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Jacob W P Potuijt, Martijn Baas, Rivka Sukenik-Halevy, Hannie Douben, Picard Nguyen, Deon J Venter, Renée Gallagher, Sigrid M Swagemakers, Steven E R Hovius, Christianne A van Nieuwenhoven, Robert-Jan H Galjaard, Peter J van der Spek, Nadav Ahituv, Annelies de Klein
PurposeThe zone of polarizing activity regulatory sequence (ZRS) is an enhancer that regulates sonic hedgehog during embryonic limb development. Recently, mutations in a noncoding evolutionary conserved sequence 500 bp upstream of the ZRS, termed the pre-ZRS (pZRS), have been associated with polydactyly in dogs and humans. Here, we report the first case of triphalangeal thumb-polysyndactyly syndrome (TPT-PS) to be associated with mutations in this region and show via mouse enhancer assays how this mutation leads to ectopic expression throughout the developing limb bud...
March 15, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Jing Zhang, Yinghong Cui, Shuwen Sun, Jianguo Cao, Xiaoling Fang
Casticin inhibits migration, invasion and induced apoptosis in numerous cancer cells; however, the Hedgehog (Hh) signaling pathway is a key factor in the epithelial-mesenchymal transition (EMT). The present study aimed to assess whether casticin affects the expression of members of the Hh signaling pathway and EMT effectors in ovarian carcinoma. The ovarian cancer SKOV3 cell line was incubated in the presence of various concentrations of casticin or cyclopamine. Next, the expression levels of the main Hh signaling effector glioma-associated oncogene-1 (Gli-1) and EMT-associated factors [Twist-related protein 1 (Twist1), E-cadherin and N-cadherin] were determined by western blotting and reverse transcription-quantitative polymerase chain reaction...
April 2018: Oncology Letters
Weiwei Qian, Xiaochuan Kong, Tao Zhang, Dengdian Wang, Jin Song, Yuan Li, Xiaoting Li, Hao Geng, Jie Min, Qi Kong, Jie Liu, Zhiqi Liu, Daming Wang, Zhiqiang Zhang, Dexin Yu, Caiyun Zhong
Cancer stem cells (CSCs) are essentially responsible for tumor initiation, growth, progression, metastasis and recurrence, and cigarette smoke (CS) is closely involved in the occurrence and development of kidney cancer. However, the effect of CS on renal CSCs has not been elucidated yet. In the present study, tumorsphere formation assay was used to enrich renal CSCs from 786-O and ACHN cells. We illustrated that CS effectively promoted renal CSCs stemness by enhancing tumorsphere formation, increasing the expression of renal CSCs markers (CD133, CD44, ALDHA1, Oct4, and Nanog) and elevating CD133+ cell population...
March 13, 2018: Oncogenesis
Thibaut Eguether, Fabrice P Cordelieres, Gregory J Pazour
The vertebrate hedgehog pathway is organized in primary cilia and hedgehog components relocate into or out of cilia during signaling. Defects in intraflagellar transport (IFT) typically disrupt ciliary assembly and attenuate hedgehog signaling. Determining if IFT drives the movement of hedgehog components is difficult due to the requirement of IFT for building cilia. Unlike most IFT proteins, IFT27 is dispensable for cilia formation but affects hedgehog signaling similar to other IFTs allowing us to examine its role in the dynamics of signaling...
March 14, 2018: Molecular Biology of the Cell
Wijeong Jang, Minwoo Baek, Yeon Soo Han, Changsoo Kim
BACKGROUND: Nociceptive sensitization is an increase in pain perception in response to stimulus. Following brief irradiation of Drosophila larvae with UV, nociceptive sensitization occurs in class IV multiple dendritic (mdIV) neurons, which are polymodal sensory nociceptors. Diverse signaling pathways have been identified that mediate nociceptive sensitization in mdIV neurons, including TNF, Hedgehog, BMP, and Tachykinin, yet the underlying mechanisms are not completely understood. RESULTS: Here we report that duox heterozygous mutant larvae, which have normal basal nociception, exhibit an attenuated hypersensitivity response to heat and mechanical force following UV irradiation...
