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https://www.readbyqxmd.com/read/29453627/a-phase-i-and-pharmacokinetic-study-of-taladegib-a-smoothened-inhibitor-in-japanese-patients-with-advanced-solid-tumors
#1
Hideki Ueno, Shunsuke Kondo, Shusuke Yoshikawa, Koichi Inoue, Valérie Andre, Masaomi Tajimi, Haruyasu Murakami
Background This phase I dose-escalation study investigated the safety of the Smoothened inhibitor taladegib in Japanese patients with advanced solid tumors. Methods Patients received taladegib orally once daily for 28-day cycles, using a 3 + 3 dose-escalation method. The primary objective was the safety and tolerability of taladegib at doses up to the global recommended dose (400 mg). Secondary objectives included pharmacokinetics, changes in skin glioma-associated oncogene homolog 1 (Gli1) transcript levels, and antitumor activity...
February 17, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29449694/interaction-between-stat3-and-gli1-tgli1-oncogenic-transcription-factors-promotes-the-aggressiveness-of-triple-negative-breast-cancers-and-her2-enriched-breast-cancer
#2
Sherona R Sirkisoon, Richard L Carpenter, Tadas Rimkus, Ashley Anderson, Alexandria Harrison, Allison M Lange, Guangxu Jin, Kounosuke Watabe, Hui-Wen Lo
Signal transducer and activator of transcription 3 (STAT3), glioma oncogene homolog 1 (GLI1), and truncated GLI1 (tGLI1) are oncogenic transcription factors playing important roles in breast cancer. tGLI1 is a gain-of-function GLI1 isoform. Whether STAT3 physically and/or functionally interacts with GLI1/tGLI1 has not been explored. To address this knowledge gap, we analyzed 47 node-positive breast cancer specimens using immunohistochemical staining and found that phosphorylated-STAT3 (Y705), GLI1, and tGLI1 are co-overexpressed in the majority of triple-negative breast carcinomas (64%) and HER2-enriched (68%) breast carcinomas, and in lymph node metastases (65%)...
February 16, 2018: Oncogene
https://www.readbyqxmd.com/read/29442331/role-of-zic-family-proteins-in-transcriptional-regulation-and-chromatin-remodeling
#3
Minoru Hatayama, Jun Aruga
Proper functions of Zic proteins are essential for animals in health and disease. Here, we summarize our current understanding of the molecular properties and functions of the Zic family across animal species and paralog subtypes. Zics are basic proteins with some posttranslational modifications and can move to the cell nucleus via importin- and CRM1-based nucleocytoplasmic shuttling mechanisms. Degradation is mediated by the ubiquitin proteasome system. Many Zic proteins are capable of binding to two types of target DNA sequences (CTGCTG-core-type and GC-stretch-type)...
2018: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29424103/alternative-activation-of-hedgehog-pathway-induced-by-ultraviolet-b-radiation-preliminary-study
#4
A Lesiak, D Sobolewska-Sztychny, I A Bednarski, K Wódz, M Sobjanek, A Woźniacka, J Narbutt
BACKGROUND: There is still much ambiguity in studies of Sonic hedgehog (Shh) pathways and its dysregulation. Some studies concerning the role of the Shh pathway in basal cell carcinoma (BCC) have been conducted, but there is a lack of studies about Shh pathway dysregulation under the influence of ultraviolet (UV)B radiation. AIM: To evaluate skin expression of Shh, Ptch1, Ptch2, Smo and Gli1 proteins in BCCs with and without the influence of UVB radiation. METHODS: In total, 34 healthy controls (HCs) and 42 patients with nodular BCC were recruited into the study...
February 9, 2018: Clinical and Experimental Dermatology
https://www.readbyqxmd.com/read/29423837/analysis-of-hedgehog-signaling-in-periocular-sebaceous-carcinoma
#5
John C Bladen, Mariya Moosajee, Dhani Tracey-White, Michèle Beaconsfield, Edel A O'Toole, Michael P Philpott
PURPOSE: Sebaceous carcinoma (SC) is a clinical masquerader of benign conditions resulting in significant eye morbidity, sometimes leading to extensive surgical treatment including exenteration, and even mortality. Little is known about the genetic or molecular basis of SC. This study identifies the involvement of Hedgehog (Hh) signaling in periocular SC. METHODS: Fifteen patients with periocular SC patients were compared to 15 patients with eyelid nodular basal cell carcinoma (nBCC; a known Hh tumor), alongside four normal individuals as a control for physiological Hh expression...
