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Hedgehog Signaling 2.0

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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 December 2020) | Viewed by 48493

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Prof. Dr. Tsuyoshi Shimo

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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
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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

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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 (14 papers)

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18 pages, 7885 KiB

Open AccessArticle

BBS Proteins Affect Ciliogenesis and Are Essential for Hedgehog Signaling, but Not for Formation of iPSC-Derived RPE-65 Expressing RPE-Like Cells

by Caroline Amalie Brunbjerg Hey, Lasse Jonsgaard Larsen, Zeynep Tümer, Karen Brøndum-Nielsen, Karen Grønskov, Tina Duelund Hjortshøj and Lisbeth Birk Møller

Int. J. Mol. Sci. 2021, 22(3), 1345; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031345 - 29 Jan 2021

Cited by 11 | Viewed by 3053

Abstract

Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinal dystrophy, renal cysts, obesity and polydactyly. BBS genes have been implicated in ciliogenesis, hedgehog signaling and retinal pigment epithelium maturation. BBS1 and BBS5 are members of the BBSome, implicated in cilia transport of proteins, and BBS10 is a member of the chaperonin-complex, mediating BBSome assembly. In this study, involvement of BBS1, BBS5 and BBS10 in ciliogenesis and hedgehog signaling were investigated in BBS-defective patient fibroblasts as well as in RPE-hTERT cells following siRNA-mediated knockdown of the BBS genes. Furthermore, the ability of BBS1-defective induced pluripotent stem-cells (iPSCs) to differentiate into RPE cells was assessed. We report that cells lacking functional BBS5 or BBS10 have a reduced number of primary cilia, whereas cells lacking functional BBS1 display shorter primary cilia compared to wild-type cells. Hedgehog signaling was substantially impaired and Smoothened, a component of hedgehog signaling, was trapped inside the cilia of the BBS-defective cells, even in the absence of Smoothened agonist. Preliminary results demonstrated the ability of BBS1-defective iPSC to differentiate into RPE-65 expressing RPE-like cells. The BBS1^−/−-defective RPE-like cells were less pigmented, compared to RPE-like cells differentiated from control iPSCs, indicating an impact of BBS1 on RPE maturation. Full article

(This article belongs to the Special Issue Hedgehog Signaling 2.0)

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12 pages, 5377 KiB

Open AccessArticle

New Insights into Development of Female Reproductive Tract—Hedgehog-Signal Response in Wolffian Tissues Directly Contributes to Uterus Development

by Ryuma Haraguchi, Gen Yamada, Aki Murashima, Daisuke Matsumaru, Riko Kitazawa and Sohei Kitazawa

Int. J. Mol. Sci. 2021, 22(3), 1211; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031211 - 26 Jan 2021

Cited by 5 | Viewed by 2458

Abstract

The reproductive tract in mammals emerges from two ductal systems during embryogenesis: Wolffian ducts (WDs) and Mullerian ducts (MDs). Most of the female reproductive tract (FRT) including the oviducts, uterine horn and cervix, originate from MDs. It is widely accepted that the formation of MDs depends on the preformed WDs within the urogenital primordia. Here, we found that the WD mesenchyme under the regulation of Hedgehog (Hh) signaling is closely related to the developmental processes of the FRT during embryonic and postnatal periods. Deficiency of Sonic hedgehog (Shh), the only Hh ligand expressed exclusively in WDs, prevents the MD mesenchyme from affecting uterine growth along the radial axis. The in vivo cell tracking approach revealed that after WD regression, distinct cells responding to WD-derived Hh signal continue to exist in the developing FRT and gradually contribute to the formation of various tissues such as smooth muscle, endometrial stroma and vascular vessel, in the mouse uterus. Our study thus provides a novel developmental mechanism of FRT relying on WD. Full article

(This article belongs to the Special Issue Hedgehog Signaling 2.0)

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17 pages, 65937 KiB

Open AccessArticle

Spreading of Isolated Ptch Mutant Basal Cell Carcinoma Precursors Is Physiologically Suppressed and Counteracts Tumor Formation in Mice

by Nadine Brandes, Slavica Hristomanova Mitkovska, Dominik Simon Botermann, Wiebke Maurer, Anna Müllen, Hanna Scheile, Sebastian Zabel, Anke Frommhold, Ina Heß, Heidi Hahn and Anja Uhmann

