Olfactory Receptors as Tumor Suppressors in Cutaneous T-Cell Lymphoma via p38γ Pathway Modulation
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE292987 | GEO | 2025/04/23
REPOSITORIES: GEO
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Project description:We screened 270,000 compounds from an NCI library for the ability to dock with the non-ATP-binding site of p38γ using virtual screen. The resulting candidate compounds were for cytotoxicity assays to the Hut78 CTCL cell line and identified CSH71 as one of the most promising agents.
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Project description:TOX is a nuclear factor essential for the development of CD4+ T cells in the thymus. TOX is found to be aberrantly up-regulated in the skin biopsies and in the blood CD4+ T cells of cutaneous T cell lymphoma. The goal of this study is to identify potential transcriptional targets of TOX in CTCL by comparison between TOX shRNA transfected CTCL cells (Hut78 and HH) and control CTCL cells. Two color experiment. Lentivirus transduced control vector vs. TOX shRNA vectors on Hut78 and HH cell lines. Biological replicates: 3 control replicates, 3 shRNA tansduced replicates for each cell line.
2014-04-29 | E-GEOD-57122 | biostudies-arrayexpress
Project description:Cutaneous T-cell lymphoma (CTCL) is a type of non-Hodgkin lymphoma that primarily affects the skin rich in hyaluronic acid（HA）. HA composes extracellular matrix in the dermis, which likely affects the development of CTCL but is poorly understood. Here, we show that low molecular weight HA (LMWHA) possibly exacerbates CTCL in mouse and human specimens, and bexarotene already being used in CTCL treatment can decrease HA production. Patients’ serum and skin sections showed higher HA expression than healthy controls. HA extracted from the skin of mice inoculated with tumors showed an increase in LMWHA. LMWHA increased lymphoma cell proliferation in vitro and accelerated tumor formation in mice in vivo. LMWHA also created a favorable environment for tumor cells by influencing fibroblasts, vascular endothelial cells, and tumor-associated macrophages. Together, increased HA, mainly LMW aids in CLCL progression by affecting tumor cells and microenvironment. Next, bexarotene treatment reduced the amount of total HA in murine tumor-inoculated skin and the supernatant of cultured normal human dermal fibroblasts (NHDFs) and HuT78 cells. Detailed in vitro assessments showed that bexarotene treatment decreased hyaluronic acid synthase (HAS) 1 and HAS2 expression in NHDFs and HAS1, HAS3, and CEMIP in HuT78. Chromatin immunoprecipitation assay revealed bexarotene reduced retinoid X receptor-alpha binding to the HAS1 and HAS2 promoters in NHDFs. Bexarotene potentially exerts its anti-tumor effect by reducing HA through decreased expression of HA synthase. These findings provide us with new insights into the developmental process of CLCT and additional insight into bexarotene treatment.
2024-11-01 | GSE248641 | GEO
Project description:TOX is a nuclear factor essential for the development of CD4+ T cells in the thymus. TOX is found to be aberrantly up-regulated in the skin biopsies and in the blood CD4+ T cells of cutaneous T cell lymphoma. The goal of this study is to identify potential transcriptional targets of TOX in CTCL by comparison between TOX shRNA transfected CTCL cells (Hut78 and HH) and control CTCL cells.
2014-04-29 | GSE57122 | GEO
Project description:IKZF2 is an important nuclear matrix protein and plays a pivotal role in T cell development and differentiation, while its expression and function in Cutaneous T cell lymphoma (CTCL) remain ambiguous. Our study aimed to investigate the expression pattern, biological function of IKZF2 in a large clinical cohort. IKZF2 is specifically over-expressed in malignant T cells with MF tumor-stage. In order to explore the function of IKZF2 in the pathogenesis of CTCL, transcriptome sequencing was performed among Hut78 cells transfected with shRNAs targeting IKZF2 (shIKZF2) and scrambled shRNA(sh0) to investigate genes regulated by IKZF2 in CTCL cells .