February 8, 2018: Graefe's Archive for Clinical and Experimental Ophthalmology
https://www.readbyqxmd.com/read/29423016/exendin-4-promotes-the-osteogenic-differentiation-of-osteoblasts-via-the-hedgehog-gli1-signaling-pathway
#6
Liu Gao, Shilun Li, Yukun Li
This study aimed to investigate the effect and mechanisms of Exendin-4 mediated-Hedgehog/Gli1 signaling pathway on the differentiation of osteoblasts in mouse. The alkaline phosphate activity, alizarin red staining and expression of Gli1, GLP-1R, Hedgehog, Runx2 and osteocalcin were analyzed using PCR and Western blot analysis after treating the osteoblastic cell line MC3T3-E1 with Exendin-4. Osteoblasts were treated with Gli1-siRNA and Hedgehog receptor antagonist Cyclopamine (Cy) and analyzed for their impact on the Hedgehog/Gli1 signaling pathway...
2018: American Journal of Translational Research
https://www.readbyqxmd.com/read/29416661/gli-is-activated-and-promotes-epithelial-mesenchymal-transition-in-human-esophageal-adenocarcinoma
#7
Lei Wang, Joy Q Jin, Yong Zhou, Ziqiang Tian, David M Jablons, Biao He
Esophageal adenocarcinoma (EAC) accounts for the most esophageal cancer cases in the US, and is notoriously aggressive. This study examines the role of Sonic Hedgehog (SHh)/Gli signaling in the regulation of epithelial-mesenchymal transition (EMT), a process tied to invasion and metastasis, in EAC. Gli/EMT protein expression levels were examined by western blot in paired EAC patient tissues (n = 24) and cell lines (OE19, OE33). Functional analyses were performed (siRNA, treatment with Gli-inhibitor, AKT-inhibitor, and N-Shh recombinant proteins) to investigate SHh/Gli signaling and EMT, cell cycle, and prognostic markers in EAC cell lines...
January 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29400712/noncanonical-hedgehog-pathway-activation-through-srf-mkl1-promotes-drug-resistance-in-basal-cell-carcinomas
#8
Ramon J Whitson, Alex Lee, Nicole M Urman, Amar Mirza, Catherine Y Yao, Alexander S Brown, Jiang R Li, Gautam Shankar, Micah A Fry, Scott X Atwood, Eunice Y Lee, S Tyler Hollmig, Sumaira Z Aasi, Kavita Y Sarin, Matthew P Scott, Ervin H Epstein, Jean Y Tang, Anthony E Oro
Hedgehog pathway-dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to identify a noncanonical hedgehog activation pathway driven by the transcription factor serum response factor (SRF). Active SRF along with its coactivator megakaryoblastic leukemia 1 (MKL1) binds DNA near hedgehog target genes and forms a previously unknown protein complex with the hedgehog transcription factor glioma-associated oncogene family zinc finger-1 (GLI1), causing amplification of GLI1 transcriptional activity...
February 5, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29396625/tsc1-and-tsc2-regulate-cilia-length-and-canonical-hedgehog-signaling-via-different-mechanisms
#9
Thomas Rosengren, Lasse Jonsgaard Larsen, Lotte Bang Pedersen, Søren Tvorup Christensen, Lisbeth Birk Møller
Primary cilia are sensory organelles that coordinate multiple cellular signaling pathways, including Hedgehog (HH), Wingless/Int (WNT) and Transforming Growth Factor-β (TGF-β) signaling. Similarly, primary cilia have been implicated in regulation of mTOR signaling, in which Tuberous Sclerosis Complex proteins 1 and 2 (TSC1/2) negatively regulate protein synthesis by inactivating the mTOR complex 1 (mTORC1) at energy limiting states. Here we report that TSC1 and TSC2 regulate Smoothened (SMO)-dependent HH signaling in mouse embryonic fibroblasts (MEFs)...
February 2, 2018: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29396391/targeted-inhibition-of-hedgehog-gli-signaling-by-novel-acylguanidine-derivatives-inhibits-melanoma-cell-growth-by-inducing-replication-stress-and-mitotic-catastrophe
#10
Silvia Pietrobono, Roberta Santini, Sinforosa Gagliardi, Francesca Dapporto, David Colecchia, Mario Chiariello, Cosima Leone, Massimo Valoti, Fabrizio Manetti, Elena Petricci, Maurizio Taddei, Barbara Stecca
Aberrant activation of the Hedgehog (HH) signaling is a critical driver in tumorigenesis. The Smoothened (SMO) receptor is one of the major upstream transducers of the HH pathway and a target for the development of anticancer agents. The SMO inhibitor Vismodegib (GDC-0449/Erivedge) has been approved for treatment of basal cell carcinoma. However, the emergence of resistance during Vismodegib treatment and the occurrence of numerous side effects limit its use. Our group has recently discovered and developed novel and potent SMO inhibitors based on acylguanidine or acylthiourea scaffolds...
