Supplementary Material for: Distinct Involvement of the Sonic Hedgehog Signaling Pathway in Gastric Adenocarcinoma of Fundic Gland Type and Conventional Gastric Adenocarcinoma
Y TajimaTakashi MurakamiTsuyoshi SaitoTakashi HiromotoYoshihiro AkazawaNoriko SasaharaHiroyuki MitomiTakashi YaoSumio Watanabe
0
Citation
0
Reference
10
Related Paper
Abstract:
Background/Aims: Gastric adenocarcinoma of fundic gland type (GAFG), which is a rare variant of gastric cancer, is reportedly associated with both Wnt/β-catenin signaling activation and guanine nucleotide binding protein, alpha stimulating complex (GNAS) mutations. This study aimed to elucidate potential roles of the Sonic hedgehog (Shh) signaling pathway in GAFG. Methods: We performed immunostaining for β-catenin and Shh signal-associated proteins, including Patched (Ptch), Smoothened (Smo), and Glioma-associated oncogene-1 (Gli1), and the direct sequencing of GNAS/BRAF/KRAS in 27 GAFGs, and compared them with 30 conventional gastric adenocarcinomas (CGAs). Results: GAFGs exhibited significantly lower immunoreactivity scores for Ptch, Smo, and Gli1 than CGAs. Moreover, while the Ptch score was significantly lower in the GAFG tumor areas than in the non-neoplastic areas adjacent to GAFG, the score was significantly higher in the CGA tumor areas than in the non-neoplastic areas. Similar trends were observed in the scores for Smo and Gli1. β-Catenin expression and GNAS mutations were found in 22 (81%) and 8 (30%) of the 27 GAFGs respectively. Gli1 expression was significantly associated with mutations in GNAS. Conclusion: GAFG and CGA exhibited distinct Ptch, Smo, and Gli1 expression patterns. Downregulation of the Shh signaling pathway, as well as activation of the Wnt/β-catenin signaling pathway, may therefore be associated with tumorigenesis in GAFG.Keywords:
Gastric adenocarcinoma
Ventral cell fates in the central nervous system are induced by Sonic hedgehog, a homolog of hedgehog, a secreted Drosophila protein. In the central nervous system, Sonic hedgehog has been identified as the signal inducing floor plate, motor neurons, and dopaminergic neurons. Sonic hedgehog is also involved in the induction of ventral cell type in the developing somites. ptc is a key gene in the Drosophila hedgehog signaling pathway where it is involved in transducing the hedgehog signal and is also a transcriptional target of the signal. PTC, a vertebrate homolog of this Drosophila gene, is genetically downstream of Sonic hedgehog (Shh) in the limb bud. We analyze PTC expression during chicken neural and somite development and find it expressed in all regions of these tissues known to be responsive to Sonic hedgehog signal. As in the limb bud, ectopic expression of Sonic hedgehog leads to ectopic induction of PTC in the neural tube and paraxial mesoderm. This conservation of regulation allows us to use PTC as a marker for Sonic hedgehog response. The pattern of PTC expression suggests that Sonic hedgehog may play an inductive role in more dorsal regions of the neural tube than have been previously demonstrated. Examination of the pattern of PTC expression also suggests that PTC may act in a negative feedback loop to attenuate hedgehog signaling.
Floor plate
Patched
Ectopic expression
Smoothened
Paraxial mesoderm
Limb bud
Indian hedgehog
Cite
Citations (331)
Smoothened
Patched
GLI1
Indian hedgehog
Cyclopamine
Cite
Citations (0)
Sonic hedgehog(SHH) pathway relates to the occurrence of cancer closely,which is overexpressed in endodermal organ of tumor.Recent research shows that SHH pathway is also closed with hepatocellular carcinoma(HCC).This paper reviews the research progress of SHH pathway and HCC.
Cite
Citations (0)
Background: Hedgehog pathway plays a crucial role in the neovascularisation and angiogenesis during the embryonic stage in humans. Three genes of hedgehog protein isolated from humans are Sonic hedgehog, Desert hedgehog and Indian hedgehog gene. Two G-protein coupled receptors identified in the sonic hedgehog pathway served as patched receptor and smoothened receptor. Materials and Methods: Particularly, sonic hedgehog gene plays a versatile role in cellular homeostasis and can be a novel therapeutic target in the prevention of cardiovascular disorders. Further various sonic hedgehog modulators have been reported working as futuristic drug molecules in the modulation of cardiovascular dysfunctions. Results: However, there was limited literature availability that has summarized the possible mechanism of targeting Sonic hedgehog signaling pathway. Conclusion: Thus, the present review is aimed at exploring the role of targeting sonic hedgehog protein signaling and modulators as well as to enlighten that how targeting sonic hedgehog protein involves in the amelioration of atherosclerosis, ischemic heart diseases, vascular endothelial dysfunction, heart failure and congenital heart diseases.
