Dataset Information

?Np63? activates CD82 metastasis suppressor to inhibit cancer cell invasion.

ABSTRACT: P63 is a p53 family member involved in multiple facets of biology, including embryonic development, cell proliferation, differentiation, survival, apoptosis, senescence and aging. The p63 gene encodes multiple protein isoforms either with (TAp63) or without (?Np63) the N-terminal transactivation domain. Amounting evidence suggests that p63 can function as a tumor suppressor, yet the precise molecular mechanisms, and particularly the specific roles of TAp63 and ?Np63 in cancer progression, are still largely unclear. Here, we demonstrated that ?Np63?, the predominant isoform expressed in epithelial cells and squamous cell carcinomas, inhibits cell invasion. Affymetrix gene expression profiling, combined with gain- and loss-of-function analyses and chromatin immunoprecipitation, indicated that cluster of differentiation 82 (CD82), a documented metastasis suppressor, is a direct transcriptional target of ?Np63?. Expression of ?Np63? inhibited outgrowth in Matrigel and cancer cell invasion, which was largely reversed by specific ablation of CD82. Conversely, ?Np63? knockdown led to increased cell invasion, which was reversed by ectopic expression of CD82. Moreover, inhibition of glycogen synthase kinase-3? (GSK3?) by either pharmacological inhibitors or by RNA interference resulted in the downregulation of ?Np63? and CD82 expression, concomitant with increased cell invasion, independently of ?-catenin. Furthermore, decreased expression of p63 and CD82 is correlated with cancer progression. Taken together, this study reveals that ?Np63? upregulates CD82 to inhibit cell invasion, and suggests that GSK3? can regulate cell invasion by modulating the ?Np63?-CD82 axis.

SUBMITTER: Wu J

PROVIDER: S-EPMC4611714 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

ΔNp63α activates CD82 metastasis suppressor to inhibit cancer cell invasion.

Wu J J Liang S S Bergholz J J He H H Walsh E M EM Zhang Y Y Xiao Z-X ZX

Cell death & disease 20140605

P63 is a p53 family member involved in multiple facets of biology, including embryonic development, cell proliferation, differentiation, survival, apoptosis, senescence and aging. The p63 gene encodes multiple protein isoforms either with (TAp63) or without (ΔNp63) the N-terminal transactivation domain. Amounting evidence suggests that p63 can function as a tumor suppressor, yet the precise molecular mechanisms, and particularly the specific roles of TAp63 and ΔNp63 in cancer progression, are st ...[more]

PMID: 24901051

Similar Datasets

Project description:The efficacy of ginsenoside Rh2 (Rh2) in cancer therapy has been reported; however, its function in lung cancer remains unknown. To analyze the role of Rh2 in the inhibition of lung cancer cell proliferation in the present study, protein expression levels of E-cadherin, vimentin, ?-catenin, Smo, Gli1, and ?-catenin were assessed by western blotting, whilst mRNA expression levels of TCF7 FZD8, Smo, Gli1, Gli2, and Gli3 were determined by reverse transcription-quantitative PCR in the A549 cell line. Phosphorylation sites were detected by proteomic methods and cell proliferation was analyzed by MTT assay. The present study revealed that Rh2 treatment significantly inhibited cell proliferation. Western blotting indicated that the expression levels of E-cadherin were increased and vimentin was downregulated in Rh2-treated cells compared with control cells. Treatment of A549 cells with Rh2 suppressed phosphorylation of five distinct proteins and increased phosphorylation of nine proteins. Among them, the phosphorylation of ?-catenin at S641 was significantly induced. Rh2 treatment suppressed the expression levels of key genes involved in Wnt (Wnt3, transcription factor 7 and frizzled class receptor 8) and hedgehog [smoothened, frizzled class receptor (Smo), GLI family zinc finger (Gli)1, Gli2, and Gli3] signaling. Immunoblotting results indicated that ?-catenin, Smo and Gli1 protein expression levels were also suppressed by treatment with Rh2 compared with control treatment. Expression of ?-catenin S641D, a phosphomimetic form of ?-catenin, inhibited the accumulation of ?-catenin and Gli1 and inhibited cell proliferation and invasion. Furthermore, knockdown of ?-catenin (CTNNB1) or Gli1 with specific small interfering RNAs inhibited cell proliferation, whereas overexpression of these genes had an opposite effect. Additionally, overexpression of ?-catenin or Gli1 activated cell proliferation, even in the presence of Rh2, suggesting that Rh2 affects A549 cell proliferation through inhibition of Wnt and hedgehog signaling by phosphorylation of ?-catenin at S641. Together, these data suggested that Rh2 treatment may inhibit the proliferation of A549 lung cancer cells. Further exploration of the underlying mechanism by which Rh2 inhibits cell proliferation is warranted.

Project description:Background: Tetraspanin CD82 is a tumor metastasis suppressor that is known to down regulate in various metastatic cancers. However, the exact mechanism by which CD82 prevents cancer metastasis is unclear. This study aims to identify genes that are regulated by CD82 in human prostate cell lines.Methods: We used whole human genome microarray to obtain gene expression profiles in a normal prostate epithelial cell line that expressed CD82 (PrEC-31) and a metastatic prostate cell line that does not express CD82 (PC3). Then, siRNA silencing was used to knock down CD82 expression in PrEC-31 while CD82 was re-expressed in PC3 to acquire differentially-expressed genes in the respective cell line.Results: Differentially-expressed genes with a P?<?0.05 were identified in 3 data sets: PrEC-31 (+CD82) vs PrEC-31(-CD82), PC3-57 (+CD82) vs. PC3-5?V (-CD82), and PC3-29 (+CD82) vs. PC3-5?V (-CD82). Top 25 gene lists did not show overlap within the data sets, except (CALB1) the calcium binding protein calbindin 1 which was significantly up-regulated (2.8 log fold change) in PrEC-31 and PC3-29 cells that expressed CD82. Other most significantly up-regulated genes included serine peptidase inhibitor kazal type 1 (SPINK1) and polypeptide N-acetyl galactosaminyl transferase 14 (GALNT14) and most down-regulated genes included C-X-C motif chemokine ligand 14 (CXCL14), urotensin 2 (UTS2D), and fibroblast growth factor 13 (FGF13). Pathways related with cell proliferation and angiogenesis, migration and invasion, cell death, cell cycle, signal transduction, and metabolism were highly enriched in cells that lack CD82 expression. Expression of two mutually inclusive genes in top 100 gene lists of all data sets, runt-related transcription factor (RUNX3) and trefoil factor 3 (TFF3), could be validated with qRT-PCR.Conclusion: Identification of genes and pathways regulated by CD82 in this study may provide additional insights into the role that CD82 plays in prostate tumor progression and metastasis, as well as identify potential targets for therapeutic intervention.

Dataset Information

?Np63? activates CD82 metastasis suppressor to inhibit cancer cell invasion.

Publications

ΔNp63α activates CD82 metastasis suppressor to inhibit cancer cell invasion.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure