MDA-9/Syntenin regulates differentiation and angiogenesis programs in Head and Neck Squamous Cell Carcinoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE57760 | GEO | 2015/11/23
SECONDARY ACCESSION(S): PRJNA248011
REPOSITORIES: GEO
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Project description:We identified MDA-9/Syntenin (8q12) as a key component of HNSCC differentiation and angiogenesis. Robust reduction in the expression of cyclinD1, CDK4, CTNNB1, STAT3 and PI3K were evident in MDA- 9/Syntenein depleted cells, which was reversed following MDA-9/Syntenin overexpression in immortalized oral epithelial cells. To further elucidate the role of MDA-9/Syntenin in tumor growth and epithelial cell differentiation in vitro and in vivo by sielnicng its expression.
2015-11-23 | E-GEOD-57760 | biostudies-arrayexpress
Project description:Little is known about the molecular pathways regulating poor differentiation and invasion of head and neck squamous cell carcinoma (HNSCC). In the present study, we aimed to determine the role of MDA-9/Syntenin, a metastasis associated molecule in HNSCC tumorigenesis. Elevated MDA-9/Syntenin expression was evident in 67% (54/81) primary HNSCC tumors (p=0.001-0.002) and 69% (9/13) pre-neoplastic tissues (p=0.02-0.03). MDA-9/Syntenin overexpression was associated with the stage (p=0.001), grade (p=0.001) and lymph node metastasis (p=0.0001). Silencing of MDA-9/Syntenin in 3 poorly differentiated HNSCC cell lines induced squamous epithelial cell differentiation, disrupted angiogenesis and reduced tumor growth in vitro and in vivo. We confirmed SPRR1B and VEGFR1 as the key molecular targets of MDA-9/Syntenin on influencing HNSCC differentiation and angiogenesis respectively. MDA-9/Syntenin disrupted SPRR1B expression interacting through its PDZ1 domain and altered VEGFR1 expression in vitro and in vivo. VEGFR1 co-localized with MDA-9/Syntenin in HNSCC cell lines and primary tumor. Downregulation of growth regulatory molecules CyclinD1, CDK4, STAT3, PI3K and CTNNB1 was also evident in the MDA-9/Syntenin depleted cells, which was reversed following over-expression of MDA-9/Syntenin in immortalized oral epithelial cells. Our results suggest that early induction of MDA-9/Syntenin expression influences HNSCC progression and should be further evaluated for potential biomarker development.
| S-EPMC4278274 | biostudies-literature
Project description:To identify the activated tyrosine kinase signaling pathways in HNSCC, we carried out phosphotyrosine profiling using a panel of HNSCC cell lines compared to a normal oral keratinocyte. A total of 61 unique phosphosites were identified across these cell lines. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) was one of the kinases hyperphosphorylated at Y321 in all the HNSCC cell lines compared to the normal oral cell line OKF6/TERT1. Inhibition of DYRK1A using its specific siRNA and inhibitor resulted in a decrease in the invasion and colony formation ability of the HNSCC cell lines. Further, the treatment of mice bearing HNSCC xenograft tumors with DYRK1A inhibitor (harmine) showed regression of tumor growth. Our results demonstrate that DYRK1A could be a novel therapeutic target in HNSCC.
2018-10-24 | PXD002132 | Pride
Project description:Rigosertib treatment of head and neck squamous cell cancer The dual pathway inhibitor rigosertib inhibits phosphoinositide 3-kinase (PI3K) pathway activation as well as polo-like kinase 1 (PLK1) activity across a broad spectrum of cancer cell lines. The importance of PIK3CA alterations in head and neck squamous cell cancer (HNSCC) has raised interest in exploring agents targeting PI3K, the product of PIK3CA. The genetic and molecular basis of rigosertib treatment response was investigated in a panel of 16 HNSCC cell lines, and direct patient tumor xenografts from 8 HNSCC patients (4 HPV16-positive). HNSCC cell lines and xenografts were characterized by pathway enrichment gene expression analysis, exon sequencing, gene copy number, western blotting, and IHC. Rigosertib had potent antiproliferative effects on 11 of the 16 HPV- HNSCC cell lines. Treatment sensitivity was confirmed in two cell lines using an orthotopic in vivo xenograft model. Growth reduction after rigosertib treatment was observed in 3/8 HNSCC direct patient tumor lines. The responsive tumor lines carried a combination of a PI3KCA activating event (amplification or mutation) and a p53 inactivating event (either HPV16-mediated or mutation-mediated TP53 inactivation). In this study, we evaluated the in vitro and in vivo efficacy of rigosertib in both HPV+ and HPV- HNSCCs focusing on inhibition of the PI3K pathway. Although consistent inhibition of the PI3K pathway was not evident in HNSCC, we identified a combination of PI3K/TP53 events necessary, but not sufficient for rigosertib-sensitivity. Sixteen HNSCC lines data were profiled at baseline to find differentially expressed genes and pathways sensitive to rigosertib.
