• DNA methylation
• biomarker
• genetic mutation
• meningioma
• prognosis

• NextGenerationEU
• Univerzita Palackého v Olomouci
• Grantová Agentura Ceské Republiky

• Extracellular matrix
• Hedgehog signalling
• Mesenchymal cells
• Microparticles
• Microtopography
• Osteogenesis
• Topography

• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Core Binding Factor Alpha 1 Subunit/genetics
• Zinc Finger Protein GLI1/genetics
• Zinc Finger Protein GLI1/metabolism
• Osteogenesis/genetics

• DNA repair
• PARP inhibitors
• genomic scars
• homologous recombination deficiency
• immunotherapy
• melanoma
• skin cancer
• synthetic lethality

• BCC
• Cancer
• Gli
• Hedgehog
• Medulloblastoma
• Phosphorylation
• Ptc
• Shh
• Signaling
• Smo

• Animals
• Humans
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Receptors, G-Protein-Coupled/metabolism
• Zinc Finger Protein GLI1/metabolism
• Signal Transduction/physiology
• Transcription Factors/genetics
• Transcription Factors/metabolism
• Neoplasms/genetics
• Drosophila/metabolism

• R35 GM118063 NIGMS NIH HHS

• GLI transcription factors
• Hedgehog signaling
• congenital heart disease
• differentiation
• epigenetics
• gene regulatory network
• heart development
• heterochrony
• neuronal development
• progenitor

• Animals
• Cell Differentiation/genetics
• Gene Regulatory Networks
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Mice
• Signal Transduction/physiology
• Zinc Finger Protein GLI1/genetics

• F32 HL136168 NHLBI NIH HHS
• R01 HL124836 NHLBI NIH HHS
• R01 HL126509 NHLBI NIH HHS
• T32 HL007381 NHLBI NIH HHS
• R01 HL092153 NHLBI NIH HHS
• R01 HL147571 NHLBI NIH HHS
• T32 GM007183 NIGMS NIH HHS

• GLI1
• Gli3
• acute myeloid leukemia
• glasdegib
• hedgehog (Hh)
• hematological malignancy
• hematopoiesis
• smoothened inhibition

• National Heart, Lung, and Blood Institute

• BRAF V600E mutation
• ameloblastoma
• immunohistochemistry
• odontogenic tumor
• sanger sequencing

• Casein kinase 1
• Mitogen-activated protein kinases
• Pancreatic cancer
• Small molecule inhibitor
• Stress-activated protein kinases
• c-Jun N-terminal kinases

• Apoptosis
• Humans
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases
• Pancreatic Neoplasms/drug therapy
• p38 Mitogen-Activated Protein Kinases

• FAM83
• Wnt proteins
• casein kinase
• cell cycle
• circadian clock

• Animals
• Casein Kinase I/genetics
• Casein Kinase I/metabolism
• Humans
• Isoenzymes/genetics
• Isoenzymes/metabolism
• Signal Transduction
• Substrate Specificity

• MC_UU_00018/6 Medical Research Council
• MC_UU_12016/3 Medical Research Council

• Qingjie Fuzheng Granules (QFG)
• angiogenesis
• apoptosis
• colorectal cancer (CRC)
• proliferation

Hedgehog (Hh) pathway plays multiple roles in many physiological processes and its dysregulation leads to congenital disorders and cancers. Hh regulates the cellular localization of Smoothened (Smo) and the stability of Cubitus interruptus (Ci) to fine-tune the signal outputs. However, the underlying mechanisms are still unclear. Here, we show that the scaffold protein Rack1 plays dual roles in Hh signaling. In the absence of Hh, Rack1 promotes Ci and Cos2 to form a Ci–Rack1–Cos2 complex, culminating in Slimb-mediated Ci proteolysis. In the presence of Hh, Rack1 dissociates from Ci–Rack1–Cos2 complex and forms a trimeric complex with Smo and Usp8, leading to Smo deubiquitination and cell surface accumulation. Furthermore, we find the regulation of Rack1 on Hh pathway is conserved from Drosophila to mammalian cells. Our findings demonstrate that Rack1 plays dual roles during Hh signal transduction and provide Rack1 as a potential drug target for Hh-related diseases.

Meningioma is the most common primary intracranial tumor in adults. The grading of meningioma is based on World Health Organization criteria, which rely on histopathological features alone. This grading system is unable to conclusively predict the clinical behavior of these tumors (i.e., recurrence or prognosis in benign or atypical grades). Advances in molecular techniques over the last decade that include genomic and epigenomic data associated with meningiomas have been used to identify genetic biomarkers that can predict tumor behavior. This review summarizes the molecular characteristics of meningioma using genetic and epigenetic biomarkers. Molecular alterations that can predict meningioma behavior may be integrated into the upcoming World Health Organization grading system.

