The Sonic Hedgehog–Patched–Gli Pathway in Human Development and Disease

Northwestern University Medical School and the Children's Memorial Institute for Education and Research, Chicago, IL 60614, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 12/2000; 67(5):1047-54. DOI: 10.1016/S0002-9297(07)62934-6
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Available from: Philip Iannaccone, Mar 05, 2014
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    • "Furthermore, tumorigenic activation of Smo can mediate overexpression of c-myc, a gene known to play an important pathogenic role in liver carcinogenesis. Recent studies have also shown that activation of Hedgehog signaling is critically related to CSCs and EMT features in many types of cancers including colonic, gastric, esophageal, hepatic, and others [33,34]. "
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    ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. The concept of cancer stem cells (CSCs) is based primarily on the clinical and experimental observations that indicate the existence of a subpopulation of cells with the capacity to self-renew and differentiate as well as show increased resistance to radiation and chemotherapy. They are considered as the factors responsible for the cases of tumor relapse. Hepatic progenitor cells (HPCs) could form the basis of some hepatocellular carcinomas (HCC) and cholangiocarcinomas. Liver CSCs have been reported in multiple subtypes of HCC and are considered as the master regulators of HCC initiation, tumor metastasis, and progression. HPCs activators such as epithelial cell adhesion molecule (EpCAM), Wnt/β-catenin, transforming growth factor-beta (TGF-β), Notch and Hedgehog signaling systems expedite tumorigenesis or conversely, serve as a powerful cancer-prevention tool. Recent work has also identified Sal-like protein 4 (SALL4) and some epigenetic regulations as important molecules, while several therapeutic drugs that directly control HPCs have been tested both in vivo and in vitro. However, liver CSCs clearly have a complex pathogenesis, with the potential for considerable crosstalk and redundancy in signaling pathways. Hence, the targeting of single molecules or pathways may have limited benefit for treatment. In addition to the direct control of liver CSCs, many other factors are needed for CSC maintenance including angiogenesis, vasculogenesis, invasion and migration, hypoxia, immune evasion, multiple drug resistance, and radioresistance. Here, we provide a brief review of molecular signaling in liver CSCs and present insights into new therapeutic strategies for their targeting.
    05/2014; 3(2):71-84. DOI:10.1159/000343863
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    • "Hh signaling pathway is critical for embryonic patterning and development in the central nervous system (CNS) 6, 8. Recent data have shown that Hh signaling pathway is involved in the initiation and maintenance of GBM 9-12. Aberrant activation of the Hh signaling pathway may result in tumorigenesis of human cancer, and also play an important role in proliferation of neoplastic cells 13, 14. While inactivation of the Hh signaling pathway leads to depletion of stem cell capacity in glioblastoma 15, 16. "
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    ABSTRACT: Aberrant activation of hedgehog (Hh) signaling pathway plays an important role in the development and proliferation of glioblastoma (GBM) cells. However, its mechanism remains unknown. MicroRNAs (miRNAs) are short non-coding RNA molecules which are involved in the post-transcriptional regulation of genes, and enrolled in signaling transduction network in tumors. This study was designed to investigate the role of miRNAs targeting the Hh signaling pathway in GBMs. According to the expression level of Gli1 mRNA measured by real time PCR, GBM samples were assigned to Gli1 high or low expression group. MiRNA microarray was applied to screen the dysregulated miRNA. As a result, 17 miRNAs were differentially expressed between Gli1 high expression and low expression groups (p < 0.005). Thirteen miRNAs including miR-125b-1 were downregulated, while only 4 miRNAs including miR-144 were upregulated in Gli1 high expression group. In summary, our study presents a subset of miRNAs which target the Hh signaling pathway in GBMs, and throws some light on the aberrant activation mechanism.
    International journal of medical sciences 03/2014; 11(5):488-93. DOI:10.7150/ijms.6764 · 2.00 Impact Factor
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    • "This transcription factor regulates downstream genes by direct binding to specific sequences in the promoter region of target genes [25]. The GLI3 protein is a downstream mediator of the sonic hedgehog pathway, and this pathway includes several genes that cause abnormal phenotypes in the human when mutated (for example, SHH, PTC1, and CBP) [26]. Shh pathway is involved in both lateral (epithelial-mesenchymal) and planar (epithelial-epithelial) signaling in early tooth development and GLI3 is expressed in both the epithelial and mesenchymal layers. "
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    ABSTRACT: Tooth agenesis is one of the most common anomalies of human dentition. Recent studies suggest that a number of genes are related to both syndromic and non-syndromic forms of hypodontia. In a previous study, we observed that polymorphism in rs929387 of GLI3 might be associated with hypodontia in the Chinese Han population based on a limited population. To further confirm this observation, in this study, we employed 89 individuals diagnosed with sporadic non-syndromic oligodontia (40 males and 49 females) to investigate the relationship between polymorphism in rs929387 of GLI3 and tooth agenesis. These individuals were analyzed with 273 subjects (125 males and 148 females) diagnosed with non-syndromic hypodontia and 200 healthy control subjects (100 males and 100 females). DNA was obtained from whole blood or saliva samples and genotyping was performed by a Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS) method. Significant differences were observed in the allele and genotype frequencies of rs929387 of GLI3. Distributions of genotypes TT, TC and CC of rs929387 polymorphism were significantly different between the case group and the control group (P = 0.013) and C allelic frequency was higher in case group [P = 0.002, OR = 1.690, 95% CI (1.200-2.379)]. Additionally, our analysis shows that this difference is more pronounced when compared between the male case group and the male control group. The function study suggests that variation in GLI3 caused by rs929387 leads to a decrease in its transcriptional activity. These data demonstrated an association between rs929387 of GLI3 and non-syndromic tooth agenesis in Chinese Han individuals. This information may provide further understanding of the molecular mechanisms of tooth agenesis. Furthermore, GLI3 can be regarded as a marker gene for the risk of tooth agenesis.
    PLoS ONE 11/2013; 8(11):e80860. DOI:10.1371/journal.pone.0080860 · 3.23 Impact Factor
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