• age-related lobular involution (ARLI)
• breast cancer risk
• cellular senescence
• embryonic development
• extracellular matrix (ECM)
• immune modulation
• mammary gland development
• postlactational involution
• postpartum breast cancer (PPBC)
• senescence-associated secretory phenotype (SASP)
• tumor microenvironment (TME)

• R01 CA229811 NCI NIH HHS
• R01 CA237602 NCI NIH HHS
• 1R01CA237602-05A1 NIH HHS

• fibrosis
• hedgehog signaling pathway
• targeted therapies

• Humans
• Hedgehog Proteins/metabolism
• Signal Transduction/drug effects
• Fibrosis
• Animals
• Molecular Targeted Therapy

• 82070660 National Natural Science Foundation of China
• 2024YFHZ0145 Regional Innovation Cooperation Project of Science and Technology Department of Sichuan Province
• 2023-107 Sichuan Provincial Cadre Healthcare Research Program

• Cdc14B
• Cyclin B1
• Medulloblastoma
• cell cycle
• cell proliferation
• sonic hedgehog (Shh)

• Sonic hedgehog signaling pathway
• cancer stem cells
• hepatocellular carcinoma
• recurrence
• resistance

• FEMH-2023-C-009, FEMH-2023-C-123: FEMH-2022-C-082 Far Eastern Memorial Hospital
• MOST 110-2314-B-418-009 the Ministry of Science of Technology, Taiwan

• Cancer
• Epigenetic
• Hedgehog
• Inhibitor
• Signaling
• Therapy

• Hedgehog Proteins/metabolism
• Humans
• Signal Transduction
• Neoplasms/metabolism
• Neoplasms/pathology
• Neoplasms/drug therapy
• Animals
• Epithelial-Mesenchymal Transition

• Non-canonical signaling
• Notch
• Platelet activation
• Sonic Hedgehog (Shh)
• Vismodegib
• Wnt

• Humans
• Hedgehog Proteins/metabolism
• Blood Platelets/metabolism
• Platelet Activation
• Thrombosis/metabolism
• Receptors, Steroid/metabolism

• Indian Council of Medical Research

• Cell cycle
• Cyclin B1
• Deubiquitinase
• Glioma
• USP39

• HPV infection
• SHh signaling
• dermatology
• genital warts

• Humans
• Male
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Zinc Finger Protein GLI1/genetics
• Zinc Finger Protein GLI1/metabolism
• Down-Regulation
• Apoptosis
• Papillomavirus Infections
• Cell Line, Tumor
• G2 Phase Cell Cycle Checkpoints
• Condylomata Acuminata
• Warts

• 81974308 National Natural Science Foundation of China
• National Natural Science Foundation of China

Metformin is a first-line drug for type 2 diabetes, and its anticancer effects have also been widely studied in recent years. The Sonic hedgehog (Shh) signaling pathway is involved in the initiation and progression of medulloblastoma. In order to develop a new treatment strategy for medulloblastoma (MB), this study investigated the inhibitory effect of metformin on MB and the underlying mechanism of metformin on the Shh signaling pathway. The effect of metformin on proliferation was evaluated by the cell counting kit-8 (CCK-8) test and colony formation experiment. The effect of metformin on metastasis was assessed by the scratch-wound assay and transwell invasion assay. Cell cycle and apoptosis were evaluated by flow cytometry, and the associated proteins were examined by western blotting. The mRNA and protein expression levels related to the Shh pathway were measured by quantitative PCR, western blotting, and immunofluorescence staining. The xenograft murine model was carried out to evaluate the anticancer effect of metformin on medulloblastoma in vivo. Metformin inhibited proliferation and metastasis of the Shh subgroup MB cell line, and the inhibitory effect on proliferation was related to apoptosis and the block of the cell cycle at the G0/G1 phase. Animal experiments showed that metformin inhibits medulloblastoma growth in vivo. Moreover, metformin decreased mRNA and protein expression levels of the Shh pathway, and this effect was reversed by the AMP-activated protein kinase (AMPK) siRNA. Furthermore, the pro-apoptotic and cell cycle arrest effects of metformin on Daoy cells could be reversed by the Shh pathway activators. Our findings demonstrated that metformin could inhibit medulloblastoma progression in vitro and in vivo, and this effect was associated with AMPK-mediated inhibition of the Shh signaling pathway in vitro studies.