• Meningioma
• Molecular diagnosis
• Pathological diagnosis

Cancer stem cells (CSCs) represent a major source of treatment resistance and tumor progression. However, regulation of CSCs stemness is not entirely understood. Here, we report that TSPAN8 expression is upregulated in breast CSCs, promotes the expression of the stemness gene NANOG, OCT4, and ALDHA1, and correlates with therapeutic resistance. Mechanistically, TSPAN8 interacts with PTCH1 and inhibits the degradation of the SHH/PTCH1 complex through recruitment of deubiquitinating enzyme ATXN3. This results in the translocation of SMO to cilia, downstream gene expression, resistance of CSCs to chemotherapeutic agents, and enhances tumor formation in mice. Accordingly, expression levels of TSPAN8, PTCH1, SHH, and ATXN3 are positively correlated in human breast cancer specimens, and high TSPAN8 and ATXN3 expression levels correlate with poor prognosis. These findings reveal a molecular basis of TSPAN8-enhanced Sonic Hedgehog signaling and highlight a role for TSPAN8 in promoting cancer stemness.

Tetraspanin 8 (TSPAN8) has been implicated in a number of different tumours, but the underlying mechanisms remain unclear. Here, in breast cancer the authors highlight a role for TSPAN8 in promoting tumorigenesis through the activation of Hedgehog signalling.

• GLI1
• Hh
• IGF2BP1
• Wnt
• basal cell carcinoma
• cross-talk
• therapeutic mechanisms

• basal cell carcinoma
• cytokeratins
• hair follicle
• sebaceous gland
• photoexposition

• Adult
• Carcinoma, Basal Cell/etiology
• Carcinoma, Basal Cell/pathology
• Female
• Hair Follicle/pathology
• Humans
• Keratins/biosynthesis
• Male
• Neoplasms, Adnexal and Skin Appendage/etiology
• Neoplasms, Adnexal and Skin Appendage/pathology
• Skin Neoplasms/etiology
• Skin Neoplasms/pathology
• Sunlight/adverse effects

• Nevoid basal cell carcinoma syndrome
• Odontogenic cysts
• Odontogenic keratocyst
• Oral diagnosis
• Sonic Hedgehog

Hedgehog–Gli1 signaling is evolutionarily conserved and plays an essential role in osteoblast proliferation and differentiation as well as bone formation. To evaluate the role of the Hedgehog–Gli1 pathway in the response of osteoblasts to hierarchical biomaterial topographies, human MG63 osteoblasts were seeded onto smooth, microstructured, and micro-/nanotextured topography (MNT) titanium to assess osteoblast proliferation and differentiation in terms of proliferative activity, alkaline phosphatase (ALP) production, and osteogenesis-related gene expression. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression of Sonic hedgehog (Shh), Smoothened (Smo), and Gli1, and the protein levels were assayed by Western blotting. MG63 cells treated with the Smo inhibitor cyclopamine were seeded onto the titanium specimens, and the cell proliferation and differentiation were studied in the presence or absence of cyclopamine. Our results showed that compared to the smooth and microstructured surfaces, the MNTs induced a higher gene expression and protein production of Shh, Smo, and Gli1 as well as the activation of Hedgehog signaling. The enhanced proliferative activity, ALP production, and expression of the osteogenesis-related genes (bone morphogenetic protein-2, ALP, and runt-related transcription factor 2) enabled by the MNTs were significantly downregulated by the presence of cyclopamine to a similar level as those on the smooth and acid-etched microstructured surfaces in the absence of cyclopamine. This evidence explicitly demonstrates pivotal roles of Hedgehog–Gli1 signaling pathway in mediating the enhanced effect of MNTs on MG63 proliferation and differentiation, which greatly advances our understanding of the mechanism involved in the biological responsiveness of biomaterial topographies. These findings may aid in the optimization of hierarchical biomaterial topographies targeting Hedgehog–Gli1 signaling.

• Hedgehog–Gli1
• MG63
• differentiation
• micro-/nanotextured topography
• proliferation

• Cancer
• Cap
• Hedgehog
• IRES
• translation

• Animals
• Antineoplastic Agents/pharmacology
• Drug Discovery/methods
• Hedgehog Proteins/antagonists & inhibitors
• Hedgehog Proteins/metabolism
• Humans
• Internal Ribosome Entry Sites/drug effects
• Molecular Targeted Therapy/methods
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Protein Biosynthesis/drug effects
• RNA, Messenger/chemistry
• RNA, Messenger/metabolism
• Signal Transduction/drug effects

