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Expression analysis of macrodactyly identifies pleiotrophin upregulation.

ABSTRACT: Macrodactyly is a rare family of congenital disorders characterized by the diffuse enlargement of 1 or more digits. Multiple tissue types within the affected digits are involved, but skeletal patterning and gross morphological features are preserved. Not all tissues are equally involved and there is marked heterogeneity with respect to clinical phenotype. The molecular mechanisms responsible for these growth disturbances offer unique insight into normal limb growth and development, in general. To date, no genes or loci have been implicated in the development of macrodactyly. In this study, we performed the first transcriptional profiling of macrodactyly tissue. We found that pleiotrophin (PTN) was significantly overexpressed across all our macrodactyly samples. The mitogenic functions of PTN correlate closely with the clinical characteristics of macrodactyly. PTN thus represents a promising target for further investigation into the etiology of overgrowth phenotypes.

SUBMITTER: Lau FH

PROVIDER: S-EPMC3407187 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Expression analysis of macrodactyly identifies pleiotrophin upregulation.

Lau Frank H FH Xia Fang F Kaplan Adam A Cerrato Felecia F Greene Arin K AK Taghinia Amir A Cowan Chad A CA Labow Brian I BI

PloS one 20120727 7

Macrodactyly is a rare family of congenital disorders characterized by the diffuse enlargement of 1 or more digits. Multiple tissue types within the affected digits are involved, but skeletal patterning and gross morphological features are preserved. Not all tissues are equally involved and there is marked heterogeneity with respect to clinical phenotype. The molecular mechanisms responsible for these growth disturbances offer unique insight into normal limb growth and development, in general. T ...[more]

PMID: 22848377

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Project description:BackgroundMeningiomas are the most common intracranial tumors, with a subset of cases bearing a progressive phenotype. The DCC netrin 1 receptor (DCC) is a candidate gene for early meningioma progression. Cancer stem cell (CSC) genes are emerging as cancer therapeutic targets, as their expression is frequently associated with aggressive tumor phenotypes. The main objective of the study was to identify deregulated CSC genes in meningiomas.Materials and methodsInterrogating two expression data repositories, significantly differentially expressed genes (DEGs) were determined using DCC low vs. DCC high expression groups and WHO grade I (GI) vs. grade II + grade III (GII + GIII) comparison groups. Human stem cell (SC) genes were compiled from two published data sets and were extracted from the DEG lists. Biofunctional analysis was performed to assess associations between genes or molecules.ResultsIn the DCC low vs. DCC high expression groups, we assessed seven studies representing each between seven and 58 samples. The type I transmembrane protein podocalyxin like (PODXL) was markedly upregulated in DCC low expression meningiomas in six studies. Other CSC genes repeatedly deregulated included, e.g., BMP/retinoic acid inducible neural specific 1 (BRINP1), prominin 1 (PROM1), solute carrier family 24 member 3 (SLC24A3), rRho GTPase activating protein 28 (ARHGAP28), Kruppel like factor 5 (KLF5), and leucine rich repeat containing G protein-coupled receptor 4 (LGR4). In the GI vs. GII + GIII comparison groups, we assessed six studies representing each between nine and 68 samples. DNA topoisomerase 2-alpha (TOP2A) was markedly upregulated in GII + GIII meningiomas in four studies. Other CSC genes repeatedly deregulated included, e.g., ARHGAP28 and PODXL. Network analysis revealed associations of molecules with, e.g., cellular development and movement; nervous system development and function; and cancer.ConclusionsThis meta-analysis on meningiomas identified a comprehensive list of deregulated CSC genes across different array expression studies. Especially, PODXL is of interest for functional assessment in progressive meningiomas.

Project description:Pleiotrophin (PTN) is a heparin-binding growth factor with significant role(s) in tumour growth and angiogenesis. Although implication of endogenous PTN has been studied in several in vivo models of tumour angiogenesis, its role in physiological angiogenesis has not been addressed. In the present work, we studied expression and functional significance of endogenous PTN during angiogenesis in the chicken embryo chorioallantoic membrane (CAM).Using molecular, cellular and biochemical assays, we studied the expression pattern of PTN in CAM and human endothelial cells and its possible interaction with nucleolin (NCL). CAM cells were transfected with a pCDNA3.1 vector, empty (PC) or containing full length cDNA for PTN in antisense orientation (AS-PTN). Angiogenesis was estimated by measuring total vessel length. In vitro, human endothelial cells migration was studied by using a transwell assay, and down-regulation of NCL was performed by using a proper siRNA.Endogenous PTN mRNA and protein levels, as well as protein levels of its receptor protein tyrosine phosphatase beta/zeta (RPTP?/?) were maximal at early stages, when CAM angiogenesis is active. Application of AS-PTN onto CAM at days of active angiogenesis was not toxic to the tissue and led to dose-dependent decreased expression of endogenous PTN, ERK1/2 activity and angiogenesis. Interestingly, endogenous PTN was also immunolocalized at the endothelial cell nucleus, possibly through interaction with NCL, a protein that has a significant role in the nuclear translocation of many proteins. Down-regulation of NCL by siRNA in human endothelial cells significantly decreased nuclear PTN, verifying this hypothesis. Moreover, it led to abolishment of PTN-induced endothelial cell migration, suggesting, for the first time, that PTN-NCL interaction has a functional significance.Expression of endogenous PTN correlates with and seems to be involved in angiogenesis of the chicken embryo CAM. Our data suggest that NCL may have a role, increasing the number of growth factors whose angiogenic/tumorigenic activities are mediated by NCL.

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Expression analysis of macrodactyly identifies pleiotrophin upregulation.

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Expression analysis of macrodactyly identifies pleiotrophin upregulation.

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