Int. J. Mol. Sci. 2020, 21(23), 9295; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239295 - 05 Dec 2020

Cited by 2 | Viewed by 2131

Abstract

Basal cell carcinoma (BCC) originate from Hedgehog/Patched signaling-activated epidermal stem cells. However, the chemically induced tumorigenesis of mice with a CD4Cre-mediated biallelic loss of the Hedgehog signaling repressor Patched also induces BCC formation. Here, we identified the cellular origin of CD4Cre-targeted BCC progenitors as rare Keratin 5⁺ epidermal cells and show that wildtype Patched offspring of these cells spread over the hair follicle/skin complex with increasing mouse age. Intriguingly, Patched mutant counterparts are undetectable in age-matched untreated skin but are getting traceable upon applying the chemical tumorigenesis protocol. Together, our data show that biallelic Patched depletion in rare Keratin 5⁺ epidermal cells is not sufficient to drive BCC development, because the spread of these cells is physiologically suppressed. However, bypassing the repression of Patched mutant cells, e.g., by exogenous stimuli, leads to an accumulation of BCC precursor cells and, finally, to tumor development. Full article

(This article belongs to the Special Issue Hedgehog Signaling 2.0)

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20 pages, 4823 KiB

Open AccessArticle

Effects of IGF-1 on Proliferation, Angiogenesis, Tumor Stem Cell Populations and Activation of AKT and Hedgehog Pathways in Oral Squamous Cell Carcinoma

by Jéssica Mariane Ferreira Mendes, Ludmila de Faro Valverde, Manuela Torres Andion Vidal, Bruno Diaz Paredes, Paulo Coelho, Kyan James Allahdadi, Ricardo Della Coletta, Bruno Solano de Freitas Souza and Clarissa Araújo Gurgel Rocha

Int. J. Mol. Sci. 2020, 21(18), 6487; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186487 - 05 Sep 2020

Cited by 19 | Viewed by 3883

Abstract

(1) Background: Activation of the PI3K-AKT pathway controls most hallmarks of cancer, and the hedgehog (HH) pathway has been associated with oral squamous cell carcinoma (OSCC) development and progression. We hypothesized that fibroblast-derived insulin-like growth factor-1 (IGF-1) acts in oral squamous cell carcinoma (OSCC) cells, leading to the non-canonical activation of the HH pathway, maintaining AKT activity and promoting tumor aggressiveness. (2) Methods: Primary fibroblasts (MF1) were genetically engineered for IGF-1 overexpression (MF1-IGF1) and CRISPR/Cas9-mediated IGF1R silencing was performed in SCC-4 cells. SCC-4 cells were co-cultured with fibroblasts or incubated with fibroblast conditioned medium (CM) or rIGF-1 for functional assays and the evaluation of AKT and HH pathways. (3) Results: Gene expression analysis confirmed IGF-1 overexpression in MF1-IGF1 and the absence of IGF-1 expression in SCC-4, while elevated IGF1R expression was detected. IGF1R silencing was associated with decreased survival of SCC-4 cells. Ihh was expressed in both MF1 and MF1-IGF1, and increased levels of GLI1 mRNA were observed in SCC-4 after stimulation with CM-MF1. Activation of both PI3K-AKT and the HH pathway (GLI1, Ihh and SMO) were identified in SCC-4 cells cultured in the presence of MF1-IGF1-CM. rIGF-1 promoted tumor cell proliferation, migration, invasion and tumorsphere formation, whereas CM-MF1 significantly stimulated angiogenesis. (4) Conclusions: IGF-1 exerts pro-tumorigenic effects by stimulating SCC-4 cell proliferation, migration, invasion and stemness. AKT and HH pathways were activated by IGF-1 in SCC-4, reinforcing its influence on the regulation of these signaling pathways. Full article

(This article belongs to the Special Issue Hedgehog Signaling 2.0)

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13 pages, 2710 KiB

Open AccessArticle

GANT61 and Lithium Chloride Inhibit the Growth of Head and Neck Cancer Cell Lines Through the Regulation of GLI3 Processing by GSK3β

by Vedran Zubčić, Nikolina Rinčić, Matea Kurtović, Diana Trnski, Vesna Musani, Petar Ozretić, Sonja Levanat, Dinko Leović and Maja Sabol