It has been found that abnormal activation of the hedgehog (Hh) signaling pathway is involved in the occurrence, invasion and metastasis of malignant tumors. In addition, epithelial-mesenchymal transition (EMT) also performs an important function in the invasion and metastasis of malignant tumors. However, the significance of the Hh signaling pathway and EMT in hepatocellular carcinoma (HCC) remains unknown. In the present study, the expression of Gli family zinc finger 1 (Gli-1) and Gli family zinc finger 2 (Gli-2), which are key transcriptional factors in the Hh signaling pathway, and Twist and E-cadherin, which are two factors involved in EMT, was examined in 42 patients with HCC and 20 cases of non-tumorous liver (NTL) tissue by immunohistochemistry. Clinicopathological information was collected in order to analyze the correlation of the Hh signaling pathway with EMT. The present study aimed to examine the difference in the expression of Gli-1, Gli-2, E-cadherin and Twist in HCC and NTL to assess the diagnostic value of these factors in HCC. Additionally, the present study aimed to elucidate the correlation between those proteins and other clinicopathological parameters. Whether abnormal activation of the Hh signaling pathway is closely associated with EMT was also evaluated. Gli-1 and Twist expression was found to be significantly increased and E-cadherin expression was found to be decreased in HCC in contrast to NTL (Gli-1, P=0.019; Twist, P=0.003; E-cadherin, P<0.001). Increased Twist expression was associated with the tumor size (P=0.043), and loss of or decreased E-cadherin expression was associated with the histological type of HCC (P=0.021). There was an inverse association between the expression of Twist and E-cadherin (P=0.006). These results showed that Twist overexpression by induction of EMT changes is involved in the occurrence and progression of HCC. However, the role of Hh signaling pathway-associated proteins in HCC may require elucidation by additional studies using additional materials in the future.

• E-cadherin
• Gli-1
• Twist
• epithelial-mesenchymal transition
• hedgehog signaling pathway
• hepatocellular carcinoma

Since the discovery of the Hedgehog (Hh) pathway in drosophila melanogaster, our knowledge of the role of Hh in embryonic development, inflammation, and cancerogenesis in humans has dramatically increased over the last decades. This is the case especially concerning the pancreas, however, real therapeutic breakthroughs are missing until now. In general, Hh signaling is essential for pancreatic organogenesis, development, and tissue maturation. In the case of acute pancreatitis, Hh has a protective role, whereas in chronic pancreatitis, Hh interacts with pancreatic stellate cells, leading to destructive parenchym fibrosis and atrophy, as well as to irregular tissue remodeling with potency of initiating cancerogenesis. In vitro and in situ analysis of Hh in pancreatic cancer revealed that the Hh pathway participates in the development of pancreatic precursor lesions and ductal adenocarcinoma including critical interactions with the tumor microenvironment. The application of specific inhibitors of components of the Hh pathway is currently subject of ongoing clinical trials (phases 1 and 2). Furthermore, a combination of Hh pathway inhibitors and established chemotherapeutic drugs could also represent a promising therapeutic approach. In this review, we give a structured survey of the role of the Hh pathway in pancreatic development, pancreatitis, pancreatic carcinogenesis and pancreatic cancer as well as an overview of current clinical trials concerning Hh pathway inhibitors and pancreas cancer.

• Pancreatic cancer
• Hedgehog
• Pancreatitis
• Pancreas
• Development

• GCMa
• GLI2
• Hedgehog signaling pathway
• cell fusion
• complex
• placenta
• protein stability
• transactivation
• trophoblast

• antipsychotics
• glioblastoma
• therapy

One of the causes of permanent disability in chronic multiple sclerosis patients is the inability of oligodendrocyte progenitor cells (OPCs) to terminate their maturation program at lesions. To identify key regulators of myelin gene expression acting at the last stages of OPC maturation we developed a drug repositioning strategy based on the mouse immortalized oligodendrocyte (OL) cell line Oli-neu brought to the premyelination stage by stably expressing a key factor regulating the last stages of OL maturation. The Prestwick Chemical Library^® of 1,200 FDA-approved compound(s) was repositioned at three dosages based on the induction of Myelin Basic Protein (MBP) expression. Drug hits were further validated using dosage-dependent reproducibility tests and biochemical assays. The glucocorticoid class of compounds was the most highly represented and we found that they can be divided in three groups according to their efficacy on MBP up-regulation. Since target identification is crucial before bringing compounds to the clinic, we searched for common targets of the primary screen hits based on their known chemical-target interactomes, and the pathways predicted by top ranking compounds were validated using specific inhibitors. Two of the top ranking compounds, Halcinonide and Clobetasol, act as Smoothened (Smo) agonists to up-regulate myelin gene expression in the Oli-neuM cell line. Further, RxRγ activation is required for MBP expression upon Halcinonide and Clobetasol treatment. These data indicate Clobetasol and Halcinonide as potential promyelinating drugs and also provide a mechanistic understanding of their mode of action in the pathway leading to myelination in OPCs. Furthermore, our classification of glucocorticoids with respect to MBP expression provides important novel insights into their effects in the CNS and a rational criteria for their choice in combinatorial therapies in de-myelinating diseases.