Down syndrome (DS), also known as trisomy 21, is a genetic disorder caused by triplication of Chromosome 21. Gene triplication may compromise different body functions but invariably impairs intellectual abilities starting from infancy. Moreover, after the fourth decade of life people with DS are likely to develop Alzheimer’s disease. Neurogenesis impairment during fetal life stages and dendritic pathology emerging in early infancy are thought to be key determinants of alterations in brain functioning in DS. Although the progressive improvement in medical care has led to a notable increase in life expectancy for people with DS, there are currently no treatments for intellectual disability. Increasing evidence in mouse models of DS reveals that pharmacological interventions in the embryonic and neonatal periods may greatly benefit brain development and cognitive performance. The most striking results have been obtained with pharmacotherapies during embryonic life stages, indicating that it is possible to pharmacologically rescue the severe neurodevelopmental defects linked to the trisomic condition. These findings provide hope that similar benefits may be possible for people with DS. This review summarizes current knowledge regarding (i) the scope and timeline of neurogenesis (and dendritic) alterations in DS, in order to delineate suitable windows for treatment; (ii) the role of triplicated genes that are most likely to be the key determinants of these alterations, in order to highlight possible therapeutic targets; and (iii) prenatal and neonatal treatments that have proved to be effective in mouse models, in order to rationalize the choice of treatment for human application. Based on this body of evidence we will discuss prospects and challenges for fetal therapy in individuals with DS as a potential means of drastically counteracting the deleterious effects of gene triplication.

• Università di Bologna

• Canonical signaling
• Cholesterol
• Hedgehog
• Non-canonical signaling
• Plasma membrane
• Ptch1
• Smo

• Animals
• Cholesterol/metabolism
• Cilia/metabolism
• Embryonic Development
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Signal Transduction/physiology

• PC200160 DOD Prostate Cancer Research Program
• P01 CA217798 NIH HHS
• R21 CA238953 NIH HHS
• RO1 CA247763 NIH HHS
• R01 CA247763 NCI NIH HHS
• R21 CA238953 NCI NIH HHS
• P01 CA217798 NCI NIH HHS
• National Institutes of Health

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and its incidence is steadily increasing. The development of HCC is a complex, multi-step process that is accompanied by alterations in multiple signaling cascades. Recent years have seen advancement in understanding molecular signaling pathways that play central roles in hepatocarcinogenesis. Aberrant activation of YAP/TAZ, Hedgehog, or Wnt/β-catenin signaling is frequently found in a subset of HCC patients. Targeting the signaling pathway via small molecule inhibitors could be a promising therapeutic option for the subset of patients. In this review, we will introduce the signaling pathways, discuss their roles in the development of HCC, and propose a therapeutic approach targeting the signaling pathways in the context of HCC.

Hepatocellular carcinoma (HCC) is a major health concern worldwide, and its incidence is increasing steadily. To date, receptor tyrosine kinases (RTKs) are the most favored molecular targets for the treatment of HCC, followed by immune checkpoint regulators such as PD-1, PD-L1, and CTLA-4. With less than desirable clinical outcomes from RTK inhibitors as well as immune checkpoint inhibitors (ICI) so far, novel molecular target therapies have been proposed for HCC. In this review, we will introduce diverse molecular signaling pathways that are aberrantly activated in HCC, focusing on YAP/TAZ, Hedgehog, and Wnt/β-catenin signaling pathways, and discuss potential therapeutic strategies targeting the signaling pathways in HCC.

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.