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Project description:Gene expression values were determined for HuT78 parental cells and cells selected with romidpesin in the presence of P-glycoprotein inhibitors. HuT78 DpVp35 cells are maintained in 35 ng/ml romidepsin with 2.5 µg/ml verapamil and HuT78 DpP100 cells are maintained in 100 ng/ml romidepsin with 1 µM valspodar To identify molecular determinants of histone deacetylase inhibitor (HDI) resistance, we selected HuT78 cutaneous T-cell lymphoma (CTCL) cells with romidepsin in the presence of P-glycoprotein (Pgp) inhibitors to prevent transporter upregulation. Resistant sublines were 250- to 385-fold resistant to romidepsin and were resistant to apoptosis induced by apicidin, entinostat, panobinostat, belinostat and vorinostat. A custom Taqman array identified increased insulin receptor (INSR) gene expression; immunoblot analysis confirmed increased expression and a 4- to 8-fold increase in mitogen activated protein kinase (MAPK) kinase (MEK) phosphorylation in resistant cells compared to parental cells. Resistant cells were exquisitely sensitive to MEK inhibitors and apoptosis correlated with restoration of proapoptotic Bim. Romidepsin combined with MEK inhibitors yielded greater apoptosis in cells expressing mutant KRAS compared to romidepsin treatment alone. Gene expression analysis of samples obtained from patients with CTCL enrolled on the NCI1312 Phase II study of romidepsin in T-cell lymphoma suggested perturbation of the MAPK pathway by romidepsin. Immunohistochemical analysis of Bim expression demonstrated decreased expression in some skin biopsies at disease progression. These findings implicate increased activation of MEK and decreased Bim expression as a resistance mechanism to HDIs, supporting combination of romidepsin with MEK inhibitors in clinical trials. Gene expression in resistant lines was compared to parental lines
2013-03-12 | E-GEOD-45018 | biostudies-arrayexpress
Project description:Cutaneous T cell lymphoma (CTCL) is defined by infiltration of activated and malignant T cells in skin. The clinical manifestations and prognosis in CTCL are highly variable. In this study, we hypothesized that gene expression analysis in lesional skin biopsies can improve understanding of the disease and its management. Based on 63 skin samples, we performed consensus clustering, revealing three patient clusters. Two clusters tended to differentiate limited CTCL (stages IA and IB) from more extensive CTCL (stages IB and III). Stage IB subjects appeared in both clusters, but those in the limited CTCL cluster were more responsive to treatment than those in the more extensive CTCL cluster. The third cluster was enriched in lymphocyte activation genes and was associated with a high proportion of tumor (stage IIB) lesions. Survival analysis revealed significant differences in event-free survival between clusters, with poorest survival seen in the activated lymphocyte cluster. Using supervised analysis, we further characterized genes significantly associated with lower stage/treatment responsive versus higher stage/treatment resistant CTCL. We conclude that transcriptional profiling of CTCL skin lesions reveals clinically relevant signatures, correlating with differences in survival and response to treatment. Additional prospective long-term studies to validate and refine these findings appear warranted. Experiment Overall Design: 63 skin biopsies from patients with different stages of disease were selected for RNA extraction and hybridization on Affymetrix microarrays
2008-06-16 | E-GEOD-9479 | biostudies-arrayexpress
Project description:Cutaneous T-cell lymphomas (CTCL) are the most frequent primary skin lymphomas. Nevertheless, diagnosis of early disease has proven difficult due to a clinical and histological resemblance to benign inflammatory skin diseases. To address if microRNA (miRNA) profiling can discriminate CTCL from benign inflammation, we study miRNA expression in 199 patients with CTCL, peripheral T-cell lymphoma (PTL), and benign skin diseases (psoriasis and dermatitis). Using microarrays we show that the most induced- (miR-326, miR-663b, miR-711) and repressed- (miR-203, miR-205) miRNAs distinguish CTCL from benign skin diseases with > 90% accuracy in a training set of 90 samples and a test set of 58 blinded samples. These miRNAs also distinguish malignant and benign lesions in an independent set of 50 patients with PTL and skin inflammation and in experimental human xenograft mouse models of psoriasis and CTCL. Q-RT-PCR analysis of 104 patients with CTCL and benign skin disorders validates differential expression of 4 out of the 5 miRNAs and confirms previous reports on miR-155 in CTCL. A q-RT-PCR-based classifier consisting of miR-155, miR-203, and miR-205 distinguishes CTCL from benign disorders with high specificity, sensitivity, and a classification accuracy of 95% indicating that miRNAs have a high diagnostic potential in CTCL.
