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Hedgehog signalling pathway

Marko Magic, Katarina Zeljic, Stevo Jovandic, Jelena Stepic, Marko Pejovic, Snjezana Colic, Zvonko Magic, Gordana Supic
OBJECTIVES: Genetic variants in the hedgehog signaling pathway and VDR gene are involved in inflammatory responses and neoplastic transformation. Current study investigated whether single-nucleotide polymorphisms in the hedgehog pathway genes PTCH1, GLI1, SMO, and VDR contribute to susceptibility to odontogenic cystic lesions, odontogenic keratocysts, or inflammatory radicular cysts. MATERIAL AND METHODS: Current study examined polymorphisms of PTCH1 (rs357564) and PTCH1 insertion (IVS1-83), GLI1 (rs2228224, rs2228226), SMO (rs2228617), and VDR (rs2228570, rs731236, rs7975232)...
October 17, 2018: Clinical Oral Investigations
Zhaohui Chen, Lijie Zhou, Liang Chen, Ming Xiong, Gallina Kazobinka, Zili Pang, Teng Hou
R-Spondin 3 (RSPO3) is a secreted protein that associates directly with Wnt/β-catenin signaling. However, its functional contribution and prognostic value in human bladder cancer remain unclear. Here, we showed that RSPO3 is upregulated in bladder cancer tissues and cells, and high expression of RSPO3 correlates with advanced clinicopathological features, poor prognosis and disease progression in bladder cancer patients. Furthermore, we observed that ectopic expression or knockdown of RSPO3 profoundly promoted or inhibited, respectively, the invasive ability of bladder cancer cells...
October 17, 2018: Carcinogenesis
Zhaoting Yang, Chengye Zhang, Wenbo Qi, Yanhua Xuan, Yan Cui
The role of Hedgehog (HH)/ glioma-associated oncogene homolog 1 (GLI1) pathway has been implicated in a variety of cancer entities, and the targeted pathway inhibition mediated by GLI1 is of therapeutic relevance. However, its oncogenicity and cross-talks with other cancer pathways including PI3K/Akt/NFκB, which modulates the HH/GLI1 signal strength, have rarely been explored in colorectal adenocarcinoma. We assessed the expression of GLI1 and its relationship with other cancer stemness genes, cell cycle markers, epithelial-mesenchymal transition (EMT), PI3K/Akt/NFκB signaling pathway genes, and HIF1α in 100 paraffin-embedded colorectal adenocarcinoma tissue samples using immunohistochemistry...
October 12, 2018: Experimental Cell Research
Natalie Geyer, Rosalie Ridzewski, Julia Bauer, Maria Kuzyakova, Kai Dittmann, Christian Dullin, Albert Rosenberger, Hans-Ulrich Schildhaus, Anja Uhmann, Simone Fulda, Heidi Hahn
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma with poor prognosis. RMS frequently show Hedgehog (HH) pathway activity, which is predominantly seen in the embryonal subtype (ERMS). They also show activation of Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling. Here we compared the therapeutic effectiveness and the impact on HH target gene expression of Smoothened (SMO) antagonists with those of the PI3K inhibitor pictilisib in ERMS with and without mutations in the HH receptor Patched1 ( PTCH )...
2018: Frontiers in Oncology
Ye Zhang, Xiaofeng Xue, Xiaoqian Zhao, Lei Qin, Yu Shen, Huiqiang Dou, Jialin Sun, Tong Wang, Da-Qing Yang
BACKGROUND: Based on previous findings, we hypothesized that Vasohibin 2 (VASH2) protein may induce epithelial-mesenchymal transition (EMT) of pancreatic cancer (PC) cells by promoting the malignant behaviors of these cells. The present study aimed to test this hypothesis and explore the possible mechanisms involved. METHODS: The expression of VASH2 in PC tissues and cell lines was detected by quantitative real-time PCR and Western blot. PC cells with overexpression or knockdown of VASH2 were used to examine the involvement of VASH2 in EMT by detecting the expression of epithelial (E-cadherin) and mesenchymal (vimentin) markers and EMT-related transcription factor ZEB1/2, in gemcitabine resistance and tumor cell invasion by apoptosis and invasion assays, and in cancer stem cell-like phenotypes by detecting the proportion of CD24+ CD44+ and side population (SP) cells in PC cells with flow cytometry...
