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Special Issue "Hedgehog Signaling 2.0"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 31 July 2020.

Special Issue Editor

Prof. Dr. Tsuyoshi Shimo
Website
Guest Editor
Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, 1757 Ishikari-Tobetsu, Hokkaido 061-0293, Japan
Interests: hedgehog; tumor micro-environment; metastasis; targeted cancer therapy; immune surveillance
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Special Issue Information

Dear Colleagues,

Hedgehog signaling pathways govern complex developmental processes, including stem-cell maintenance, proliferation, differentiation, and patterning. However, hedgehog signaling is frequently activated in various human cancers. Several recent studies have shown that the aberrant activation of hedgehog signaling is associated with neoplastic transformation, cancer cell proliferation, metastasis, the drug resistance of multiple cancers, and survival rate.

Recent evidence indicates that Hedgehog signaling is involved, through different mechanisms, in human malignancies, where it promotes growth, enables the proliferation of tumor stem cells, and regulates the tumor-stroma interaction. A ligand-independent Shh pathway activation has been described in familial cancers, such as basal cell carcinoma, medulloblastoma, and rhabdomyosarcoma, as a consequence of genetic aberrations, targeting mainly the Ptch inhibitory receptor. Ligand-independent non-canonical Shh pathway activation has been reported in several tumor models as a result of a crosstalk with different tumorigenic pathways. Finally, ligand-dependent autocrine or paracrine activation has also been described. Research articles, reviews, and communications on every aspect of Hedgehog signaling in development, organogenesis, cancer and other human diseases, as well as on the role of Hedgehog molecules as diagnostic, prognostic, and therapeutic targets are invited.
This Special Issue focuses on several aspects of hedgehog signaling research, and we invite contributions of reviews and/or original papers reporting on the recent efforts in the field of hedgehog signaling.

Prof. Dr. Tsuyoshi Shimo
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • hedgehog
  • tumor micro-environment
  • metastasis
  • angiogenesis
  • cancer stem cell
  • tumor–stroma interaction
  • target genes
  • primary cilia
  • hedgehog signaling pathway
  • hedgehog signaling inhibitors
  • targeted cancer therapy
  • cancer treatment resistance
  • immune surveillance
  • development
  • organogenesis

Published Papers (3 papers)