• basal cell carcinoma
• drug resistance
• hedgehog inhibitor
• hedgehog signaling
• smoothened inhibitor
• targeted cancer therapy

• Animals
• Clinical Trials as Topic
• Drug Resistance, Neoplasm
• Hedgehog Proteins/metabolism
• Humans
• Models, Biological
• Molecular Targeted Therapy
• Signal Transduction

• Acrocephalosyndactylia/complications
• Acrocephalosyndactylia/metabolism
• Animals
• Cells, Cultured
• Child
• Hedgehog Proteins/metabolism
• Humans
• Mastocytosis/complications
• Mastocytosis/metabolism
• Mice, Inbred C57BL
• Mice, SCID
• Signal Transduction
• Tumor Cells, Cultured
• Mice

The formation of the external genitalia is a highly complex developmental process, considering it involves a wide range of cell types and results in sexually dimorphic outcomes. Development is controlled by several secreted signalling factors produced in complex spatiotemporal patterns, including the hedgehog (HH), bone morphogenic protein (BMP), fibroblast growth factor (FGF) and WNT signalling families. Many of these factors act on or are influenced by the actions of the androgen receptor (AR) that is critical to masculinisation. This complexity of expression makes it difficult to conceptualise patterns of potential importance. Mapping expression during key stages of development is needed to develop a comprehensive model of how different cell types interact in formation of external genitalia, and the global regulatory networks at play. This is particularly true in light of the sensitivity of this process to environmental disruption during key stages of development. The goal of this review is to integrate all recent studies on gene expression in early penis development to create a comprehensive spatiotemporal map. This serves as a resource to aid in visualising potentially significant interactions involved in external genital development.

Diagrams of published RNA and protein localisation data for key secreted signalling factors during early penis development.

• Wnt
• androgen receptor
• bone morphogenic protein
• fibroblast growth factor
• genital tubercle
• hedgehog
• localization
• penis

The Hedgehog/GLI (Hh/GLI) pathway plays a major role during development and it is commonly dysregulated in many diseases, including cancer. This highly concerted series of ligands, receptors, cytoplasmic signaling molecules, transcription factors, and co-regulators is involved in regulating the biological functions controlled by this pathway. Activation of Hh/GLI in cancer is most often through a non-canonical method of activation, independent of ligand binding. This review is intended to summarize our current understanding of the Hh/GLI signaling, non-canonical mechanisms of pathway activation, its implication in disease, and the current therapeutic strategies targeting this cascade.

The Hh/GLI signaling pathway was originally discovered in Drosophila as a major regulator of segment patterning in development. This pathway consists of a series of ligands (Shh, Ihh, and Dhh), transmembrane receptors (Ptch1 and Ptch2), transcription factors (GLI1–3), and signaling regulators (SMO, HHIP, SUFU, PKA, CK1, GSK3β, etc.) that work in concert to repress (Ptch1, Ptch2, SUFU, PKA, CK1, GSK3β) or activate (Shh, Ihh, Dhh, SMO, GLI1–3) the signaling cascade. Not long after the initial discovery, dysregulation of the Hh/GLI signaling pathway was implicated in human disease. Activation of this signaling pathway is observed in many types of cancer, including basal cell carcinoma, medulloblastoma, colorectal, prostate, pancreatic, and many more. Most often, the activation of the Hh/GLI pathway in cancer occurs through a ligand-independent mechanism. However, in benign disease, this activation is mostly ligand-dependent. The upstream signaling component of the receptor complex, SMO, is bypassed, and the GLI family of transcription factors can be activated regardless of ligand binding. Additional mechanisms of pathway activation exist whereby the entirety of the downstream signaling pathway is bypassed, and PTCH1 promotes cell cycle progression and prevents caspase-mediated apoptosis. Throughout this review, we summarize each component of the signaling cascade, non-canonical modes of pathway activation, and the implications in human disease, including cancer.

• GLI
• Hh pathway inhibitors
• SUFU
• cancer
• canonical and non-canonical activation
• hedgehog

• GLI family zinc finger
• Sonic Hedgehog
• bladder cancer
• cervical cancer
• drug resistance
• frizzled class receptor
• kidney cancer
• microRNA
• ovarian cancer
• patched 1
• prostate cancer
• smoothened