Smoothened
Patched
GLI2
Cite
Citations (0)
Sonic Hedgehog signaling pathway is an important regulating phase in angiogenesis.Sonic Hedgehog could regulate the length, diameter and branching of vessels.Sonic Hedgehog could act upon interstitial mesenchymal cells to secrete an array of angiogenic growth factors and induce the morphogenesis of arterial vessels.Sonic Hedgehog could regulate angiogenesis through three different mechanisms (COUP-TFⅡ , SHH/GLI/SMO and PI3K pathways), and it may become a new potential targeting factor in the research of angiogenesis.
Smoothened
Cite
Citations (0)
Smoothened
Signalling
Patched
Cite
Citations (118)
Abstract Recently, it has become clear that the developmental hedgehog pathway is activated in ischaemic adult tissue where it aids in salvaging damaged tissue. The exact driving force for the initial hedgehog response is unclear and as most physiological and cellular processes are disturbed in ischaemic tissue, hedgehog‐activating signals are hard to dissect. Here, we demonstrate that hypoxia per se is able to induce a rapid systemic hedgehog response in adult mice, as evident from expression of the pathway ligand, Sonic hedgehog, as well as the pathway activity marker Patched1 in various organs. Using in vitro models of hypoxia, we showed that the hedgehog response was transient and preceded by the accumulation of HIF‐1α, which we hypothesized to communicate between hypoxia and hedgehog expression. Indeed, pharmacological inhibition, knockdown or genetic ablation of HIF‐1α abolished hedgehog pathway activation. In conclusion, we have established that hypoxia is translated into a hedgehog response through HIF‐1α and this mechanism is likely to be responsible for the hedgehog response observed in various ischaemia models.
Hypoxia
Indian hedgehog
Cite
Citations (86)
To investigate the expression status of Sonic Hedgehog signaling genes and molecules in human hepatocellular carcinomas(HCC), and to explore the relationship between these genes and clinical prognosis.HCC tissue and adjacent normal tissue from 29 HCC patients were assayed for the expression of hedgehog signaling genes by reverse transcription-polymerase chain reaction chain reaction (RT-PCR) techniques and for the expression of hedgehog signaling molecules by immunohistochemistry. The expressions of Shh, Ptch, Smoh, Gli-1 mRNA were assayed as well as Shh, Ptch proteins in 29 cases of HCC and in 29 liver tissues adjacent to the tumor.Expression of Shh mRNA was detectable in about 51% of HCCs examined. Consistent with this, hedgehog target genes Ptch, Smoh and Gli-1 mRNA were expressed in over 68%, 48% and 62% of the tumors, respectively, and the expressions of Shh and Ptch proteins in HCC tumor tissues correlated with those of Shh and Ptch mRNA in tumor tissues (P=0.041 and P=0.035). This suggested that the hedgehog pathway was frequently activated in HCCs. The simultaneous expression of Gli-1 in HCC and liver tissues adjacent to the tumor had significantly relationship with poor prognosis.Hedgehog signaling activation is an important event for development of human HCCs. It also suggests that markers for hedgehog signaling activation may be useful for the determination of prognosis.
HCCS
GLI2
GLI1
Cite
Citations (7)
GLI3
GLI2
Smoothened
Patched
GLI1
Limb development
Cite
Citations (387)
Abstract Rationale The therapeutic potential of Hedgehog (Hh) signaling agonists for vascular diseases is of growing interest. However, molecular and cellular mechanisms underlying the role of the Hh signaling in vascular biology remain poorly understood. Objective The purpose of the present paper is to clarify some conflicting literature data. Findings With this goal we have demonstrated that, unexpectedly, ectopically administered N-terminal Sonic Hedgehog (N-Shh) and endogenous endothelial-derived Desert Hedgehog (Dhh) induce opposite effects in endothelial cells. (ECs). Notably, endothelial Dhh acts under its full-length soluble form (FL-Dhh) and activates Smoothened in ECs, while N-Shh inhibits it. At molecular level, N-Shh prevents FL-Dhh binding to Patched-1 demonstrating that N-Shh acts as competitive antagonist to FL-Dhh. Besides, we found that even though FL-Hh ligands and N-Hh ligands all bind Patched-1, they induce specific Patched-1 localization. Finally, we confirmed that in a pathophysiological setting i.e. brain inflammation, astrocyte-derived N-Shh act as a FL-Dhh antagonist. Conclusion The present study highlights for the first time that FL-Dhh and N-Hh ligands have antagonistic properties especially in ECs, and demonstrates that Hh ligands or forms of Hh ligands cannot be used instead of another for therapeutic purposes.
Patched
Smoothened
Morphogen
Cite
Citations (2)