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Research

Open AccessArticle
Sonic Hedgehog and Triiodothyronine Pathway Interact in Mouse Embryonic Neural Stem Cells
Int. J. Mol. Sci. 2020, 21(10), 3672; https://doi.org/10.3390/ijms21103672 - 23 May 2020
Abstract
Neural stem cells are fundamental to development of the central nervous system (CNS)—as well as its plasticity and regeneration—and represent a potential tool for neuro transplantation therapy and research. This study is focused on examination of the proliferation dynamic and fate of embryonic [...] Read more.
Neural stem cells are fundamental to development of the central nervous system (CNS)—as well as its plasticity and regeneration—and represent a potential tool for neuro transplantation therapy and research. This study is focused on examination of the proliferation dynamic and fate of embryonic neural stem cells (eNSCs) under differentiating conditions. In this work, we analyzed eNSCs differentiating alone and in the presence of sonic hedgehog (SHH) or triiodothyronine (T3) which play an important role in the development of the CNS. We found that inhibition of the SHH pathway and activation of the T3 pathway increased cellular health and survival of differentiating eNSCs. In addition, T3 was able to increase the expression of the gene for the receptor smoothened (Smo), which is part of the SHH signaling cascade, while SHH increased the expression of the T3 receptor beta gene (Thrb). This might be the reason why the combination of SHH and T3 increased the expression of the thyroxine 5-deiodinase type III gene (Dio3), which inhibits T3 activity, which in turn affects cellular health and proliferation activity of eNSCs. Full article
(This article belongs to the Special Issue Hedgehog Signaling 2.0)
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Open AccessArticle
Hedgehog Inhibitors Suppress Osteoclastogenesis in In Vitro Cultures, and Deletion of Smo in Macrophage/Osteoclast Lineage Prevents Age-Related Bone Loss
Int. J. Mol. Sci. 2020, 21(8), 2745; https://doi.org/10.3390/ijms21082745 - 15 Apr 2020
Abstract
The functional role of the Hedgehog (Hh)-signaling pathway has been widely investigated in bone physiology/development. Previous studies have, however, focused primarily on Hh functions in bone formation, while its roles in bone resorption have not been fully elucidated. Here, we found that cyclopamine [...] Read more.
The functional role of the Hedgehog (Hh)-signaling pathway has been widely investigated in bone physiology/development. Previous studies have, however, focused primarily on Hh functions in bone formation, while its roles in bone resorption have not been fully elucidated. Here, we found that cyclopamine (smoothened (Smo) inhibitor), GANT-58 (GLI1 inhibitor), or GANT-61 (GLI1/2 inhibitor) significantly inhibited RANKL-induced osteoclast differentiation of bone marrow-derived macrophages. Although the inhibitory effects were exerted by cyclopamine or GANT-61 treatment during 0–48 h (early stage of osteoclast differentiation) or 48–96 h (late stage of osteoclast differentiation) after RANKL stimulation, GANT-58 suppressed osteoclast formation only during the early stage. These results suggest that the Smo-GLI1/2 axis mediates the whole process of osteoclastogenesis and that GLI1 activation is requisite only during early cellular events of osteoclastogenesis. Additionally, macrophage/osteoclast-specific deletion of Smo in mice was found to attenuate the aging phenotype characterized by trabecular low bone mass, suggesting that blockage of the Hh-signaling pathway in the osteoclast lineage plays a protective role against age-related bone loss. Our findings reveal a specific role of the Hh-signaling pathway in bone resorption and highlight that its inhibitors show potential as therapeutic agents that block osteoclast formation in the treatment of senile osteoporosis. Full article
(This article belongs to the Special Issue Hedgehog Signaling 2.0)
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Open AccessArticle
The FDA-Approved Anti-Asthma Medicine Ciclesonide Inhibits Lung Cancer Stem Cells through Hedgehog Signaling-Mediated SOX2 Regulation
Int. J. Mol. Sci. 2020, 21(3), 1014; https://doi.org/10.3390/ijms21031014 - 04 Feb 2020
Abstract
Ciclesonide is an FDA-approved glucocorticoid (GC) used to treat asthma and allergic rhinitis. However, its effects on cancer and cancer stem cells (CSCs) are unknown. Our study focuses on investigating the inhibitory effect of ciclesonide on lung cancer and CSCs and its underlying [...] Read more.
Ciclesonide is an FDA-approved glucocorticoid (GC) used to treat asthma and allergic rhinitis. However, its effects on cancer and cancer stem cells (CSCs) are unknown. Our study focuses on investigating the inhibitory effect of ciclesonide on lung cancer and CSCs and its underlying mechanism. In this study, we showed that ciclesonide inhibits the proliferation of lung cancer cells and the growth of CSCs. Similar glucocorticoids, such as dexamethasone and prednisone, do not inhibit CSC formation. We show that ciclesonide is important for CSC formation through the Hedgehog signaling pathway. Ciclesonide reduces the protein levels of GL1, GL2, and Smoothened (SMO), and a small interfering RNA (siRNA) targeting SMO inhibits tumorsphere formation. Additionally, ciclesonide reduces the transcript and protein levels of SOX2, and an siRNA targeting SOX2 inhibits tumorsphere formation. To regulate breast CSC formation, ciclesonide regulates GL1, GL2, SMO, and SOX2. Our results unveil a novel mechanism involving Hedgehog signaling and SOX2 regulated by ciclesonide in lung CSCs, and also open up the possibility of targeting Hedgehog signaling and SOX2 to prevent lung CSC formation. Full article
(This article belongs to the Special Issue Hedgehog Signaling 2.0)
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