Peroxisomal matrix proteins are imported into peroxisomes via membrane-bound docking/translocation machinery. One central component of this machinery is Pex14p, a peroxisomal membrane protein involved in the docking of Pex5p, the receptor for peroxisome targeting signal type 1 (PTS1). Studies in several yeast species have shown that Pex14p is phosphorylated in vivo, whereas no function has been assigned to Pex14p phosphorylation in yeast and mammalian cells. Here, we investigated peroxisomal protein import and its dynamics in mitotic mammalian cells. In mitotically arrested cells, Pex14p is phosphorylated at Ser-232, resulting in a lower import efficiency of catalase, but not the majority of proteins including canonical PTS1 proteins. Conformational change induced by the mitotic phosphorylation of Pex14p more likely increases homomeric interacting affinity and suppresses topological change of its N-terminal part, thereby giving rise to the retardation of Pex5p export in mitotic cells. Taken together, these data show that mitotic phosphorylation of Pex14p and consequent suppression of catalase import are a mechanism of protecting DNA upon nuclear envelope breakdown at mitosis.

• Bone shortening
• Chondrocyte proliferation
• Growth plate
• Indian hedgehog (IHH)
• Mucopolysaccharidosis (MPS)

• Gorlin syndrome
• hedgehog pathway
• nerved basal cell carcinoma

• Animals
• Basal Cell Nevus Syndrome/diagnosis
• Basal Cell Nevus Syndrome/genetics
• Basal Cell Nevus Syndrome/metabolism
• Bone and Bones/metabolism
• Bone and Bones/pathology
• Genetic Testing/methods
• Genomic Instability
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Humans
• Patched Receptors/genetics
• Patched Receptors/metabolism

• 18H03007 JSPS
• 18K09753 SPS KAKENHI

The hedgehog (HH) signaling pathway regulates normal cell growth and differentiation. As a consequence of improper control, aberrant HH signaling results in tumorigenesis and supports aggressive phenotypes of human cancers, such as neoplastic transformation, tumor progression, metastasis, and drug resistance. Canonical activation of HH signaling occurs through binding of HH ligands to the transmembrane receptor Patched 1 (PTCH1), which derepresses the transmembrane G protein-coupled receptor Smoothened (SMO). Consequently, the glioma-associated oncogene homolog 1 (GLI1) zinc-finger transcription factors, the terminal effectors of the HH pathway, are released from suppressor of fused (SUFU)-mediated cytoplasmic sequestration, permitting nuclear translocation and activation of target genes. Aberrant activation of this pathway has been implicated in several cancer types, including medulloblastoma, rhabdomyosarcoma, basal cell carcinoma, glioblastoma, and cancers of lung, colon, stomach, pancreas, ovarian, and breast. Therefore, several components of the HH pathway are under investigation for targeted cancer therapy, particularly GLI1 and SMO. GLI1 transcripts are reported to undergo alternative splicing to produce truncated variants: loss-of-function GLI1ΔN and gain-of-function truncated GLI1 (tGLI1). This review covers the biochemical steps necessary for propagation of the HH activating signal and the involvement of aberrant HH signaling in human cancers, with a highlight on the tumor-specific gain-of-function tGLI1 isoform.

• development
• hedgehog signaling
• tGLI1
• target therapy
• tumor–stroma interaction

• Alternative Splicing
• Antineoplastic Agents/therapeutic use
• Carcinogenesis/genetics
• Carcinogenesis/metabolism
• Carcinogenesis/pathology
• Cell Differentiation/drug effects
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Gene Expression Regulation, Neoplastic
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Humans
• Lymphatic Metastasis
• Molecular Targeted Therapy
• Neoplasms/classification
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/metabolism
• Patched-1 Receptor/genetics
• Patched-1 Receptor/metabolism
• Protein Isoforms/genetics
• Protein Isoforms/metabolism
• Repressor Proteins/genetics
• Repressor Proteins/metabolism
• Signal Transduction/genetics
• Smoothened Receptor/genetics
• Smoothened Receptor/metabolism
• Zinc Finger Protein GLI1/genetics
• Zinc Finger Protein GLI1/metabolism

• R01 NS087169 NINDS NIH HHS
• T32 CA079448 NCI NIH HHS
• T32 CA247819 NCI NIH HHS
• P30 CA012197 NCI NIH HHS
• R01 CA228137 NCI NIH HHS