October 14, 2018: Cancer Medicine
Kun Li, Chunmei Xiu, Qiang Zhou, Li Ni, Jun Du, Tingting Gong, Meng Li, Saijilafu, Huilin Yang, Jianquan Chen
Osteoblasts, the chief bone-forming cells, are differentiated from mesenchymal stromal/stem cells. Disruption of this differentiation process can cause osteoporosis, a bone disease characterized by low bone mass and deteriorated bone structure. Cholesterol has been implicated in pathogenesis of osteoporosis, and was recently identified as an endogenous activator of Hedgehog (Hh) signaling. However, its pathological and physiological roles in osteoblast differentiation are still poorly understood. Moreover, it is unclear whether these potential roles played by cholesterol are related to its capability to modulate Hh pathway...
October 14, 2018: Journal of Cellular Physiology
Rajeev Singh, Philipp Simon Holz, Katrin Roth, Anna Hupfer, Wolfgang Meissner, Rolf Müller, Malte Buchholz, Thomas M Gress, Hans-Peter Elsässer, Ralf Jacob, Matthias Lauth
The posttranslational modification (PTM) of tubulin subunits is important for the physiological functions of the microtubule (MT) cytoskeleton. Although major advances have been made in the identification of enzymes carrying out MT-PTMs, little knowledge is available on how intercellular signaling molecules and their associated pathways regulate MT-PTM-dependent processes inside signal-receiving cells. Here we show that Hedgehog (Hh) signaling, a paradigmatic intercellular signaling system, affects the MT acetylation state in mammalian cells...
October 13, 2018: Cellular and Molecular Life Sciences: CMLS
Massimo Ganassi, Sara Badodi, Huascar Pedro Ortuste Quiroga, Peter S Zammit, Yaniv Hinits, Simon M Hughes
Each skeletal muscle acquires its unique size before birth, when terminally differentiating myocytes fuse to form a defined number of multinucleated myofibres. Although mice in which the transcription factor Myogenin is mutated lack most myogenesis and die perinatally, a specific cell biological role for Myogenin has remained elusive. Here we report that loss of function of zebrafish myog prevents formation of almost all multinucleated muscle fibres. A second, Myogenin-independent, fusion pathway in the deep myotome requires Hedgehog signalling...
October 12, 2018: Nature Communications
Juan Bautista Blanco-Canosa, Judith Palà-Pujadas, Fernando Albericio
A simple procedure for C-terminal activation of peptides in solution and its application in native chemical ligation and protein synthesis is described. This method involves a mild thioesterification based on the conversion of an aryloxy-o-methylaminoanilide to thioester under aqueous conditions and in situ ligation with an N-terminal cysteine peptide. The versatility is shown in ph-controlled sequential ligations. To illustrate the usefulness of this methodology, we synthesized the palmitoylated N-terminal domain of human Sonic Hedgehog, a morphogen protein that binds the transmembrane receptor Patched and activates the Hedgehog signaling pathway, involved in embryonic development and in the proliferation of many tumors...
October 11, 2018: Angewandte Chemie
Xiao-Li Niu, Xin Jiang, Guo-Dong Xu, Gui-Min Zheng, Zhi-Peng Tang, Nan Yin, Xiu-Qin Li, Yan-Yan Yang, Pei-Yuan Lv
BACKGROUND: DL-3-n-butylphthalide (NBP) has been approved to be effective in improving cognitive deficits. The aim of the current study was to determine whether NBP protects against cognitive deficits in a rat model of vascular dementia (VD) induced by chronic cerebral hypoperfusion (CCH) by regulating the sonic hedgehog (Shh)/patched1 (Ptch1) pathway and endoplasmic reticulum stress (ERS)-related markers. METHODS: Adult male Sprague-Dawley rats were subjected to permanent bilateral occlusion of the common carotid arteries (2VO) to established the model of VD...