Int. J. Mol. Sci. 2020, 21(17), 6410; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176410 - 03 Sep 2020

Cited by 12 | Viewed by 3083

Abstract

Several signaling pathways are aberrantly activated in head and neck squamous cell carcinoma (HNSCC), including the Hedgehog-Gli (HH-GLI), WNT, EGFR, and NOTCH pathways. The HH-GLI pathway has mostly been investigated in the context of canonical signal transduction and the inhibition of the membrane components of the pathway. In this work we investigated the role of downstream inhibitors GANT61 and lithium chloride (LiCl) on cell viability, wound closure, and colony forming ability of HNSCC cell lines. Five HNSCC cell lines were treated with HH-GLI pathway inhibitors affecting different levels of signal transduction. GANT61 and LiCl reduce the proliferation and colony formation capabilities of HNSCC cell lines, and LiCl has an additional effect on wound closure. The major effector of the HH-GLI signaling pathway in HNSCC is the GLI3 protein, which is expressed in its full-length form and is functionally regulated by GSK3β. LiCl treatment increases the inhibitory Ser9 phosphorylation of the GSK3β protein, leading to increased processing of GLI3 from full-length to repressor form, thus inhibiting HH-GLI pathway activity. Therefore, downstream inhibition of HH-GLI signaling may be a promising therapeutic strategy for HNSCC. Full article

(This article belongs to the Special Issue Hedgehog Signaling 2.0)

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19 pages, 3806 KiB

Open AccessArticle

GANT61 Reduces Hedgehog Molecule (GLI1) Expression and Promotes Apoptosis in Metastatic Oral Squamous Cell Carcinoma Cells

by Taís Bacelar Sacramento de Araújo, Leonardo de Oliveira Siquara da Rocha, Manuela Torres Andion Vidal, Paulo Lucas Cerqueira Coelho, Mitermayer Galvão dos Reis, Bruno Solano de Freitas Souza, Milena Botelho Pereira Soares, Thiago Almeida Pereira, Ricardo Della Coletta, Daniel Pereira Bezerra, Rosane Borges Dias and Clarissa Araújo Gurgel Rocha

Int. J. Mol. Sci. 2020, 21(17), 6076; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176076 - 24 Aug 2020

Cited by 10 | Viewed by 3662

Abstract

Due to its importance in the pathogenesis of oral squamous cell carcinoma (OSCC), the Hedgehog (HH) pathway is considered a potential therapeutic target. We investigated the effects of GANT61, a GLI inhibitor, on HH gene expression, as well as on metastatic OSCC cell proliferation and death. Following culture in DMEM medium, cytotoxicity of GANT61 against different tumor and non-tumor cell types was assessed by alamarBlue assays. Cytotoxicity analysis revealed that the metastatic HSC3 cell line was the most sensitive (IC₅₀: 36 µM) to the tested compound. The compound’s effects on the expression of HH pathways components were analyzed by qPCR and Western blot; cell viability was analyzed by trypan blue assay and flow cytometry were used to investigate cell cycle phase, morphology, and death patterns in HSC3 cells. A significant reduction in mRNA levels of the GLI1 transcription factor was found after 12 h of treatment withGANT61. Protein expression levels of other HH pathway components (PTCH1, SHH, and Gli1) and HSC3 cell viability also decreased after 24 h of treatment. Cell cycle analysis and death pattern evaluations revealed significantly increased nuclear fragmentation in sub-G1 phase, as well as cell death due to apoptosis. In conclusion, the significantly reduced GLI1 gene expression seen in response to the GLI inhibitor indicates diminished downstream activation in HH pathway components. GANT61 significantly reduced cell viability in the metastatic cell line of OSCC and promoted a significant increase in nuclear fragmentation and cell death by apoptosis. Full article

(This article belongs to the Special Issue Hedgehog Signaling 2.0)

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15 pages, 4174 KiB

Open AccessArticle

Downregulation of GLI3 Expression Mediates Chemotherapy Resistance in Acute Myeloid Leukemia

by Fabian Freisleben, Lena Behrmann, Vanessa Thaden, Jana Muschhammer, Carsten Bokemeyer, Walter Fiedler and Jasmin Wellbrock

