Hedgehog signalling in gut development, physiology and cancer

Internal Medicine, 109 Zina Pitcher PL, BSRB, 2051, University of Michigan, Ann Arbor, MI 48105-2200, USA.
The Journal of Physiology (Impact Factor: 5.04). 12/2011; 590(Pt 3):421-32. DOI: 10.1113/jphysiol.2011.220681
Source: PubMed


The Hedgehog pathway is one of the most common signal transduction pathways used by mammalian cells. Most studies have focused on its role during development, primarily of the nervous system, skin, bone and pancreas. Due to the activation of this pathway during proliferation and neoplastic transformation, more recent studies have examined its role in adult tissues. Significant levels of sonic hedgehog are expressed in the gastric mucosa, which has served to direct analysis of its role during organogenesis, gastric acid secretion and neoplastic transformation. Therefore the goal of this review is to apply current knowledge of this pathway to further our understanding of gastrointestinal physiology and neoplasia, using the stomach as a prototype.

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    • "The vertebrate Gli repressor function largely depends on Gli3, while the primary Gli activator function largely depends on Gli2. Gli1 acts as a transcriptional activator and thus a reliable indicator of Hh pathway activity [9,10]. In Drosophila, the Hh signal is mediated by the Cubitus Interruptus (Ci) transcription factor. "
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    ABSTRACT: Background Recent evidence suggests that aberrant activation of Hedgehog (Hh) signaling by Gli transcription factors is characteristic of a variety of aggressive human carcinomas including gastric cancer. Speckle-type POZ protein, SPOP, is an E3 ubiquitin ligase adaptor, and it is found to inhibit oncogenic signaling. However, the molecular mechanisms are largely unknown.Methods In this study, we characterized the expression of SPOP in 88 pairs of gastric cancer tissues and adjacent tissues by immunohistochemical staining and Western blotting. The relationship between SPOP expression and clinical pathologic factors was analyzed. Transfected gastric cancer cell lines were used in cell viability, wound healing and colony formation assays. The interaction of SPOP with Gli2 and other related apoptotic proteins was assessed by immunoprecipitation, Western blotting, real-time PCR and dual luciferase reporter assays. Intracellular interaction of SPOP and Gli2 was visualized by immunofluorescent staining in gastric cancer cells.ResultsImmunohistochemical staining of SPOP can be detected in gastric cancer tissues but much less than adjacent gastric tissues (P¿<¿0.01). High SPOP expression is negatively correlated with lymph node metastasis, poor histological differentiation, and tumor malignancy according to TNM staging. In vitro experiments revealed that over-expression of SPOP prevented tumor cells from proliferation, migration and colony formation in gastric cancer cell lines. Likewise, repression of SPOP promoted cell viability, migration, proliferation, and attenuated apoptosis. Mechanistic studies revealed that increasing SPOP accelerated Gli2 degradation but regardless of Gli2 synthesis. Furthermore, cytoplasmic Gli2 decreased markedly along with the abundant expression of SPOP in MKN45 cells.Conclusions Our findings indicate that SPOP plays critical roles in suppressing gastric tumorigenesis through inhibiting Hh/Gli2 signaling pathway. It may provide an alternative strategy for developing therapeutic agents of gastric cancer in future.
    Journal of Experimental & Clinical Cancer Research 09/2014; 33(1):75. DOI:10.1186/PREACCEPT-1585232004128170 · 4.43 Impact Factor
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    • "The pathogenesis of HCC is unclear [4] . Studies have reported [5] [6] [7] , activation of Sonic Hedgehog (SHH) pathway exists in the HCC tissue and may promote tumor growth and angiogenesis, indicating that SHH signaling pathway molecules are involved in the onset of HCC process. SHH signaling pathway is a key regulator pathway for cell proliferation in the process of embryonic development. "
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    ABSTRACT: Objective To investigate clinical significance of Sonic Hedgehog (SHH) signaling pathway molecular Shh, Smo and Gli2 in primary hepatocellular carcinoma (HCC) tissue. Methods A total of 30 HCC tissue samples were collected. Protein expression of SHH signaling pathway molecules Shh, Smo and Gli2 in HCC tissues and para – carcinoma tissue were detected by using immunohistochemical method. Cirrhosis and normal liver tissue specimens were observed as control to analyze the expression of SHH signaling pathway molecular Shh, Smo and Gli2 mRNA in HCC tissues and corresponding para-carcinoma tissues and its relationship with the onset of HCC. Results There was no expression of Shh, Smo and Gli2 protein in normal liver tissue, while their positive rates were 63.3%, 76.7% and 66.7% in HCC tissues, respectively, with a significantly higher expression level than that in the para – carcinoma tissue (P<0.05). The protein expressions in HepG2 cells were slightly lower than that in Huh7 cells, with no statistical difference (P>0.05); Shh and Smo protein was detected in part of cirrhosis with positive expression, but Gli2 protein was not observable in cirrhosis tissues. Conclusions In HCC tissues, the high expression level of SHH signaling pathway molecules signal peptide (Shh), membrane protein receiptor (Smo) and nuclear transcription molecular (Gli2) can be indicators of the onset of liver cancer.
    Asian Pacific Journal of Tropical Medicine 09/2014; 7(9):735–738. DOI:10.1016/S1995-7645(14)60126-7 · 0.93 Impact Factor
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    • "Co-receptors that bind ligand and cooperate with Ptch to modulate the cellular response such as proliferation include members of the immunoglobulin superfamily, Growth arrest specific 1 (Gas1), CAM-related/downregulated by oncogenes (Cdo) and brother of Cdo (Boc) [17] [18] [19]. Mammalian cells express three Hh ligands – Sonic Hh (Shh), Indian Hh (Ihh) and Desert Hh (Dhh) that bind the Ptch receptor with apparently the same affinity [6] (Table 1). In the gastrointestinal tract, the major ligands expressed are Shh in the proximal gut (esophagus, stomach, liver and pancreas) and Ihh in the midgut and hindgut (small intestine and colon) [20]. "
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    ABSTRACT: This review summarizes emerging information regarding the Hedgehog (Hh) signaling pathway during neoplastic transformation in the gastrointestinal tract. Although there is a role for the well-established canonical pathway in which Hedgehog ligands interact with their receptor Patched, there is sufficient evidence that downstream components of the Hh pathway, e.g., Gli1, are hijacked by non-Hh signaling pathways to promote the conversion of the epithelium to dysplasia and carcinoma. We review the canonical pathway and involvement of primary cilia, and then focus on current evidence for Hh signaling in luminal bowel cancers as well as accessory organs, i.e., liver, pancreas and biliary ducts. We conclude that targeting the Hh pathway with small molecules, nutriceuticals and other mechanisms will likely require a combination of inhibitors that target Gli transcription factors in addition to canonical modulators such as Smoothened.
    Cancer Treatment Reviews 08/2013; 40(1). DOI:10.1016/j.ctrv.2013.08.003 · 7.59 Impact Factor
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