February 2, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29393402/interplay-between-the-nf%C3%A2-%C3%AE%C2%BAb-and-hedgehog-signaling-pathways-predicts-prognosis-in-esophageal-squamous-cell-carcinoma-following-neoadjuvant-chemoradiotherapy
#11
Lingyun Wei, Nang Yan, Lei Sun, Chuanen Bao, Demin Li
Tumor recurrence and metastasis in esophageal squamous cell carcinoma (ESCC) are primary causes of patient mortality. The nuclear factor (NF)‑κB signaling pathway and hedgehog signaling pathway were previously reported to contribute to cell growth and metastasis in ESCC. The present study therefore investigated the roles of the NF‑κB and hedgehog pathways in ESCC tumors following neoadjuvant chemoradiotherapy (NCRT). By immunohistochemistry staining, it was observed that NF‑κB and glioma‑associated oncogene homolog 1 (Gli1), key components of the NF‑κB and hedgehog pathways, respectively, were decreased following NCRT, which was further confirmed by western blotting and reverse transcription‑quantitative polymerase chain reaction analysis...
February 1, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29343518/fibroblast-specific-%C3%AE-catenin-signaling-dictates-the-outcome-of-aki
#12
Dong Zhou, Haiyan Fu, Liangxiang Xiao, Hongyan Mo, Hui Zhuo, Xiaojun Tian, Lin Lin, Jianhua Xing, Youhua Liu
AKI is a devastating condition with high morbidity and mortality. The pathologic features of AKI are characterized by tubular injury, inflammation, and vascular impairment. Whether fibroblasts in the renal interstitium have a role in the pathogenesis of AKI is unknown. In this study, we investigated the role of fibroblast-specific β -catenin signaling in dictating the outcome of AKI, using conditional knockout mice in which β -catenin was specifically ablated in fibroblasts (Gli1- β -cat-/-). After ischemia-reperfusion injury (IRI), Gli1- β -cat-/- mice had lower serum creatinine levels and less morphologic injury than Gli1- β -cat+/+ littermate controls...
January 17, 2018: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/29342244/gli2-rescues-delays-in-brain-development-induced-by-kif3a-dysfunction
#13
Jia-Long Chen, Chia-Hsiang Chang, Jin-Wu Tsai
The primary cilium in neural stem cells plays distinct roles in different stages during cortical development. Ciliary dysfunctions in human (i.e., ciliopathy) cause developmental defects in multiple organs, including brain developmental delays, which lead to intellectual disabilities and cognitive deficits. However, effective treatment to this devastating developmental disorder is still lacking. Here, we first investigated the effects of ciliopathy on neural stem cells by knocking down Kif3a, a kinesin II motor required for ciliogenesis, in the neurogenic stage of cortical development by in utero electroporation of mouse embryos...
January 12, 2018: Cerebral Cortex
https://www.readbyqxmd.com/read/29339090/patched-1-expression-correlates-with-biochemical-relapse-in-high-risk-prostate-cancer-patients
#14
Annelies Gonnissen, Sofie Isebaert, Christiaan Perneel, Chad M McKee, Filip Van Utterbeeck, Evelyne Lerut, Clare Verrill, Richard J Bryant, Steven Joniau, Ruth J Muschel, Karin Haustermans
There is an unmet clinical need for adequate biomarkers to aid risk stratification and management of prostate cancer (PCa) patients. Even within the high-risk PCa category not all patients will invariably have a poor prognosis, and improved stratification of this heterogeneous group is needed. In this context, components of the hedgehog (Hh) pathway may have promise as biomarkers, as the available evidence suggests increased Hh pathway activity may confer a poorer outcome in advanced and castrate-resistant PCa...
