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Loss of DLX3 tumor suppressive function promotes progression of SCC through EGFR-ERBB2 pathway.

ABSTRACT: Emerging evidence suggests that homeoproteins can act as modulators of tumor initiation and progression. Our findings show that loss of DLX3 tumor suppressive function acts as a tumor promoter through regulation of ERBB2 and EGFR signaling and also support an important inhibitory role of DLX3 in skin cancer promotion and progression, that may potentially be used as a promising prognostic marker.

ORGANISM(S): Mus musculus

PROVIDER: GSE161372 | GEO | 2021/06/02

REPOSITORIES: GEO

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Loss of DLX3 tumor suppressive function promotes progression of SCC through EGFR-ERBB2 pathway.

Project description:Loss of DLX3 tumor suppressive function promotes progression of SCC through EGFR-ERBB2 pathway.

| PRJNA677975 | ENA

Loss of DLX3 tumor suppressive function promotes progression of SCC through EGFR-ERBB2 pathway.

Project description:Cutaneous squamous cell carcinoma (cSCC) ranks second in the frequency of all skin cancers. The balance between keratinocyte proliferation and differentiation is disrupted in the pathological development of cSCC. DLX3 is a homeobox transcription factor which plays pivotal roles in embryonic development and epidermal homeostasis. To investigate the impact of DLX3 expression on cSCC prognosis, we carried out clinicopathologic analysis of DLX3 expression which showed statistical correlation between tumors of higher pathologic grade and levels of DLX3 protein expression. Further, Kaplan-Meier survival curve analysis demonstrated that low DLX3 expression correlated with poor patient survival. To model the function of Dlx3 in skin tumorigenesis, a two-stage dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA) study was performed on mice genetically depleted of Dlx3 in skin epithelium (Dlx3cKO). Dlx3cKO mice developed significantly more tumors, with more rapid tumorigenesis compared to control mice. In Dlx3cKO mice treated only with DMBA, tumors developed after ~16 weeks suggesting that loss of Dlx3 has a tumor promoting effect. Whole transcriptome analysis of tumor and skin tissue from our mouse model revealed spontaneous activation of the EGFR-ERBB2 pathway in the absence of Dlx3. Together, our findings from human and mouse model system support a tumor suppressive function for DLX3 in skin and underscore the efficacy of therapeutic approaches that target EGFR-ERBB2 pathway.

| S-EPMC8159909 | biostudies-literature

β-catenin signaling is a critical event in ErbB2-mediated mammary tumor progression.

Project description:Although ERBB2 amplification and overexpression is correlated with poor outcome in breast cancer, the molecular mechanisms underlying the aggressive nature of these tumors has not been fully elucidated. To investigate this further, we have used a transgenic mouse model of ErbB2-driven tumor progression (ErbB2KI model) that recapitulates clinically relevant events, including selective amplification of the core erbB2 amplicon. By comparing the transcriptional profiles of ErbB2KI mammary tumors and human ERBB2-positive breast cancers, we demonstrate that ErbB2KI tumors possess molecular features of the basal subtype of ERBB2-positive human breast cancer, including activation of canonical β-catenin signaling. Inhibition of β-catenin-dependent signaling in ErbB2KI-derived tumor cells using RNA interference impaired tumor initiation and metastasis. Furthermore, treatment of ErbB2KI or human ERBB2-overexpressing tumor cells with a selective β-catenin/CBP inhibitor significantly decreased proliferation and ErbB2 expression. Collectively, our data indicate that ERBB2-mediated breast cancer progression requires β-catenin signaling and can be therapeutically targeted by selective β-catenin/CBP inhibitors. Common reference design. 9 samples (including 2 normal tissue, 2 NIC tumors, and 5 KI tumor tissue samples) replicated twice as dye swaps, generating a total of 18 arrays.

2013-06-02 | E-GEOD-37954 | biostudies-arrayexpress

β-catenin signaling is a critical event in ErbB2-mediated mammary tumor progression.