2013-06-13 | E-GEOD-47864 | biostudies-arrayexpress
Project description:Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease whose underlying etiology has not been explained by traditional prognostic factors such as tumor site, stage, or histology. Although previous studies have shown that molecular subtypes of HNSCC exist, the benefit of such a classification scheme has not been fully realized. We show that molecular subtypes of HNSCC exist; that these subtypes have distinct patterns of chromosomal gain and loss, some of which affect canonical oncogenes and tumor suppressors; and that the subtypes are biologically and clinically relevant. These subtypes provide new insight into HNSCC etiology, as well as a valuable method for classifying HNSCC tumors.
2013-03-01 | GSE39366 | GEO
Project description:Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease whose underlying etiology has not been explained by traditional prognostic factors such as tumor site, stage, or histology. Although previous studies have shown that molecular subtypes of HNSCC exist, the benefit of such a classification scheme has not been fully realized. We show that molecular subtypes of HNSCC exist; that these subtypes have distinct patterns of chromosomal gain and loss, some of which affect canonical oncogenes and tumor suppressors; and that the subtypes are biologically and clinically relevant. These subtypes provide new insight into HNSCC etiology, as well as a valuable method for classifying HNSCC tumors. A total of 163 samples were considered. Quality control procedures were applied to microarray probe-level intensity files. A total of 138 tumor arrays remained after removing low-quality arrays, duplicate arrays, and arrays from non-HNSCC samples. The normexp background correction and loess normalization procedures were applied to the probe-level data. After log transformation, probes were matched to a common gene database to produce expression values for 15595 genes.
2013-03-01 | E-GEOD-39366 | biostudies-arrayexpress
Project description:This study represents a proteomic resource for HNSCC and SQCLC with quantitative protein expression data for 7800 proteins and provides a proteomic diagnostic signature for classification for undetermined secondary lung tumors in HNSCC patients. By quantitative mass-spectrometry-based proteomics, we characterized a cohort of 63 squamous cell carcinomas of the lung (SQCLC), 49 of the head and neck region (HNSCC) and 51 HNSCC-correlated lung tumors with squamous cell histology that evolved in the course of the disease.
2018-08-06 | PXD007705 | Pride
Project description:Overall survival remains very poor for patients diagnosed with head and neck squamous cell carcinoma (HNSCC). Identification of additional biomarkers and novel therapeutic strategies are important for improving patient outcome. Patient-derived xenografts (PDXs), generated by implanting fresh tumor tissue directly from patients into immune-deficient mice, recapitulate many of the features of their corresponding clinical cancers, including histopathological and molecular profiles. Using a large collection of PDX models of HNSCC we demonstrate that rapid engraftment into immune-compromised mice is highly prognostic, and show that genomic deregulation of the G1/S checkpoint pathway correlates with engraftment. Furthermore, CCND1 and CDKN2A genomic alterations are predictive of response to the CDK4/6 inhibitor abemaciclib. Overall, our study supports the pursuit of CDK4/6 inhibitors as a therapeutic strategy for a substantial proportion of HNSCC patients, and demonstrates the potential of using PDX models to identify novel targeted therapies for those patients who have the poorest outcomes.
| EGAS00001002979 | EGA
Project description:Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease whose underlying etiology has not been explained by traditional prognostic factors such as tumor site, stage, or histology. Although previous studies have shown that molecular subtypes of HNSCC exist, the benefit of such a classification scheme has not been fully realized. We show that molecular subtypes of HNSCC exist; that these subtypes have distinct patterns of chromosomal gain and loss, some of which affect canonical oncogenes and tumor suppressors; and that the subtypes are biologically and clinically relevant. These subtypes provide new insight into HNSCC etiology, as well as a valuable method for classifying HNSCC tumors.
2013-03-01 | GSE39367 | GEO
Project description:A "Cartes d'Identite des Tumeurs" (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net). 81 samples on Affymetrix HG-U133 Plus 2.0 GeneChips arrays for 81 patients with primary Head and Neck Squamous Cell Carcinoma (HNSCC; oral cavity, tongue, oro- or hypopharynx); metastases as first recurrent event in a 36-month follow up; histologically tumor-free margins (?3 mm); patients had undergone surgical resection as the first treatment and had no clinically evident distant metastases.
2007-08-23 | E-TABM-302 | biostudies-arrayexpress