March 14, 2018: Molecular Brain
Yun Zuo, Yan Lv, Xiaolan Qian, Shaokai Wang, Zhipen Chen, Qin Jiang, Cong Cao, Yu Song
BACKGROUND/AIMS: Human hedgehog-interacting protein (HHIP) is a negative regulator of the hedgehog (HH) signaling pathway. It is deregulated in gastric cancer. The underlying molecular mechanism of HHIP-induced inhibition of HH signaling remains to be determined. METHODS: A lentiviral HHIP expression vector ("LV-HHIP") was established to exogenously over-express HHIP in gastric cancer cells. HHIP protein and mRNA were tested by Western blotting assay and quantitative real-time PCR assay, respectively...
February 28, 2018: Cellular Physiology and Biochemistry
Dario Presutti, Manuela Ceccarelli, Laura Micheli, Giuliana Papoff, Simonetta Santini, Simone Samperna, Cristiana Lalli, Lorena Zentilin, Giovina Ruberti, Felice Tirone
Medulloblastoma (MB), the tumor of the cerebellum, is the most frequent brain cancer in childhood and a major cause of pediatric mortality. Based on gene profiling, four MB subgroups have been identified, i.e., Wnt or Sonic Hedgehog (Shh) types, and subgroup 3 or 4. The Shh-type MB has been shown to arise from the cerebellar precursors of granule neurons (GCPs), where a hyperactivation of the Shh pathway leads to their neoplastic transformation. We have previously shown that the gene Tis21 (PC3/Btg2) inhibits the proliferation and promotes the differentiation and migration of GCPs...
2018: PloS One
Kirti K Chahal, Milind Parle, Ruben Abagyan
The hedgehog (Hh) pathway plays an important role in cancer development and maintenance, as ~25% of all cancers have aberrant Hh pathway activation. Targeted therapy for inhibition of the Hh pathway was thought to be promising for achieving clinical response in the Hh-dependent cancers. However, the results of new clinical trials with smoothened (SMO) antagonists do not show much success in cancers other than basal cell carcinoma. The studies suggest that the Hh pathway involves multiple mechanisms of activation or inhibition in primary cilia and interactions between several related pathways in different types of cells, which makes this pathway extremely complex...
March 13, 2018: Anti-cancer Drugs
Tomohiro Katagiri, Minoru Kobayashi, Michio Yoshimura, Akiyo Morinibu, Satoshi Itasaka, Masahiro Hiraoka, Hiroshi Harada
Hypoxic and stroma-rich microenvironments, characteristic features of pancreatic cancers, are strongly associated with a poor prognosis. However, whether and how hypoxia increases stromal compartments remain largely unknown. Here, we investigated the potential importance of a master regulator of the cellular adaptive response to hypoxia, hypoxia-inducible factor-1 (HIF-1), in the formation of stroma-rich microenvironments of pancreatic tumors. We found that pancreatic cancer cells secreted more Sonic hedgehog protein (SHH) under hypoxia by upregulating its expression and efficiency of secretion in a HIF-1-dependent manner...
February 13, 2018: Oncotarget
Xin Shi, Shengcai Wei, Kevin J Simms, Devan N Cumpston, Thomas J Ewing, Ping Zhang
Activation and reprogramming of hematopoietic stem/progenitor cells play a critical role in the granulopoietic response to bacterial infection. Our current study determined the significance of Sonic hedgehog (SHH) signaling in the regulation of hematopoietic precursor cell activity during the host defense response to systemic bacterial infection. Bacteremia was induced in male Balb/c mice via intravenous injection (i.v.) of Escherichia coli (5 × 107 CFUs/mouse). Control mice received i.v. saline. SHH protein level in bone marrow cell (BMC) lysates was markedly increased at both 24 and 48 h of bacteremia...