Genetic activation of hedgehog/glioma‐associated oncogene homolog (HH/GLI) signaling causes basal cell carcinoma (BCC), a very frequent nonmelanoma skin cancer. Small molecule targeting of the essential HH effector Smoothened (SMO) has proven an effective therapy of BCC, though the frequent development of drug resistance poses major challenges to anti‐HH treatments. In light of recent breakthroughs in cancer immunotherapy, we analyzed the possible immunosuppressive mechanisms in HH/GLI‐induced BCC in detail. Using a genetic mouse model of BCC, we identified profound differences in the infiltration of BCC lesions with cells of the adaptive and innate immune system. Epidermal activation of Hh/Gli signaling led to an accumulation of immunosuppressive regulatory T cells, and to an increased expression of immune checkpoint molecules including programmed death (PD)‐1/PD‐ligand 1. Anti‐PD‐1 monotherapy, however, did not reduce tumor growth, presumably due to the lack of immunogenic mutations in common BCC mouse models, as shown by whole‐exome sequencing. BCC lesions also displayed a marked infiltration with neutrophils, the depletion of which unexpectedly promoted BCC growth. The study provides a comprehensive survey of and novel insights into the immune status of murine BCC and serves as a basis for the design of efficacious rational combination treatments. This study also underlines the need for predictive immunogenic mouse models of BCC to evaluate the efficacy of immunotherapeutic strategies in vivo.

• basal cell carcinoma
• cancer immunotherapy
• hedgehog/gli signaling
• immune checkpoint molecules
• neutrophils
• regulatory T cells

• Cleft lip with or without palate
• Clinical genetics
• Genotype-phenotype analysis
• PTCH1
• Whole-exome sequencing

• GPCR
• GRK2
• HDAC6
• Interactome
• Phosphorylation

• Animals
• G-Protein-Coupled Receptor Kinase 2/metabolism
• Humans
• Phosphorylation/physiology
• Signal Transduction/physiology

• SAF2017-84125-R Ministerio de Ciencia, Innovación y Universidades
• SAF2017-82886-R Ministerio de Ciencia, Innovación y Universidades
• CB16/11/00278 Instituto de Salud Carlos III
• PI17-00576 Instituto de Salud Carlos III
• PI18/01662 Instituto de Salud Carlos III
• B2017/BMD-3671-INFLAMUNE Comunidad de Madrid
• B2017/BMD-3671-INFLAMUNE Comunidad de Madrid

• cancer
• cell biology

• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Apoptosis/physiology
• Cell Proliferation/drug effects
• Cell Proliferation/physiology
• Cerebellar Neoplasms/drug therapy
• Cerebellar Neoplasms/metabolism
• Cisplatin/pharmacology
• Etoposide/pharmacology
• G-Protein-Coupled Receptor Kinase 2/metabolism
• HEK293 Cells
• Humans
• Medulloblastoma/drug therapy
• Medulloblastoma/metabolism
• Phosphorylation/drug effects

• R21 NS094990 NINDS NIH HHS
• R21 NS109751 NINDS NIH HHS
• U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
• Concern Foundation
• T.J. Martell Foundation (T.J. Martell Foundation for Leukemia, Cancer and AIDS Research)
• Pediatric Cancer Research Foundation (PCRF)
• Harriet H. Samuelsson Foundation
• Nautica Malibu Triathlon Fund Barbara Mandel Family Fund Helen Dyess Pediatric Cancer Research Fund

• Hedgehog signaling pathway
• NPC1
• Patched-1
• Patched-2
• membrane protein
• protein chimera
• sonic hedgehog (SHH)
• sterol-sensing domain
• transmembrane domain
• transporter

• Animals
• Cell Membrane/genetics
• Cell Membrane/metabolism
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Humans
• Mice
• Mice, Knockout
• Patched-1 Receptor/chemistry
• Patched-1 Receptor/genetics
• Patched-1 Receptor/metabolism
• Patched-2 Receptor/chemistry
• Patched-2 Receptor/genetics
• Patched-2 Receptor/metabolism
• Protein Binding
• Protein Domains
• Signal Transduction

• MOP-142490 CIHR
• Government of Canada | Canadian Institutes of Health Research (CIHR)

Basal cell carcinoma (BCC) is a frequent malignant tumor of skin cancers with high morbidity. The objective of this study was to identify critical genes and pathways related to the carcinogenesis of BCC and gain more insights into the underlying molecular mechanisms of BCC.

