Homeobox D10 Gene, a Candidate Tumor Suppressor, Is Downregulated through Promoter Hypermethylation and Associated with Gastric Carcinogenesis

Wang, Liangjing; Chen, Shujie; Xue, Min; Zhong, Jing; Wang, Xian; Gan, Lihong; Lam, Emily Ky; Liu, Xin; Zhou, Tian; Yu, Jun; Jin, Hongchuan; Si, Jianmin

doi:10.2119/molmed.2011.00172

Cited by 57 publications

(57 citation statements)

References 42 publications

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“…It encodes a nuclear protein which functions as a sequence-specific TF. It regulates multiple downstream genes including IGFBP3 (also present in our network) which is a pro-apoptotic and anti-angiogenic protein in prostate cancer and activates caspase 3 and caspase 8, and subsequently induces cell apoptosis [37]. Low IGFBP-3 levels are associated with greater risk of aggressive prostate cancers [8].…”

Section: Resultsmentioning

confidence: 99%

MicroRNA and Transcription Factor Gene Regulatory Network Analysis Reveals Key Regulatory Elements Associated with Prostate Cancer Progression

et al. 2016

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Technological and methodological advances in multi-omics data generation and integration approaches help elucidate genetic features of complex biological traits and diseases such as prostate cancer. Due to its heterogeneity, the identification of key functional components involved in the regulation and progression of prostate cancer is a methodological challenge. In this study, we identified key regulatory interactions responsible for primary to metastasis transitions in prostate cancer using network inference approaches by integrating patient derived transcriptomic and miRomics data into gene/miRNA/transcription factor regulatory networks. One such network was derived for each of the clinical states of prostate cancer based on differentially expressed and significantly correlated gene, miRNA and TF pairs from the patient data. We identified key elements of each network using a network analysis approach and validated our results using patient survival analysis. We observed that HOXD10, BCL2 and PGR are the most important factors affected in primary prostate samples, whereas, in the metastatic state, STAT3, JUN and JUNB are playing a central role. Benefiting integrative networks our analysis suggests that some of these molecules were targeted by several overexpressed miRNAs which may have a major effect on the dysregulation of these molecules. For example, in the metastatic tumors five miRNAs (miR-671-5p, miR-665, miR-663, miR-512-3p and miR-371-5p) are mainly responsible for the dysregulation of STAT3 and hence can provide an opportunity for early detection of metastasis and development of alternative therapeutic approaches. Our findings deliver new details on key functional components in prostate cancer progression and provide opportunities for the development of alternative therapeutic approaches.

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Section: Resultsmentioning

confidence: 99%

MicroRNA and Transcription Factor Gene Regulatory Network Analysis Reveals Key Regulatory Elements Associated with Prostate Cancer Progression

et al. 2016

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“…Hoxd10 is a member of the Abd-B homeobox family and encodes a protein with a homeobox DNA-binding domain. Recent studies suggest that HoxD10 functions as a candidate tumor suppressor [11, 12]. …”

Section: Discussionmentioning

confidence: 99%

Pooled analysis of genome-wide association studies of cervical intraepithelial neoplasia 3 (CIN3) identifies a new susceptibility locus

et al. 2016

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Recent genome-wide association studies (GWASs) in subjects of European descent have identified associations between cervical cancer risk and three independent loci as well as multiple classical human leukocyte antigen (HLA) alleles at 6p21.3. To search for novel loci associated with development of cervical cancer, we performed a pooled analysis of data from two GWASs by imputing over 10 million genetic variants and 424 classical HLA alleles, for 1,553 intraepithelial neoplasia 3 (CIN3), 81 cervical cancer and 4,442 controls from the Swedish population. Notable findings were validated in an independent study of 961 patients (827 with CIN3 and 123 with cervical cancer) and 1,725 controls. Our data provided increased support for previously identified loci at 6p21.3 (rs9271898, P = 1.2 × 10−24; rs2516448, 1.1 × 10−15; and rs3130196, 2.3 × 10−9, respectively) and also confirmed associations with reported classical HLA alleles including HLA-B*07:02, -B*15:01, -DRB1*13:01, -DRB1*15:01, -DQA1*01:03, -DQB1*06:03 and -DQB1*06:02. In addition, we identified and subsequently replicated an independent signal at rs73730372 at 6p21.3 (odds ratio = 0.60, 95% confidence interval = 0.54–0.67, P = 3.0 × 10−19), which was found to be an expression quantitative trait locus (eQTL) of both HLA-DQA1 and HLA-DQB1. This is one of the strongest common genetic protective variants identified so far for CIN3. We also found HLA-C*07:02 to be associated with risk of CIN3. The present study provides new insights into pathogenesis of CIN3.

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“…In gastric carcinoma HOXD10 is downregulated and its forced expression is associated with reduced proliferation, invasion, migration and tumor growth [18]. In glioma cells HOXD10 also appears to have a tumor suppressive function as judged by repression of the invasion-related MMP-14 and uPAR genes [19].…”

Section: Discussionmentioning

confidence: 99%

POU2F1 activity regulates HOXD10 and HOXD11 promoting a proliferative and invasive phenotype in Head and Neck cancer

et al. 2014

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

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Homeobox D10 Gene, a Candidate Tumor Suppressor, Is Downregulated through Promoter Hypermethylation and Associated with Gastric Carcinogenesis

Cited by 57 publications

References 42 publications

MicroRNA and Transcription Factor Gene Regulatory Network Analysis Reveals Key Regulatory Elements Associated with Prostate Cancer Progression

MicroRNA and Transcription Factor Gene Regulatory Network Analysis Reveals Key Regulatory Elements Associated with Prostate Cancer Progression

Pooled analysis of genome-wide association studies of cervical intraepithelial neoplasia 3 (CIN3) identifies a new susceptibility locus

POU2F1 activity regulates HOXD10 and HOXD11 promoting a proliferative and invasive phenotype in Head and Neck cancer

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