• Animals
• Anti-Inflammatory Agents/pharmacology
• Cell Line
• Clobetasol/pharmacology
• Cytoskeletal Proteins/agonists
• Cytoskeletal Proteins/metabolism
• Drug Repositioning
• Gene Expression/drug effects
• Halcinonide/pharmacology
• Immunoblotting
• Mice
• Microscopy, Fluorescence
• Muscle Proteins/agonists
• Muscle Proteins/metabolism
• Myelin Basic Protein/metabolism
• Myelin Sheath/metabolism
• Oligodendroglia/drug effects
• Oligodendroglia/metabolism
• Retinoid X Receptor gamma/genetics
• Retinoid X Receptor gamma/metabolism
• Reverse Transcriptase Polymerase Chain Reaction
• Transcription Factors/genetics

• cancer stem cells
• hedgehog signaling
• tumourigenesis

• odontogenic tumors
• molecular pathology
• translocation
• mutation
• ewsr1
• braf
• ptch

• Humans
• Odontogenic Tumors/genetics
• Odontogenic Tumors/pathology

• Keratocystic odontogenic tumors
• Mutation
• PTCH1

• ADORA
• Adenosine receptors
• GLI proteins
• Hedgehog signaling
• Imiquimod
• PKA
• Protein Kinase A
• basal cell carcinoma

Members of the highly conserved and ubiquitously expressed pleiotropic CK1 family play major regulatory roles in many cellular processes including DNA-processing and repair, proliferation, cytoskeleton dynamics, vesicular trafficking, apoptosis, and cell differentiation. As a consequence of cellular stress conditions, interaction of CK1 with the mitotic spindle is manifold increased pointing to regulatory functions at the mitotic checkpoint. Furthermore, CK1 is able to alter the activity of key proteins in signal transduction and signal integration molecules. In line with this notion, CK1 is tightly connected to the regulation and degradation of β-catenin, p53, and MDM2. Considering the importance of CK1 for accurate cell division and regulation of tumor suppressor functions, it is not surprising that mutations and alterations in the expression and/or activity of CK1 isoforms are often detected in various tumor entities including cancer of the kidney, choriocarcinomas, breast carcinomas, oral cancer, adenocarcinomas of the pancreas, and ovarian cancer. Therefore, scientific effort has enormously increased (i) to understand the regulation of CK1 and its involvement in tumorigenesis- and tumor progression-related signal transduction pathways and (ii) to develop CK1-specific inhibitors for the use in personalized therapy concepts. In this review, we summarize the current knowledge regarding CK1 regulation, function, and interaction with cellular proteins playing central roles in cellular stress-responses and carcinogenesis.

• casein kinase 1
• cellular stress
• centrosome
• disease
• inhibitor
• p53
• signal transduction
• tumorigenesis

• Cancer cell biology
• Cell signaling
• Targeted therapies
• Tumorigenesis

Although the number of new cases of Basal Cell Carcinoma (BCC) has increased rapidly in the last few decades, the molecular basis of its pathogenesis is not completely understood. Activation of Hedgehog (Hh) signaling pathway has been shown to be a key factor driving the development of BCC. The Wnt/β-catenin signaling pathway was also shown to be activated in BCCs and to perhaps modulate the activity of Hh pathway. We have previously identified a novel mechanism by which Wnt signaling regulates the transcriptional outcome of Hh signaling pathway. We demonstrated that CRD-BP, a direct target of the Wnt/β-catenin signaling, binds to GLI1 mRNA, stabilizes it, and consequently upregulates its levels (mRNA and protein) and activities. We hypothesized that Wnt-induced and CRD-BP-dependent regulation of GLI1 expression and activities is important to the development of BCC. In this study, we show that CRD-BP is over-expressed in BCC and that its expression positively correlates with the activation of both Wnt and Hh signaling pathways. We also describe the generation and characterization of a human BCC cell line. This cell line was utilized to demonstrate the importance of CRD-BP-dependent regulation of GLI1 expression and activities in the development of BCC.

• Clinical Trials as Topic
• Drug Resistance, Neoplasm/genetics
• Gene Expression Regulation, Neoplastic
• Hedgehog Proteins/antagonists & inhibitors
• Hedgehog Proteins/metabolism
• Humans
• Molecular Targeted Therapy
• Neoplasm Metastasis
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Receptors, G-Protein-Coupled/genetics
• Receptors, G-Protein-Coupled/metabolism
• Signal Transduction/genetics
• Smoothened Receptor