2013-06-02 | GSE37954 | GEO

Chimeric EGFR ChIP-seq of an MCF-10A clone expressing chimeric EGFR and Erbb2 receptors

Project description:Synthetic activation of chimeric EGFR-Erbb2 receptors causes nuclear translocation of the heterodimers at long time scales. To identify genomic loci bound by nuclear EGFR-Erbb2, chromatin from an MCF10A-5E clone coexpressing chimeric EGFR and Erbb2 was prepared with or without synthetic activation and immunoprecipitated for chimeric EGFR by its GluGlu epitope tag.

2023-03-22 | GSE216242 | GEO

DLX3 binding sites in rat enamel organ

Project description:DLX3 is a homeodomain transcription factor involved in amelogenesis. Mutations in DLX3 in human lead to Tricho-Dento-Osseous syndrome featuring enamel hypoplasia and hypomineralization. Here we investigated the distribution of DLX3 DNA binding sites in rat enamel organ using ChIP-seq.

2020-02-11 | GSE85451 | GEO

DLX3 binding sites in Supabasal Keratinocytes

Project description:DLX3 is a homeodomain transcription factor involved in epidermal differentiation. Here we investigated the distribution of DLX3 DNA binding sites in suprabasal differentiating keratinocytes using ChIP-seq.

2017-06-12 | GSE89884 | GEO

Dlx3 Regulates Lifr and Chrdl1 Expression in Mouse Embryonic Stem Cell Differentiation

Project description:Dlx3 over-expression in mouse embryonic fibroblasts changed the expression level of numerous genes involved in osteogenesis and embryonic stem cell-related pathways as revealed by microarray analysis. From the list of Dlx3 modulated genes we focused our attention on the study of two candidates, Lifr and Chrdl1. Chromatin immunoprecipitation demonstrated the recruitment of Dlx3 transcription factor to the promoters of Lifr and Chrdl1, and luciferase assays confirmed the role of Dlx3 in the regulation of Lifr expression. Over-expression of Dlx3 in mouse embryonic stem cells stimulated Lifr and Chrdl1 expression and inhibited expression of Id proteins and Bmp4. We show that Dlx3 increases the expression of both soluble and transmembrane forms of Lifr. Soluble Lifr may regulate extracellular Lif levels via solution binding, while transmembrane Lifr mediates the signal transduction pathway. The data suggests that Dlx3 may be involved in stem cell differentiation in a dosage dependent way through its interaction with Lifr and with Chrdl1, a known antagonist of Bmp4. We speculate that Dlx3 may also be involved in osteoblast differentiation through interactions involving Lifr, Bmp, and Id proteins and signaling via the JAK/STAT and MAPK pathways. In summary, our data suggests that Dlx3 proteins play a significant role in a highly tuned network in early embryogenesis. Keywords: treated vs.untreated Stable and Transient transfection of Dlx3 in MEF. Total of 4 hybridizations including biological replicates.

2009-08-15 | E-GEOD-11727 | biostudies-arrayexpress

Molecular consequences of Dlx3 deletion in mouse enamel organ as determined by RNASeq analysis

Project description:DLX3 is a homeodomain transcription factor involved in ameloblast differentiation and enamel formation. Mutations in DLX3 in human lead to defects in enamel. However, the downstream targets of Dlx3 transcriptional activity in the enamel organ have not been identified yet. In this study, we compared the transcriptome of enamel organs where Dlx3 has been deleted to control tissues. Total RNA was extracted from enamel organs (mandibular incisors) from Dlx3-WT (N=4) and Dlx3-K14cKO (N=4) mice at P10. cDNA libraries were generated using NEBnext and NuGen kits. Sequencing was performed on the HiSeq2000.

2015-05-14 | E-GEOD-57984 | biostudies-arrayexpress

Role of DLX3 in primary human keratinocytes

Project description:DLX3 is expressed by differentiated cells in human skin and it has a functional role in epidermal maturation. We used microarray data analysis to assess gene expression in keratinocytes as consequence of DLX3 expression. We identified a specific subset of genes which are involved in cell cycle regulation and modulate the differentiation program in epidermal cells.

2017-02-09 | GSE63049 | GEO

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