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Hedgehog Signaling 3.0
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Hedgehog Signaling 3.0

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

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 20110

Special Issue Editor

Prof. Dr. Tsuyoshi Shimo

E-Mail 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: cancer biology; cell proliferation; signal transduction; cell differentiation; cell adhesion
Special Issues, Collections and Topics in MDPI journals

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, drug resistance of multiple cancers, and survival rate.

Recent evidences indicate that Hh signaling is involved, through different mechanisms, in human malignancies where it promotes growth, enables proliferation of tumor stem cells and regulates 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 Hh signaling in cancer and other human diseases as well as on the role of Hh moleculs 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

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • hedgehog
  • tumor microenvironment
  • 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

Published Papers (5 papers)

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Research

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24 pages, 8069 KiB  
Article
The Role of Hedgehog Signaling in the Melanoma Tumor Bone Microenvironment
by Karnoon Shamsoon, Daichi Hiraki, Koki Yoshida, Kiyofumi Takabatake, Hiroaki Takebe, Kenji Yokozeki, Naohiro Horie, Naomasa Fujita, Nisrina Ekayani Nasrun, Tatsuo Okui, Hitoshi Nagatsuka, Yoshihiro Abiko, Akihiro Hosoya, Takashi Saito and Tsuyoshi Shimo
Int. J. Mol. Sci. 2023, 24(10), 8862; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24108862 - 16 May 2023
Cited by 1 | Viewed by 1639
Abstract
A crucial regulator in melanoma progression and treatment resistance is tumor microenvironments, and Hedgehog (Hh) signals activated in a tumor bone microenvironment are a potential new therapeutic target. The mechanism of bone destruction by melanomas involving Hh/Gli signaling in such a tumor microenvironment [...] Read more.
A crucial regulator in melanoma progression and treatment resistance is tumor microenvironments, and Hedgehog (Hh) signals activated in a tumor bone microenvironment are a potential new therapeutic target. The mechanism of bone destruction by melanomas involving Hh/Gli signaling in such a tumor microenvironment is unknown. Here, we analyzed surgically resected oral malignant melanoma specimens and observed that Sonic Hedgehog, Gli1, and Gli2 were highly expressed in tumor cells, vasculatures, and osteoclasts. We established a tumor bone destruction mouse model by inoculating B16 cells into the bone marrow space of the right tibial metaphysis of 5-week-old female C57BL mice. An intraperitoneal administration of GANT61 (40 mg/kg), a small-molecule inhibitor of Gli1 and Gli2, resulted in significant inhibition of cortical bone destruction, TRAP-positive osteoclasts within the cortical bone, and endomucin-positive tumor vessels. The gene set enrichment analysis suggested that genes involved in apoptosis, angiogenesis, and the PD-L1 expression pathway in cancer were significantly altered by the GANT61 treatment. A flow cytometry analysis revealed that PD-L1 expression was significantly decreased in cells in which late apoptosis was induced by the GANT61 treatment. These results suggest that molecular targeting of Gli1 and Gli2 may release immunosuppression of the tumor bone microenvironment through normalization of abnormal angiogenesis and bone remodeling in advanced melanoma with jaw bone invasion. Full article
(This article belongs to the Special Issue Hedgehog Signaling 3.0)
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19 pages, 34578 KiB  
Article
Mebendazole Mediates Proteasomal Degradation of GLI Transcription Factors in Acute Myeloid Leukemia
by Fabian Freisleben, Franziska Modemann, Jana Muschhammer, Hauke Stamm, Franziska Brauneck, Alexander Krispien, Carsten Bokemeyer, Karl N. Kirschner, Jasmin Wellbrock and Walter Fiedler
Int. J. Mol. Sci. 2021, 22(19), 10670; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910670 - 01 Oct 2021
Cited by 6 | Viewed by 2526
Abstract
The prognosis of elderly AML patients is still poor due to chemotherapy resistance. The Hedgehog (HH) pathway is important for leukemic transformation because of aberrant activation of GLI transcription factors. MBZ is a well-tolerated anthelmintic that exhibits strong antitumor effects. Herein, we show [...] Read more.
The prognosis of elderly AML patients is still poor due to chemotherapy resistance. The Hedgehog (HH) pathway is important for leukemic transformation because of aberrant activation of GLI transcription factors. MBZ is a well-tolerated anthelmintic that exhibits strong antitumor effects. Herein, we show that MBZ induced strong, dose-dependent anti-leukemic effects on AML cells, including the sensitization of AML cells to chemotherapy with cytarabine. MBZ strongly reduced intracellular protein levels of GLI1/GLI2 transcription factors. Consequently, MBZ reduced the GLI promoter activity as observed in luciferase-based reporter assays in AML cell lines. Further analysis revealed that MBZ mediates its anti-leukemic effects by promoting the proteasomal degradation of GLI transcription factors via inhibition of HSP70/90 chaperone activity. Extensive molecular dynamics simulations were performed on the MBZ-HSP90 complex, showing a stable binding interaction at the ATP binding site. Importantly, two patients with refractory AML were treated with MBZ in an off-label setting and MBZ effectively reduced the GLI signaling activity in a modified plasma inhibitory assay, resulting in a decrease in peripheral blood blast counts in one patient. Our data prove that MBZ is an effective GLI inhibitor that should be evaluated in combination to conventional chemotherapy in the clinical setting. Full article
(This article belongs to the Special Issue Hedgehog Signaling 3.0)
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Review