2011-11-22 | GSE31408 | GEO
Project description:Cutaneous T-cell lymphomas (CTCL) are the most frequent primary skin lymphomas. Nevertheless, diagnosis of early disease has proven difficult due to a clinical and histological resemblance to benign inflammatory skin diseases. To address if microRNA (miRNA) profiling can discriminate CTCL from benign inflammation, we study miRNA expression in 199 patients with CTCL, peripheral T-cell lymphoma (PTL), and benign skin diseases (psoriasis and dermatitis). Using microarrays we show that the most induced- (miR-326, miR-663b, miR-711) and repressed- (miR-203, miR-205) miRNAs distinguish CTCL from benign skin diseases with > 90% accuracy in a training set of 90 samples and a test set of 58 blinded samples. These miRNAs also distinguish malignant and benign lesions in an independent set of 50 patients with PTL and skin inflammation and in experimental human xenograft mouse models of psoriasis and CTCL. Q-RT-PCR analysis of 104 patients with CTCL and benign skin disorders validates differential expression of 4 out of the 5 miRNAs and confirms previous reports on miR-155 in CTCL. A q-RT-PCR-based classifier consisting of miR-155, miR-203, and miR-205 distinguishes CTCL from benign disorders with high specificity, sensitivity, and a classification accuracy of 95% indicating that miRNAs have a high diagnostic potential in CTCL. miRNA microarray. From each sample 100 ng of total RNA was labeled with Hy3 fluorescent dye using the miRCURY LNA Array power labeling kit (Exiqon, Denmark). All samples were labeled the same day with the same master mix, in order to minimize technical variation. The Hy3-labelled samples were hybridized to miRCURY LNA arrays (v11.0) (Exiqon, Denmark), containing capture probes targeting all human miRNAs registered in the miRBASE version 15.0 at the Sanger Institute. The hybridization was performed overnight at 56°C according to manufacturer specifications using a Tecan HS4800 hybridization station (Tecan, Austria). Since it was not possible to hybridize all arrays in one go, samples were randomly split into 5 batches as to minimize day to day variation in the hybridization process. After hybridization the microarray slides were scanned using an Agilent G2565BA Microarray Scanner System (Agilent Technologies, Inc., USA) at 5µm resolution, and the resulting TIFF images were analyzed using the ImaGene 8.0 software on standard settings (BioDiscovery, Inc., USA).
2011-11-22 | E-GEOD-31408 | biostudies-arrayexpress
Project description:Cutaneous T cell lymphoma (CTCL) is defined by infiltration of activated and malignant T cells in skin. The clinical manifestations and prognosis in CTCL are highly variable. In this study, we hypothesized that gene expression analysis in lesional skin biopsies can improve understanding of the disease and its management. Based on 63 skin samples, we performed consensus clustering, revealing three patient clusters. Two clusters tended to differentiate limited CTCL (stages IA and IB) from more extensive CTCL (stages IB and III). Stage IB subjects appeared in both clusters, but those in the limited CTCL cluster were more responsive to treatment than those in the more extensive CTCL cluster. The third cluster was enriched in lymphocyte activation genes and was associated with a high proportion of tumor (stage IIB) lesions. Survival analysis revealed significant differences in event-free survival between clusters, with poorest survival seen in the activated lymphocyte cluster. Using supervised analysis, we further characterized genes significantly associated with lower stage/treatment responsive versus higher stage/treatment resistant CTCL. We conclude that transcriptional profiling of CTCL skin lesions reveals clinically relevant signatures, correlating with differences in survival and response to treatment. Additional prospective long-term studies to validate and refine these findings appear warranted. Keywords: disease state analysis
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