The gene expression profiles of GSE7553 and GSE103439 were downloaded from the Gene Expression Omnibus database with 19 tumors and 6 normal skin tissues. Differentially expressed genes (DEGs) were screened between BCC samples and normal tissues, followed by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Subsequently, protein–protein interaction (PPI) network was constructed for these DEGs, and module analysis was performed.

A total of 313 DEGs were obtained. Among them, 222 genes were upregulated and 91 genes were downregulated. Enrichment analysis indicated that the upregulated genes were significantly enriched in cell cycle and mitosis, while the downregulated genes were mainly associated with unsaturated fatty acid metabolic process and cell differentiation. In addition, TOP2A, CDK1, and CCNB1 were identified as the top three hub genes ranked by degrees in the PPI network. Meanwhile, three subnetworks were derived, which indicated that these DEGs were significantly enriched in pathways, including “cell cycle”, “extracellular matrix–receptor interaction”, “basal cell carcinoma”, and “hedgehog signaling pathway”.

The novel critical DEGs and pathways identified in this study may serve pivotal roles in the carcinogenesis of BCC and indicate more molecular targets for the treatment of BCC.

• basal cell carcinoma
• bioinformatics analysis
• differentially expressed genes
• enrichment analysis

• HHAT
• PTCH1
• SHH
• WNT pathway
• cancer organoid
• cancer stem cell
• colon cancer
• non-canonical Hedgehog signaling

• Alzheimer’s disease (AD)
• Caspase-3
• Cyclin D1
• Histone H3
• Proliferating cell nuclear antigen (PCNA)
• Retinoblastoma protein (pRb)

Ever since its initial discovery in Drosophila, hedgehog signaling has been linked to foregut development, The mammalian genome expresses three Hedgehog paralogues, sonic hedgehog (Shh), Indian Hedgehog, and desert hedgehog. In the mucosa of the embryonic and adult foregut, Shh expression is the highest. It has now become clear that hedgehog signaling is of pivotal importance in gastric homeostasis. Aberrant activation of hedgehog signaling is associated with a range of pathological consequences including various cancers. Also in gastric cancer, clinical and preclinical data support a role of Hedgehog signaling in neoplastic transformation, and gastrointestinal cancer development, also through cancer stroma interaction. Technological advance are facilitating monitoring Hedgehog signaling broadening options for the more efficient screening of individuals predisposed to eventually developing gastric cancer and targeting Hedgehog signaling may provide opportunities for prophylactic therapy once atrophic gastritis develops. Nevertheless, convincing evidence that Hedgehog antagonists are of clinically useful in the context of gastric cancer is still conspicuously lacking. Here we analyze review the role of Hedgehog in gastric physiology and the potential usefulness of targeting Hedgehog signaling in gastric cancer.

• patched
• precision medicine
• receptors
• smoothened receptor
• zinc finger protein GLI1

• Nonalcoholic fatty liver disease
• hedgehog
• treatment
• wound-healing response

• Hedgehog pathway
• Liver disease
• Wound healing response

• APP, RCAN1, OLIG1/2
• Apoptotic cell death
• Astrogliogenesis
• Brain development
• DYRK1A
• Down syndrome
• Neurogenesis

• Animals
• Down Syndrome/metabolism
• Down Syndrome/pathology
• Humans
• Nervous System Malformations/metabolism
• Nervous System Malformations/pathology
• Neural Stem Cells/metabolism
• Neural Stem Cells/pathology
• Neurogenesis