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27 pages, 2654 KiB  
Review
Hedgehog Pathway Inhibitors as Targeted Cancer Therapy and Strategies to Overcome Drug Resistance
by Ngoc Minh Nguyen and Jungsook Cho
Int. J. Mol. Sci. 2022, 23(3), 1733; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031733 - 03 Feb 2022
Cited by 44 | Viewed by 7238
Abstract
Hedgehog (Hh) signaling is a highly conserved pathway that plays a vital role during embryonic development. Recently, uncontrolled activation of this pathway has been demonstrated in various types of cancer. Therefore, Hh pathway inhibitors have emerged as an important class of anti-cancer agents. [...] Read more.
Hedgehog (Hh) signaling is a highly conserved pathway that plays a vital role during embryonic development. Recently, uncontrolled activation of this pathway has been demonstrated in various types of cancer. Therefore, Hh pathway inhibitors have emerged as an important class of anti-cancer agents. Unfortunately, however, their reputation has been tarnished by the emergence of resistance during therapy, necessitating clarification of mechanisms underlying the drug resistance. In this review, we briefly overview canonical and non-canonical Hh pathways and their inhibitors as targeted cancer therapy. In addition, we summarize the mechanisms of resistance to Smoothened (SMO) inhibitors, including point mutations of the drug binding pocket or downstream molecules of SMO, and non-canonical mechanisms to reinforce Hh pathway output. A distinct mechanism involving loss of primary cilia is also described to maintain GLI activity in resistant tumors. Finally, we address the main strategies to circumvent the drug resistance. These strategies include the development of novel and potent inhibitors targeting different components of the canonical Hh pathway or signaling molecules of the non-canonical pathway. Further studies are necessary to avoid emerging resistance to Hh inhibitors and establish an optimal customized regimen with improved therapeutic efficacy to treat various types of cancer, including basal cell carcinoma. Full article
(This article belongs to the Special Issue Hedgehog Signaling 3.0)
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9 pages, 450 KiB  
Review
Patidegib in Dermatology: A Current Review
by Terenzio Cosio, Monia Di Prete, Cosimo Di Raimondo, Virginia Garofalo, Flavia Lozzi, Caterina Lanna, Emi Dika, Augusto Orlandi, Maria Cristina Rapanotti, Luca Bianchi and Elena Campione
Int. J. Mol. Sci. 2021, 22(19), 10725; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910725 - 03 Oct 2021
Cited by 15 | Viewed by 2235
Abstract
Background: Basal cell carcinoma is one of the most common types of non-melanoma skin cancers, which can be locally destructive despite low-rate metastasis. Surgery is the treatment of choice, but it lacks of efficacy on advanced cases. Hedgehog pathway inhibitors are a class [...] Read more.
Background: Basal cell carcinoma is one of the most common types of non-melanoma skin cancers, which can be locally destructive despite low-rate metastasis. Surgery is the treatment of choice, but it lacks of efficacy on advanced cases. Hedgehog pathway inhibitors are a class of drugs providing a new therapeutic option for patients affected by advanced disease. Besides systemic therapy, such as vismodegib and sonidegib, also topical inhibitors have been developed. Patidegib is able to decrease tumor burden, reducing the adverse effects induced by systemic targeted therapies. Methods: We performed comprehensive research to summarize the use of patidegib in advanced and recurrent aggressive basal cell carcinomas. Only English language human studies were included in the search. Results: Seven trials reported the application of patidegib. Both topical and systemic patidegib demonstrated safety, tolerability, and efficacy in naïve patients with stage II and III basal cell carcinomas, while stage IV disease and not-naïve patients did not show any benefit. Conclusion: Unlike systemic Hedgehog pathway inhibitors, patidegib 2% gel is not associated with systemic adverse effects and allows a better patient management. Considering the multidisciplinary management of neoplasia, in the era of precision medicine, it is mandatory to confide in pharmacogenomics to obtain personalized combined or sequential therapies. Full article
(This article belongs to the Special Issue Hedgehog Signaling 3.0)
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20 pages, 1622 KiB  
Review
The Role of Sonic Hedgehog in Human Holoprosencephaly and Short-Rib Polydactyly Syndromes
by Christine K. C. Loo, Michael A. Pearen and Grant A. Ramm
Int. J. Mol. Sci. 2021, 22(18), 9854; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189854 - 12 Sep 2021
Cited by 9 | Viewed by 5379
Abstract
The Hedgehog (HH) signalling pathway is one of the major pathways controlling cell differentiation and proliferation during human development. This pathway is complex, with HH function influenced by inhibitors, promotors, interactions with other signalling pathways, and non-genetic and cellular factors. Many aspects of [...] Read more.
The Hedgehog (HH) signalling pathway is one of the major pathways controlling cell differentiation and proliferation during human development. This pathway is complex, with HH function influenced by inhibitors, promotors, interactions with other signalling pathways, and non-genetic and cellular factors. Many aspects of this pathway are not yet clarified. The main features of Sonic Hedgehog (SHH) signalling are discussed in relation to its function in human development. The possible role of SHH will be considered using examples of holoprosencephaly and short-rib polydactyly (SRP) syndromes. In these syndromes, there is wide variability in phenotype even with the same genetic mutation, so that other factors must influence the outcome. SHH mutations were the first identified genetic causes of holoprosencephaly, but many other genes and environmental factors can cause malformations in the holoprosencephaly spectrum. Many patients with SRP have genetic defects affecting primary cilia, structures found on most mammalian cells which are thought to be necessary for canonical HH signal transduction. Although SHH signalling is affected in both these genetic conditions, there is little overlap in phenotype. Possible explanations will be canvassed, using data from published human and animal studies. Implications for the understanding of SHH signalling in humans will be discussed. Full article
(This article belongs to the Special Issue Hedgehog Signaling 3.0)
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