Deregulation Of Wnt Signaling Pathway Research Articles

The relation between clinical course of pheochromocytoma-paraganglioma (PPGL) and complex genetic etiology

Recent years brought a remarkable progress on understanding the pathophysiology of rare, neuroendocrine tumours– pheochormocytomas and paragangliomas (PPGLs). Approximately 70% PPGLs are associated with germline or somatic mutation in one of more than 25 identified susceptibility genes, which were grouped into three clusters.Cluster 1 includes genes encoding proteins involved in Krebs cycle and hypoxia pathway – cluster 1 related PPGL are usually located extra-adrenally (often manifest as head and neck paragangliomas), they are also characterized by noradrenergic/dopaminergic biochemical phenotype and increased metastatic risk. Cluster 2 encompasses genes involved in kinase signaling pathway, PPGL related to cluster 2 are predominantly pheochromocytomas with adrenergic biochemical phenotype, the patients rarely develop metastases. The least known cluster 3, associated with deregulation of Wnt signaling pathway, includes exclusively somatic mutations leading to aggressive pheochromocytomas.This review summarizes molecular background and the differences between PPGL clusters regarding clinical course, biochemical phenotype, optimal imaging modalities and targeted molecular therapies for metastatic PPGL.

Involvement of the Wnt pathway in BVDV cytopathogenic strain replication in primary bovine cells

BackgroundBovine viral diarrhea virus 1 (BVDV-1) of the pestivirus genus is an economically crippling virus in the cattle industry; this positive RNA virus causes mucosal disease resulting in reproductive losses and other disease syndromes. The pathogenesis mechanism of the disease caused by BVDV infection is not well understood; for a better understanding of in vivo host BVDV-1 interactions, we conducted a transcriptomic study of infected cells at different times post-infection.MethodsWe compared the permissiveness and cellular response of a BVDV-1 cytopathogenic strain on Madin-Darby Bovine Kidney cells (MDBK) and bovine lung primary cells, a model closer to in vivo infection. Then a RNAseq analysis was realized on the infected bovine lung primary cells, at 10 hpi and 30 hpi (hours post-infection), to identify transcriptomic signatures.ResultsRNAseq analysis on BVDV-1 infected bovine primary cells showed 2,759 and 5,376 differentially expressed genes at respectively 10 hpi and 30 hpi with an absolute Fold Change ≥ 2. Among the different pathways deregulated, data analysis revealed a deregulation of Wnt signaling pathway, a conserved process that play a critical role in embryogenesis, cellular proliferation, and differentiation as well as in viral responses against viruses such as Influenza or Hepatitis C. We demonstrated here that the deregulation of the Wnt/βcatenin signaling pathway plays a role in viral replication of BVDV cp strain. Interestingly, we showed that the inhibition of this Wnt pathway using two inhibitors, FZM1 and iCRT14, induced a delay in onset of the establishment of a cytopathic effect of primary cells.ConclusionsThereby, this study highlighted a role of the Wnt signaling pathway in the BVDV-1 viral replication in bovine cells, suggesting an interesting option to explore as a new therapeutic target.

Identification of differentially expressed gene pathways between cytopathogenic and non-cytopathogenic BVDV-1 strains by analysis of the transcriptome of infected primary bovine cells

The bovine viral diarrhea virus 1 (BVDV-1), belonging to the Pestivirus genus, is characterized by the presence of two biotypes, cytopathogenic (cp) or non-cytopathogenic (ncp). For a better understanding of the host pathogen interactions, we set out to identify transcriptomic signatures of bovine lung primary cells (BPCs) infected with a cp or a ncp strain. For this, we used both a targeted approach by reverse transcription droplet digital PCR and whole genome approach using RNAseq. Data analysis showed 3571 differentially expressed transcripts over time (Fold Change >2) and revealed that the most deregulated pathways for cp strain are signaling pathways involved in responses to viral infection such as inflammatory response or apoptosis pathways. Interestingly, our data analysis revealed a deregulation of Wnt signaling pathway, a pathway described in embryogenesis, that was specifically seen with the BVDV-1 cp but not the ncp suggesting a role of this pathway in viral replication.

Targeting β-Catenin Signaling by Natural Products for Cancer Prevention and Therapy.

The mutations and deregulation of Wnt signaling pathway occur commonly in human cancer and cause the aberrant activation of β-catenin and β-catenin-dependent transcription, thus contributing to cancer development and progression. Therefore, β-catenin has been demonstrated as a promising target for cancer prevention and therapy. Many natural products have been characterized as inhibitors of the β-catenin signaling through down-regulating β-catenin expression, modulating its phosphorylation, promoting its ubiquitination and proteasomal degradation, inhibiting its nuclear translocation, or other molecular mechanisms. These natural product inhibitors have shown preventive and therapeutic efficacy in various cancer models in vitro and in vivo. In the present review, we comprehensively discuss the natural product β-catenin inhibitors, their in vitro and in vivo anticancer activities, and underlying molecular mechanisms. We also discuss the current β-catenin-targeting strategies and other potential strategies that may be examined for identifying new β-catenin inhibitors as cancer preventive and therapeutic drugs.

Molecular and phenotypic responses of Japanese medaka (Oryzias latipes) early life stages to environmental concentrations of cadmium in sediment.

Japanese medaka embryos were exposed to environmental concentrations of cadmium (Cd) to investigate adverse and adaptive responses in fish early life stages. Embryos were exposed during their whole development by static sediment-contact to environmental Cd concentrations (2 and 20μg/g dry weight). Cd bioaccumulation, developmental defects, biochemical and biomolecular (qRT-PCR) responses were analyzed in embryos and hatchlings. A dose-dependent increase of Cd bioaccumulation and developmental defects was observed at hatching. Cd had clear impacts on heartbeat and cardiac morphogenesis and also induced to spinal deformities. The profile and the level of gene transcription were differentially modulated according to the Cd concentration, the duration of exposure and/or the developmental stage of fish. Pro-apoptotic bax and DNA repair rad51 transcripts were significantly repressed in embryos exposed to the highest Cd concentration. Repression of these genes was correlated to the increase of heart rate in 6-day-old embryos. NADH-dehydrogenase nd5 gene transcription was inhibited in larvae at the lowest concentration suggesting mitochondrial respiratory chain impairment, in association with Cd-induced teratogenicity. Finally, wnt1 gene was overexpressed indicating putative deregulation of Wnt signaling pathway, and suggested to be implied in the occurrence of some spinal and cardiac deformities. Results of this study permitted to propose some promising markers at the transcriptional and phenotypical level, responding to environmental concentrations of Cd. The present work also highlights the usefulness of the modified version of the medaka embryo-larval assay with sediment-contact exposure (MELAc) to investigate the toxicity and the modes of action of sediment-bound pollutants.

SOX7, down-regulated in colorectal cancer, induces apoptosis and inhibits proliferation of colorectal cancer cells

The sex-determining region Y-box 7 (Sox7) is a member of high mobility group (HMG) transcription factor family, essential for embryonic development and endoderm differentiation. Deregulation of Wnt signaling pathway is a hallmark of colorectal cancer. Our results showed that the expression level of SOX7 was frequently down-regulated in human colorectal cancer cell lines and in primary colorectal tumor tissues, and the SOX7 silencing was partially due to the aberrant DNA methylation of the gene. Restoration of SOX7 induced colorectal cancer cell apoptosis, inhibited cell proliferation and colony formation. In addition, SOX7 efficiently suppressed β-catenin-mediated transcriptional activity.