• cancer
• gli
• hedgehog signaling
• natural inhibitors

• PTCH1-3'UTR
• WGCNA
• metastasis
• miR-101-3p
• non-small cell lung cancer

Liver fibrosis is a wound healing response initiated by inflammation responding for different iterative parenchymal damages caused by diverse etiologies. Immune cells, which exert their ability of either inducing injury or promoting repair, have been regarded as crucial participants in the fibrogenic response. A characteristic feature of the fibrotic microenvironment associated with chronic liver injury is aberrant activation of hedgehog (Hh) signaling pathway. Growing evidence from a number of different studies in vivo and in vitro has indicated that immune-mediated events involved in liver fibrogenesis are regulated by Hh signaling pathway. In this review, we emphasize the impacts of injury-activated Hh signaling on liver fibrogenesis through modulating repair-related inflammation and focus on the regulatory action of aberrant Hh signaling on repair-related inflammatory responses mediated by hepatic classical and non-classical immune cell populations in the progression of liver fibrosis. Moreover, we also assess the potentiality of Hh pathway inhibitors as good candidates for anti-fibrotic therapeutic agents because of their immune regulation actions for fibrogenic liver repair. The identification of immune-modulatory mechanisms of Hh signaling pathway underlying the fibrotic process of chronic liver diseases might provide a basis for Hh-centered therapeutic strategies for liver fibrosis.

• hedgehog pathway inhibitor
• hedgehog signaling pathway
• immune-modulatory action
• liver fibrosis
• repair-associated inflammation

• Hedegehog signaling pathway
• Hepatocellular carcinoma
• MiR-1249

Patched 1 (Ptch1) has epithelial, stromal and systemic roles in murine mammary gland organogenesis, yet specific functions remain undefined. Cre-recombinase-mediated Ptch1 ablation in mammary epithelium increased proliferation and branching, but did not phenocopy transgenic expression of activated smoothened (SmoM2). The epithelium showed no evidence of canonical hedgehog signaling, and hyperproliferation was not blocked by smoothened (SMO) inhibition, suggesting a non-canonical function of PTCH1. Consistent with this possibility, nuclear localization of cyclin B1 was increased. In non-epithelial cells, heterozygous Fsp-Cre-mediated Ptch1 ablation increased proliferation and branching, with dysplastic terminal end buds (TEB) and ducts. By contrast, homozygous Ptch1 ablation decreased proliferation and branching, producing stunted ducts filled with luminal cells showing altered ovarian hormone receptor expression. Whole-gland transplantation into wild-type hosts or estrogen/progesterone treatment rescued outgrowth and hormone receptor expression, but not the histological changes. Bone marrow transplantation failed to rescue outgrowth. Ducts of Fsp-Cre;Ptch1^fl/fl mice were similar to Fsp-Cre;SmoM2 ducts, but Fsp-Cre;SmoM2 outgrowths were not stunted, suggesting that the histology might be mediated by Smo in the local stroma, with systemic Ptch1 required for ductal outgrowth and proper hormone receptor expression in the mammary epithelium.

Summary: Systemic and tissue-specific depletion of patched 1 in epithelial and stromal compartments of the mammary gland defines functions in ductal patterning, proliferation and gene expression.

• Epithelial-stromal interactions
• Hedgehog signaling
• Patched-1
• Smoothened

• Neurogenesis
• Neurological disorders
• Small molecules
• Sonic hedgehog

• Drosophila
• IRX
• chick embryo
• iroquois
• limb bud
• morphogen
• mouse
• neural tube
• proliferation
• temporal adaptation
• zebrafish

• MC_PC_13052 Medical Research Council

• Cell cycle
• DEN
• Hepatocarcinoma
• Sonic hedgehog

• Hedgehog signaling pathway
• Patched-1
• Smoothened
• cell signaling
• cilia
• oligomerization
• sonic hedgehog (SHH)

• hedgehog pathway
• nonalcoholic fatty liver disease
• wound-healing response

• Animals
• Disease Models, Animal
• Hedgehog Proteins
• Humans
• Non-alcoholic Fatty Liver Disease/etiology
• Non-alcoholic Fatty Liver Disease/metabolism
• Non-alcoholic Fatty Liver Disease/pathology
• Non-alcoholic Fatty Liver Disease/therapy
• Signal Transduction
• Wound Healing

• R01 DK053792 NIDDK NIH HHS
• R01 DK077794 NIDDK NIH HHS
• R37 AA010154 NIAAA NIH HHS