2018: Frontiers in Immunology
Bo Zhang, Honglan Wang, Ting Jiang, Kai Jin, Zimiao Luo, Wei Shi, Heng Mei, Huafang Wang, Yu Hu, Zhiqing Pang, Xinguo Jiang
As one of the most intractable tumors, pancreatic ductal adenocarcinoma (PDA) has a dense extracellular matrix (ECM) which could increase solid stress within tumors to compress tumor vessels, reduce tumor perfusion, and compromise nanomedicine delivery for PDA. Thus, alleviating solid stress represents a potential therapeutic target for PDA treatment. In this study, cyclopamine, a special inhibitor of the hedgehog signaling pathway which contributes a lot to ECM formation of PDA, was exploited to alleviate solid stress and improve nanomedicine delivery to PDA...
March 13, 2018: Journal of Drug Targeting
Kelsey H Elliott, Grethel Millington, Samantha A Brugmann
BACKGROUND: Submandibular glands (SMGs) are specialized epithelial structures which generate saliva necessary for mastication and digestion. Loss of SMGs can lead to inflammation, oral lesions, fungal infections, problems with chewing/swallowing, and tooth decay. Understanding the development of the SMG is important for developing therapeutic options for patients with impaired SMG function. Recent studies have suggested Sonic hedgehog (Shh) signaling in the epithelium plays an integral role in SMG development; however, the mechanism by which Shh influences gland development remains nebulous...
March 13, 2018: Developmental Dynamics: An Official Publication of the American Association of Anatomists
I-Li Tan, Alexandre Wojcinski, Harikrishna Rallapalli, Zhimin Lao, Reeti M Sanghrajka, Daniel Stephen, Eugenia Volkova, Andrey Korshunov, Marc Remke, Michael D Taylor, Daniel H Turnbull, Alexandra L Joyner
The main cell of origin of the Sonic hedgehog (SHH) subgroup of medulloblastoma (MB) is granule cell precursors (GCPs), a SHH-dependent transient amplifying population in the developing cerebellum. SHH-MBs can be further subdivided based on molecular and clinical parameters, as well as location because SHH-MBs occur preferentially in the lateral cerebellum (hemispheres). Our analysis of adult patient data suggests that tumors with Smoothened ( SMO ) mutations form more specifically in the hemispheres than those with Patched 1 ( PTCH1 ) mutations...
March 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
Felipe de Oliveira, José Alberto Landeiro, Igor de Castro
Background: Medulloblastoma is an embryonal neoplasm and accounts for 1% of all adult intracranial tumors. It is associated with many familiar cancer syndromes, but there is no known cause for medulloblastoma. Many studies have documented differences between childhood and adult medulloblastomas in terms of location, proliferation, and apoptotic indices. There are four histological groups - classic and the variant forms (desmoplastic/nodular, anaplasic, and large cell). There are four major subgroups according to molecular configuration: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4 with differences between them according to prognostic outcomes...
2018: Surgical Neurology International
Carminia Maria Della Corte, Vincenza Ciaramella, Claudia Cardone, Silvia La Monica, Roberta Alfieri, Pier Giorgio Petronini, Umberto Malapelle, Elena Vigliar, Francesco Pepe, Giancarlo Troncone, Maria Domenica Castellone, Teresa Troiani, Erika Martinelli, Fortunato Ciardiello, Floriana Morgillo
HYPOTHESIS: Osimertinib showed great clinical efficacy for activated-EGFR-NSCLC patients treatment. The aim of this work was to test the efficacy of a complete EGFR-inhibition by osimertinib plus the monoclonal antibody, cetuximab, or the MEK1/2-inhibitor, selumetinib, in EGFR-mutated-NSCLC in vivo models. METHODS: We evaluated combinations of osimertinib plus selumetinib/cetuximab in HCC827 (E746-A759del/T790M-), H1975 (L858R/T790M+) and PC9-T790M (E746-A759del /T790M+) xenografts, in second-line after the developing of resistance to osimertinib and in first-line, and we explored mechanisms of resistance to these treatments...