January 12, 2018: American Journal of Pathology
https://www.readbyqxmd.com/read/29338454/chemical-computational-and-functional-insights-into-the-chemical-stability-of-the-hedgehog-pathway-inhibitor-gant61
#15
Andrea Calcaterra, Valentina Iovine, Bruno Botta, Deborah Quaglio, Ilaria D'Acquarica, Alessia Ciogli, Antonia Iazzetti, Romina Alfonsi, Ludovica Lospinoso Severini, Paola Infante, Lucia Di Marcotullio, Mattia Mori, Francesca Ghirga
This work aims at elucidating the mechanism and kinetics of hydrolysis of GANT61, the first and most-widely used inhibitor of the Hedgehog (Hh) signalling pathway that targets Glioma-associated oncogene homologue (Gli) proteins, and at confirming the chemical nature of its bioactive form. GANT61 is poorly stable under physiological conditions and rapidly hydrolyses into an aldehyde species (GANT61-A), which is devoid of the biological activity against Hh signalling, and a diamine derivative (GANT61-D), which has shown inhibition of Gli-mediated transcription...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/29337143/the-role-of-hedgehog-responsive-fibroblasts-in-facial-nerve-regeneration
#16
Gabriela L Bobarnac Dogaru, Subhash C Juneja, Alireza Shokrani, Roseanne Y Hui, Yang Chai, Jon-Paul Pepper
BACKGROUND: Facial nerve paralysis is a significant cause of morbidity, affecting facial appearance, emotional expression, speech, oral competence, and vision. A more complete understanding of the complex cellular events required for successful nerve regeneration may reveal new therapeutic targets. The role of fibroblasts in regeneration, and the process by which the nerve reforms its three-dimensional structure after a transection injury, are not fully understood. The Hedgehog signaling pathway has been shown to mediate nerve sheath formation during development...
January 11, 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29329585/involvement-of-hedgehog-pathway-in-early-onset-aggressive-molecular-subtypes-and-metastatic-potential-of-breast-cancer
#17
Syeda Kiran Riaz, Jahangir Sarwar Khan, Syed Tahir Abbas Shah, Fen Wang, Lin Ye, Wen G Jiang, Muhammad Faraz Arshad Malik
BACKGROUND: Dysregulation of hedgehog pathway is observed in numerous cancers. Relevance of hedgehog pathway genes in cancer cohort and inhibition of its downstream effector (GLI1) towards metastasis in cell lines are explored in the study. METHOD: One hundred fifty fresh tumours of breast cancer patients were collected for the study. Based on differential expression, panel of 6 key regulators of the pathway (SHH, DHH, IHH, PTCH1, SMO and GLI1) in microarray datasets were identified...
January 8, 2018: Cell Communication and Signaling: CCS
https://www.readbyqxmd.com/read/29328464/inhibition-of-gli-leads-to-antitumor-growth-and-enhancement-of-cisplatin-induced-cytotoxicity-in-large-cell-neuroendocrine-carcinoma-of-the-lung
#18
Tsukasa Ishiwata, Shunichiro Iwasawa, Takahiro Ebata, Mengmeng Fan, Yuji Tada, Koichiro Tatsumi, Yuichi Takiguchi
Large cell neuroendocrine carcinoma (LCNEC) of the lung is a highly aggressive tumor without established standard treatment. The Hedgehog (Hh) signal, which is critical in embryogenesis, is known to play important roles in maintaining a malignant phenotype in various cancers. The present study explored the possibility of targeting the Hh signal in the treatment of LCNEC by suppressing Hh downstream molecules, Smoothened (Smo) and GLI family zinc finger 1/2 (Gli1/2), in 3 human LCNEC cell lines. Smo inhibitor, BMS-833923, and Gli inhibitor, GANT61, downregulated Gli1 and 2, resulting in the suppression of the cell viability of the 3 cell lines as assessed using an MTT assay...
January 3, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29321573/correlation-of-gli1-and-her2-expression-in-gastric-cancer-identification-of-novel-target
#19
Xinyu Shao, Xiaoyi Kuai, Zhi Pang, Liping Zhang, Longyun Wu, Lijuan Xu, Chunli Zhou
HER2 becomes the standard of care for guiding adjuvant treatment of gastric cancer with trastuzumab in recent years. However, the usage of this target agent is still limited because of the resistance to trastuzumab or the negative expression of HER2 in tumor tissues. The Gli1 and HER2 both play an important role in the pathogenesis of gastric cancer. However, the correlation of them is still unclear. Here we found Gli1 and HER2 are highly expressed in gastric cancer tissues, and they are positively related...
January 10, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29316328/anti-fibrotic-effects-of-pirfenidone-by-interference-with-the-hedgehog-signalling-pathway-in-patients-with-systemic-sclerosis-associated-interstitial-lung-disease
#20
Hua Xiao, Guang-Feng Zhang, Xiang-Ping Liao, Xiao-Jie Li, Jian Zhang, Haobo Lin, Zhe Chen, Xiao Zhang
AIM: To determine whether pirfenidone attenuates lung fibrosis by interfering with the hedgehog (Hh) signalling pathway in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). METHODS: Twenty-five SSc-ILD patients (20 first visit, five who underwent pirfenidone treatment for 6 months) and 10 healthy controls were recruited. Lung tissues were obtained by open-chest surgery, and primary lung fibroblasts were isolated, cultured and stimulated with pirfenidone...
January 7, 2018: International Journal of Rheumatic Diseases
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