Int. J. Mol. Sci. 2020, 21(14), 5084; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145084 - 18 Jul 2020

Cited by 15 | Viewed by 2999

Abstract

Aberrant activation of the hedgehog (HH) pathway is observed in many neoplasms, including acute myeloid leukemia (AML). The glioma-associated oncogene homolog (GLI) transcription factors are the main downstream effectors of the HH signaling cascade and are responsible for the proliferation and maintenance of leukemic stem cells, which support chemotherapy resistance and leukemia relapse. Cytarabine (Ara-C)-resistant variants of AML cell lines were established through long-term cultivation with successively increasing Ara-C concentrations. Subsequently, differences in GLI expression were analyzed by RT-qPCR. GLI3 mRNA levels were detectable in parental Kasumi-1, OCI-AML3, and OCI-AML5 cells, whereas GLI3 expression was completely silenced in all resistant counterparts. Therefore, we generated GLI3-knockdown cell lines using small hairpin RNAs (shRNA) and evaluated their sensitivity to Ara-C in vitro. The knockdown of GLI3 partly abolished the effect of Ara-C on colony formation and induction of apoptosis, indicating that GLI3 downregulation results in Ara-C resistance. Moreover, we analyzed the expression of several genes involved in Ara-C metabolism and transport. Knockdown of GLI3 resulted in the upregulation of SAM and HD domain-containing protein 1 (SAMHD1), cytidine deaminase (CDA), and ATP-binding cassette C11 (ABCC11)/multidrug resistance-associated protein 8 (MRP8), each of which has been identified as a predictive marker for Ara-C response in acute myeloid leukemia. Our results demonstrate that GLI3 downregulation is a potential mechanism to induce chemotherapy resistance in AML. Full article

(This article belongs to the Special Issue Hedgehog Signaling 2.0)

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14 pages, 3311 KiB

Open AccessArticle

Sonic Hedgehog and Triiodothyronine Pathway Interact in Mouse Embryonic Neural Stem Cells

by Pavel Ostasov, Jan Tuma, Pavel Pitule, Jiri Moravec, Zbynek Houdek, Frantisek Vozeh, Milena Kralickova, Jan Cendelin and Vaclav Babuska

Int. J. Mol. Sci. 2020, 21(10), 3672; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103672 - 23 May 2020

Cited by 3 | Viewed by 2225

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 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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12 pages, 2613 KiB

Open AccessArticle

Hedgehog Inhibitors Suppress Osteoclastogenesis in In Vitro Cultures, and Deletion of Smo in Macrophage/Osteoclast Lineage Prevents Age-Related Bone Loss

by Yukihiro Kohara, Ryuma Haraguchi, Riko Kitazawa, Yuuki Imai and Sohei Kitazawa

Int. J. Mol. Sci. 2020, 21(8), 2745; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082745 - 15 Apr 2020

Cited by 14 | Viewed by 3124

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 (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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13 pages, 3952 KiB

Open AccessArticle

The FDA-Approved Anti-Asthma Medicine Ciclesonide Inhibits Lung Cancer Stem Cells through Hedgehog Signaling-Mediated SOX2 Regulation

by Hack Sun Choi, Su-Lim Kim, Ji-Hyang Kim and Dong-Sun Lee

Int. J. Mol. Sci. 2020, 21(3), 1014; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21031014 - 04 Feb 2020

Cited by 11 | Viewed by 3952

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 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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Review

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24 pages, 1774 KiB

Open AccessReview

Hedging against Neuropathic Pain: Role of Hedgehog Signaling in Pathological Nerve Healing

by Nathan Moreau and Yves Boucher

Int. J. Mol. Sci. 2020, 21(23), 9115; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239115 - 30 Nov 2020