March 8, 2018: Journal of Thoracic Oncology
Li Yang, Qing-Hua Zou, Yan Zhang, Yin Shi, Chun-Rong Hu, Cai-Xia Hui, Xiao-Fei Liu, Yong-Fei Fang
Rheumatoid arthritis (RA) patients may suffer from comorbid neuropsychiatric symptoms including mild cognitive impairment (MCI). Although comorbidity of MCI is common, there are currently no validated plasma biomarkers to aid MCI diagnosis. This study screened plasma from patients with RA with and without comorbid MCI to identify potential biomarkers useful in the differential diagnosis of comorbid MCI. Plasma samples were collected from patients with RA without comorbid MCI, with comorbid MCI, and from healthy controls...
March 10, 2018: Clinical Rheumatology
Miki Iwasaki, Junpei Kuroda, Koichi Kawakami, Hironori Wada
Bone is a connective tissue composed of many cell types, including osteoblasts. How bones acquire their unique size and shape during development remains poorly understood. Herein we investigated the molecular and cellular mechanisms of bone morphogenesis in the zebrafish scale by using transgenic lines to enable visualization of specific types of osteoblasts. We demonstrate that the zebrafish scale contains three distinct types of osteoblasts: (i) a monolayer of central osteoblasts along the inner surface of scales; (ii) marginal osteoblasts elongated along the scale edge; and (iii) submarginal osteoblasts located between the central and marginal osteoblast populations...
March 7, 2018: Developmental Biology
Jennifer C Hocking, Jakub K Famulski, Kevin H Yoon, Sonya A Widen, Cassidy S Bernstein, Sophie Koch, Omri Weiss, Seema Agarwala, Adi Inbal, Ordan J Lehmann, Andrew J Waskiewicz
The eye primordium arises as a lateral outgrowth of the forebrain, with a transient fissure on the inferior side of the optic cup providing an entry point for developing blood vessels. Incomplete closure of the inferior ocular fissure results in coloboma, a disease characterized by gaps in the inferior eye and recognized as a significant cause of pediatric blindness. Here, we identify eight patients with defects in tissues of the superior eye, a congenital disorder that we term superior coloboma. The embryonic origin of superior coloboma could not be explained by conventional models of eye development, leading us to reanalyze morphogenesis of the dorsal eye...
March 9, 2018: PLoS Genetics
Sabine Schürmann, Georg Steffes, Dominique Manikowski, Philipp Kastl, Ursula Malkus, Shyam Bandari, Stefanie Ohlig, Corinna Ortmann, Rocio Rebollido-Rios, Mandy Otto, Harald Nüsse, Daniel Hoffmann, Christian Klämbt, Milos Galic, Jürgen Klingauf, Kay Grobe
Cell fate determination during development often requires morphogen transport from producing to distant responding cells. Hedgehog (Hh) morphogens present a challenge to this concept, as all Hhs are synthesized as terminally lipidated molecules that form insoluble clusters at the surface of producing cells. While several proposed Hh transport modes tie directly into these unusual properties, the crucial step of Hh relay from producing cells to receptors on remote responding cells remains unresolved. Using wing development in Drosophila melanogaster as a model, we show that Hh relay and direct patterning of the 3-4 intervein region strictly depend on proteolytic removal of lipidated N-terminal membrane anchors...
March 9, 2018: ELife
Jichun Gu, Hexige Saiyin, Deliang Fu, Ji Li
Pancreatic cancer is a uniformly lethal malignancy with an abundant dense desmoplastic stroma. Because of its dense stroma, conventional drugs were considered to not penetrate this physical barrier, and this caused a systemic drug resistance. Thus, abolishing this barrier with targeted agents is considered to improve the efficiency of chemotherapeutic treatment. The Hedgehog (Hh) signaling pathway is a critical regulator of pancreas development and plays diversified roles in pancreatic cancer stroma and neoplastic cells...
April 2018: Pancreas
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