October 10, 2018: Journal of Cellular Physiology
Dengliang Huang, Yiting Wang, Linlin Xu, Limin Chen, Minzhang Cheng, Wei Shi, Huanting Xiong, Detina Zalli, Shiwen Luo
BACKGROUND: The Hedgehog (Hh) signaling pathway plays critical roles in modulating embryogenesis and maintaining tissue homeostasis, with glioma-associated oncogene (GLI) transcription factors being the main mediators. Aberrant activation of this pathway is associated with various human malignancies including glioblastoma, although the mechanistic details are not well understood. METHODS: We performed a microarray analysis of genes that are differentially expressed in glioblastoma U87 cells overexpressing GLI2A, the active form of GLI2, relative to the control cells...
October 11, 2018: Journal of Experimental & Clinical Cancer Research: CR
Eoghainín Ó hAinmhire, Haojia Wu, Yoshiharu Muto, Erinn L Donnelly, Flavia G Machado, Lucy X Fan, Monica Chang-Panesso, Benjamin D Humphreys
Gli1-positive resident mesenchymal stem cell-like cells are the predominant source of kidney myofibroblasts in fibrosis but investigating Gli1-positive myofibroblast progenitor activation is hampered by the difficulty of isolating and propagating primary cultures of these cells. Using a genetic strategy with positive and negative selection, we isolated Kidney-Gli1 (KG1) cells that maintain expression of appropriate mesenchymal stem cell-like cell markers, respond to hedgehog pathway activation and display robust myofibroblast differentiation upon treatment with TGFb...
October 10, 2018: American Journal of Physiology. Renal Physiology
Amankeldi A Salybekov, Ainur K Salybekova, Roberto Pola, Takayuki Asahara
The Hedgehog (HH) signaling pathway plays an important role in embryonic and postnatal vascular development and in maintaining the homeostasis of organs. Under physiological conditions, Sonic Hedgehog (SHH), a secreted protein belonging to the HH family, regulates endothelial cell growth, promotes cell migration and stimulates the formation of new blood vessels. The present review highlights recent advances made in the field of SHH signaling in endothelial progenitor cells (EPCs). The canonical and non-canonical SHH signaling pathways in EPCs and endothelial cells (ECs) related to homeostasis, SHH signal transmission by extracellular vesicles (EVs) or exosomes containing single-strand non-coding miRNAs and impaired SHH signaling in cardiovascular diseases are discussed...
October 5, 2018: International Journal of Molecular Sciences
Maria Tsoli, Carol Wadham, Mark Pinese, Tim Failes, Swapna Joshi, Emily Mould, Julia X Yin, Velimir Gayevskiy, Amit Kumar, Warren Kaplan, Paul G Ekert, Federica Saletta, Laura Franshaw, Jie Liu, Andrew Gifford, Martin A Weber, Michael Rodriguez, Richard J Cohn, Greg Arndt, Vanessa Tyrrell, Michelle Haber, Toby Trahair, Glenn M Marshall, Kerrie McDonald, Mark J Cowley, David S Ziegler
Pediatric high grade gliomas (HGG) are primary brain malignancies that result in significant morbidity and mortality. One of the challenges in their treatment is inter- and intra-tumoral heterogeneity. Precision medicine approaches have the potential to enhance diagnostic, prognostic and/or therapeutic information. In this case study we describe the molecular characterization of a pediatric HGG and the use of an integrated approach based on genomic, in vitro and in vivo testing to identify actionable targets and treatment options...
October 9, 2018: Cancer Biology & Therapy
Donna M Brennan-Crispi, Andrew M Overmiller, Lukas Tamayo-Orrego, Molly R Marous, Joya Sahu, Kathleen P McGuinn, Felicia Cooper, Ioanna Ch Georgiou, Maxwell Frankfurter, Julio C Salas-Alanis, Frédéric Charron, Sarah E Millar, Mỹ G Mahoney, Natalia A Riobo-Del Galdo
Activation of the Hedgehog (Hh) pathway is causative of virtually all sporadic and Gorlin syndrome-related basal cell carcinomas (BCC), with loss of function of Patched1 (Ptc1) being the most common genomic lesion. Sporadic BCCs also overexpress desmoglein-2 (Dsg2), a desmosomal cadherin normally found in the basal layer. Using a mouse model of Gorlin syndrome (Ptc1+/lacZ mice), we found that overexpressing Dsg2 in the basal layer (K14-Dsg2/Ptc1+/lacZ ) or the superficial epidermis (Inv-Dsg2/Ptc1+/lacZ mice) resulted in increased spontaneous BCC formation at 3 and 6 months, respectively...