Cited by 17 | Viewed by 3030

Abstract

The peripheral nervous system has important regenerative capacities that regulate and restore peripheral nerve homeostasis. Following peripheral nerve injury, the nerve undergoes a highly regulated degeneration and regeneration process called Wallerian degeneration, where numerous cell populations interact to allow proper nerve healing. Recent studies have evidenced the prominent role of morphogenetic Hedgehog signaling pathway and its main effectors, Sonic Hedgehog (SHH) and Desert Hedgehog (DHH) in the regenerative drive following nerve injury. Furthermore, dysfunctional regeneration and/or dysfunctional Hedgehog signaling participate in the development of chronic neuropathic pain that sometimes accompanies nerve healing in the clinical context. Understanding the implications of this key signaling pathway could provide exciting new perspectives for future research on peripheral nerve healing. Full article

(This article belongs to the Special Issue Hedgehog Signaling 2.0)

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16 pages, 1348 KiB

Open AccessReview

Gorlin Syndrome: Recent Advances in Genetic Testing and Molecular and Cellular Biological Research

by Shoko Onodera, Yuriko Nakamura and Toshifumi Azuma

Int. J. Mol. Sci. 2020, 21(20), 7559; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207559 - 13 Oct 2020

Cited by 36 | Viewed by 5391

Abstract

Gorlin syndrome is a skeletal disorder caused by a gain of function mutation in Hedgehog (Hh) signaling. The Hh family comprises of many signaling mediators, which, through complex mechanisms, play several important roles in various stages of development. The Hh information pathway is essential for bone tissue development. It is also the major driver gene in the development of basal cell carcinoma and medulloblastoma. In this review, we first present the recent advances in Gorlin syndrome research, in particular, the signaling mediators of the Hh pathway and their functions at the genetic level. Then, we discuss the phenotypes of mutant mice and Hh signaling-related molecules in humans revealed by studies using induced pluripotent stem cells. Full article

(This article belongs to the Special Issue Hedgehog Signaling 2.0)

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20 pages, 1377 KiB

Open AccessReview

The Role of Smoothened in Cancer

by Kuo-Shyang Jeng, I-Shyan Sheen, Chuen-Miin Leu, Ping-Hui Tseng and Chiung-Fang Chang

Int. J. Mol. Sci. 2020, 21(18), 6863; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186863 - 18 Sep 2020

Cited by 37 | Viewed by 4009

Abstract

Smoothened (SMO) belongs to the Hedgehog (HH) signaling pathway, which regulates cell growth, migration, invasion and stem cells in cancer. The HH signaling pathway includes both canonical and noncanonical pathways. The canonical HH pathway functions through major HH molecules such as HH ligands, PTCH, SMO and GLI, whereas the noncanonical HH pathway involves the activation of SMO or GLI through other pathways. The role of SMO has been discussed in different types of cancer, including breast, liver, pancreatic and colon cancers. SMO expression correlates with tumor size, invasiveness, metastasis and recurrence. In addition, SMO inhibitors can suppress cancer formation, reduce the proliferation of cancer cells, trigger apoptosis and suppress cancer stem cell activity. A better understanding of the role of SMO in cancer could contribute to the development of novel therapeutic approaches. Full article

(This article belongs to the Special Issue Hedgehog Signaling 2.0)

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17 pages, 1758 KiB

Open AccessReview

Hedgehog Signaling in Skeletal Development: Roles of Indian Hedgehog and the Mode of Its Action

by Shinsuke Ohba

Int. J. Mol. Sci. 2020, 21(18), 6665; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186665 - 11 Sep 2020

Cited by 59 | Viewed by 4736

Abstract

Hedgehog (Hh) signaling is highly conserved among species and plays indispensable roles in various developmental processes. There are three Hh members in mammals; one of them, Indian hedgehog (Ihh), is expressed in prehypertrophic and hypertrophic chondrocytes during endochondral ossification. Based on mouse genetic studies, three major functions of Ihh have been proposed: (1) Regulation of chondrocyte differentiation via a negative feedback loop formed together with parathyroid hormone-related protein (PTHrP), (2) promotion of chondrocyte proliferation, and (3) specification of bone-forming osteoblasts. Gli transcription factors mediate the major aspect of Hh signaling in this context. Gli3 has dominant roles in the growth plate chondrocytes, whereas Gli1, Gli2, and Gli3 collectively mediate biological functions of Hh signaling in osteoblast specification. Recent studies have also highlighted postnatal roles of the signaling in maintenance and repair of skeletal tissues. Full article

(This article belongs to the Special Issue Hedgehog Signaling 2.0)

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