors, plays a vital role in various carcinomas. In this study, we used a tissue microarray (TMA) consisting of 462 CRC samples to demonstrate that HOXC6 is more abundantly expressed in colorectal cancer (CRC) tissues than adjacent normal mucosa. Clinicopathological data indicated that higher HOXC6 expression correlated with poor overall survival and was associated with primary tumor location in the right colon, primary tumor (pT) stage 3/4 and primary node (pN) stage 1/2. Multivariate analysis showed that high HOXC6 expression was an independent risk factor for poor CRC patient prognosis. HOXC6 downregulation via lentivirus-mediated expression of HOXC6-targeting shRNA reduced HCT116 cell viability and colony formation in vitro, and reduced growth of subcutaneous xenografts in nude mouse. HOXC6 thus appears to promote CRC cell proliferation and tumorigenesis through autophagy inhibition and mTOR pathway activation.

Expression of proliferation related transcription factor genes in U87 glioma cells with IRE1 knockdown: upon glucose and glutamine deprivation.

Glycolysis and glutaminolysis as well as endoplasmic reticulum stress are required for tumor progression suggests through regulation of the cell cycle. Inhibition of ERN1/IRE1 (endoplasmic reticulum to nucleus signaling 1/inositol requiring enzyme 1), a central mediator of endoplasmic reticulum stress, significantly suppresses glioma cell proliferation and tumor growth as well as modifies sensitivity gene expressions to glucose and glutamine deprivation. We have studied the expression of genes encoded transcription factors such as E2F8 (E2F transcription factor 8), EPAS1 (endothelial PAS domain protein 1), HOXC6 (homeobox C6), TBX3 (T-box 3), TBX2 (T-box 2), GTF2F2 (general transcription factor IIF), GTF2B (general transcription factor IIB), MAZ (MYC-associated zinc finger protein, purine-binding transcription factor), SNAI2 (snail family zinc finger 2), TCF3 (transcription factor 3), and TCF8/ZEB1 (zinc finger E-box binding homeobox 1)in U87 glioma cells upon glucose and glutamine deprivation in relation to inhibition of IRE1.We demonstrated that glutamine deprivation leads to up-regulation of the expression of EPAS1, TBX3, GTF2B, and MAZ genes and down-regulation of E2F8, GTF2F2, TCF8, and TBX2 genes in control glioma cells.At the same time, glucose deprivation enhances the expression of EPAS1 and GTF2B genes and decreases of E2F8, HOXC6, TCF3, and TBX2 genes in these glioma cells. Inhibition of IRE1 by dnIRE1 significantly modifies the expression most of studied genes with different magnitude. Present study demonstrates that fine-tuning of the expression of proliferation related transcription factor genes depends upon glucose and glutamine deprivation in IRE1-dependent manner and possibly contributes to slower tumor growth after inhibition of IRE1.

Embigin, regulated by HOXC8, plays a suppressive role in breast tumorigenesis.

The transmembrane glycoprotein embigin (EMB) belongs to the immunoglobulin superfamily (IgSF) and a number of IgSF members have been identified as biomarkers for cancer progression. In this study, we show that embigin is transcriptionally regulated by Homeobox C8 (HOXC8) in breast cancer cells and embigin expression suppresses breast tumorigenesis. With aid of Western blot, luciferase reporter gene assay and chromatin immunoprecipitation, we reveal that HOXC8 binds to the EMB promoter at the region of nucleotides -2303 to -2315 and acts as a transcription inhibitor to suppress embigin expression. Depletion of embigin leads to increase in proliferation, anchorage-independent growth and migration of breast cancer cells, and the inhibitory effects mediated by HOXC8 knockdown on breast tumorigenesis can be largely rescued by depletion of embigin expression in breast cancer cells, suggesting that HOXC8 regulates breast tumorigenesis, at least partly, through regulating embigin expression. Moreover, we show that loss of embigin promotes proliferation, anchorage-independent growth, and migration ability of normal mammary epithelial MCF10A cells. The analyses of publically available human breast tumor microarray gene expression database show that low embigin levels correlate with short survival of breast tumor patients, particularly with basal-like tumor patients, and embigin expression is low specifically in patients with basal-like, ER-/HER2- tumors. Taken together, our study demonstrates that low/loss of embigin plays an important role in the progression of breast tumors.

HOXC8 (homeobox C8)

Review on HOXC8 (homeobox C8), with data on DNA, on the protein encoded, and where the gene is implicated.