October 3, 2018: Journal of Investigative Dermatology
Mattias Hogvall, Graham E Budd, Ralf Janssen
Background: Morphogen signalling represents a key mechanism of developmental processes during animal development. Previously, several evolutionary conserved morphogen signalling pathways have been identified, and their players such as the morphogen receptors, morphogen modulating factors (MMFs) and the morphogens themselves have been studied. MMFs are factors that regulate morphogen distribution and activity. The interactions of MMFs with different morphogen signalling pathways such as Wnt signalling, Hedgehog (Hh) signalling and Decapentaplegic (Dpp) signalling are complex because some of the MMFs have been shown to interact with more than one signalling pathway, and depending on genetic context, to have different, biphasic or even opposing function...
2018: EvoDevo
Siyi Gong, Feng Ji, Bin Wang, Yingying Zhang, Xingshun Xu, Miao Sun
Primary cilium is a ubiquitous, tiny organelle on the apex of the mammalian cells. Non-motile (primary) ciliopathies are diseases caused by the dysfunction of the primary cilium and they are characterized by diverse clinical and genetic heterogeneity. To date, nearly 200 genes have been shown to be associated with primary ciliopathies. Among them, tectonic genes are the important causative genes of ciliopathies. Tectonic proteins including TCTN1, TCTN2, and TCTN3 are important component proteins residing at the transition zone of cilia...
October 4, 2018: Cellular Physiology and Biochemistry
Maria Montserrat Garcia Romero, Gareth McCathie, Philip Jankun, Henry Hamilton Roehl
Many aquatic vertebrates have a remarkable ability to regenerate limbs and tails after amputation. Previous studies indicate that reactive oxygen species (ROS) signalling initiates regeneration, but the mechanism by which this takes place is poorly understood. Developmental signalling pathways have been shown to have proregenerative roles in many systems. However, whether these are playing roles that are specific to regeneration, or are simply recapitulating their developmental functions is unclear. Here, we analyse zebrafish larval tail regeneration and find evidence that ROS released upon wounding cause repositioning of notochord cells to the damage site...
October 1, 2018: Nature Communications
Maria Fernanda Setúbal Destro Rodrigues, Lucyene Miguita, Nathália Paiva De Andrade, Daniele Heguedusch, Camila Oliveira Rodini, Raquel Ajub Moyses, Tatiana Natasha Toporcov, Ricardo Ribeiro Gama, Eloiza Elena Tajara, Fabio Daumas Nunes
Oral squamous cell carcinoma (OSCC) is an extremely aggressive disease associated with a poor prognosis. Previous studies have established that cancer stem cells (CSCs) actively participate in OSCC development, progression and resistance to conventional treatments. Furthermore, CSCs frequently exhibit a deregulated expression of normal stem cell signalling pathways, thereby acquiring their distinctive abilities, of which self-renewal is an example. In this study, we examined the effects of GLI3 knockdown in OSCC, as well as the differentially expressed genes in CSC-like cells (CSCLCs) expressing high (CD44high) or low (CD44low) levels of CD44...
September 26, 2018: International Journal of Oncology
Rongrong Li, Youlei Wang, Xiaodong Song, Wenjing Sun, Jinjin Zhang, Yuxia Liu, Hongbo Li, Chao Meng, Jie Zhang, Qingyin Zheng, Changjun Lv
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive type of interstitial pneumonia with unknown causes, poor prognosis and no effective therapy available. Circular RNAs (circRNAs), which serve as potential therapeutic targets and diagnostic biomarkers for certain diseases, represent a recent hotspot in the field of RNA research. In the present study, a total of 67 significantly dysregulated circRNAs were identified in the plasma of IPF patients by using a circRNA microarray. Among these circRNAs, 38 were upregulated, whereas 29 were downregulated...
September 24, 2018: International Journal of Molecular Medicine
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