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https://www.readbyqxmd.com/read/27905054/crosstalk-between-shh-and-stemness-state-signaling-pathways-in-esophageal-squamous-cell-carcinoma
#1
Maryam Najafi, Mohammad Reza Abbaszadegan, Abolfazl Rad, Mahtab Dastpak, Samaneh Boroumand-Noughabi, Mohammad Mahdi Forghanifard
The expression of GLI1 as a downstream gene of sonic hedgehog (Hh) pathway, studied in a variety of cancers including esophageal squamous cell carcinoma (ESCC). However, the interaction of Hh with other developmental pathways needs to be elucidated. In this study, we aimed to investigate the correlation of GLI1 expression with transcription factors (TFs) of stem cell signaling pathways, and their association with clinico-pathological data of ESCC. Using real-time PCR, we assessed the expression of GLI1 mRNA in 49 ESCC patients, and analyzed the correlation between GLI1 and selected TFs...
November 30, 2016: Journal of Cell Communication and Signaling
https://www.readbyqxmd.com/read/27903983/dyrk1b-blocks-canonical-and-promotes-non-canonical-hedgehog-signaling-through-activation-of-the-mtor-akt-pathway
#2
Rajeev Singh, Pavan Kumar Dhanyamraju, Matthias Lauth
Hedgehog (Hh) signaling plays important roles in embryonic development and in tumor formation. Apart from the well-established stimulation of the GLI family of transcription factors, Hh ligands promote the phosphorylation and activation of mTOR and AKT kinases, yet the molecular mechanism underlying these processes are unknown. Here, we identify the DYRK1B kinase as a mediator between Hh signaling and mTOR/AKT activation. In fibroblasts, Hh signaling induces DYRK1B protein expression, resulting in activation of the mTOR/AKT kinase signaling arm...
November 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27894350/gant61-a-gli-inhibitor-sensitizes-glioma-cells-to-the-temozolomide-treatment
#3
Jianlong Li, Jinquan Cai, Shihong Zhao, Kun Yao, Ying Sun, Yongli Li, Lingchao Chen, Ruiyan Li, Xiuwei Zhai, Junhe Zhang, Chuanlu Jiang
BACKGROUND: The aim of this study was to investigate the effect of downregulating Hedgehog pathway by GANT61 on human glioma cells, examine the consequent changes of temozolomide (TMZ)-induced effects and explore the molecular mechanisms. METHODS: The cytotoxicity of a Gli1/2 inhibitor, GANT61 was examined both alone and in combination with TMZ in human glioma cell lines. The mRNA and protein expression alterations were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot, respectively...
November 28, 2016: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/27894099/peroxiredoxin-2-is-essential-for-maintaining-cancer-stem-cell-like-phenotype-through-activation-of-hedgehog-signaling-pathway-in-colon-cancer
#4
Rong Wang, Jinlai Wei, Shouru Zhang, Xingye Wu, Jinbao Guo, Maoxi Liu, Kunli Du, Jun Xu, Linglong Peng, Zhenbing Lv, Wenxian You, Yongfu Xiong, Zhongxue Fu
Cancer stem cells (CSCs) are a key target for reducing tumor growth, metastasis, and recurrence. Redox status is a critical factor in the maintenance of CSCs, and the antioxidant enzyme Peroxiredoxin 2 (Prdx2) plays an important role in the development of colon cancer. Therefore, we investigated the contribution of Prdx2 to the maintenance of stemness of colon CSCs. Here, we used short-hairpin RNAs and a Prdx2-overexpression vector to determine the effects of Prdx2. We demonstrated that knockdown of Prdx2 reduced the self-renewal and sphere formation and resulted in increased 5-FU-induced apoptosis in human colon CSCs...
November 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/27887870/involvement-of-indian-hedgehog-signaling-in-mesenchymal-stem-cell-augmented-rotator-cuff-tendon-repair-in-an-athymic-rat-model
#5
Jian-Chun Zong, Michael J Mosca, Ryan M Degen, Amir Lebaschi, Camila Carballo, Andrew Carbone, Guang-Ting Cong, Liang Ying, Xiang-Hua Deng, Scott A Rodeo
BACKGROUND: Bone marrow aspirate has been used in recent years to augment tendon-to-bone healing, including in rotator cuff repair. However, the healing mechanism in cell-based therapy has not been elucidated in detail. METHODS: Sixteen athymic nude rats were randomly allocated to 2 groups: experimental (human mesenchymal stem cells in fibrin glue carrier) and control (fibrin glue only). Animals were sacrificed at 2 and 4 weeks. Immunohistochemical staining was performed to evaluate Indian hedgehog (Ihh) signaling and SOX9 signaling in the healing enthesis...
November 22, 2016: Journal of Shoulder and Elbow Surgery
https://www.readbyqxmd.com/read/27878234/prometastatic-mechanisms-of-caf-mediated-emt-regulation-in-pancreatic-cancer-cells
#6
Tao Shan, Shuo Chen, Xi Chen, Wan Run Lin, Wei Li, Jiancang Ma, Tao Wu, Hong Ji, Yiming Li, Xijuan Cui, Ya'an Kang
Tumor metastasis are accompanied by the EMT (epithelial-mesenchymal transition)-MET (mesenchymal-epithelial transition) two-step process. In this study, we investigated the importance of cancer associated fibroblasts (CAF) in the process. First, the primary cultures of isolated pancreatic CAF, fibroblasts of normal pancreatic tissues (NF), and normal hepatic stellate cells (HSF) were identified and verified via the expression of α-SMA and vimentin. Using an indirect three-dimensional co-culture model, the morphological changes were observed by light microscopy and laser scanning confocal microscopy...
November 23, 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/27877222/hedgehog-signaling-non-canonical-activated-by-pro-inflammatory-cytokines-in-pancreatic-ductal-adenocarcinoma
#7
Yuqiong Wang, Gang Jin, Quanjiang Li, Zhiping Wang, Weimin Hu, Ping Li, Shude Li, Hongyu Wu, Xiangyu Kong, Jun Gao, Zhaoshen Li
Hedgehog(HH) pathway is found to be activated through a manner of canonical, or the non-canonical HH pathways. Distinct hyperplasia stroma around tumor cells is supposed to express pro-inflammatory cytokines abundantly, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), etc. in pancreatic ductal adenocarcinoma (PDAC) tissues. In this study we observed the effects of TNF-α and IL-1β on HH pathway activation in PDAC cells, and explored their activation manners. Our results showed that pro-inflammatory cytokines, TNF-α and IL-1β, could up-regulate the expression of GLI1 gene, increase its nuclear protein expression and promote malignant cell behaviors including migration, invasion, epithelial-mesenchymal transition (EMT) and drug resistance as well...
2016: Journal of Cancer
https://www.readbyqxmd.com/read/27863397/targeting-gli-by-gant61-involves-mechanisms-dependent-on-inhibition-of-both-transcription-and-dna-licensing
#8
Ruowen Zhang, Jiahui Wu, Sylvain Ferrandon, Katie J Glowacki, Janet A Houghton
The GLI genes are transcription factors and in cancers are oncogenes, aberrantly and constitutively activated. GANT61, a specific GLI inhibitor, has induced extensive cytotoxicity in human models of colon cancer. The FOXM1 promoter was determined to be a transcriptional target of GLI1. In HT29 cells, inhibition of GLI1 binding at the GLI consensus sequence by GANT61 led to inhibited binding of Pol II, the pause-release factors DSIF, NELF and p-TEFb. The formation of R-loops (RNA:DNA hybrids, ssDNA), were reduced by GANT61 at the FOXM1 promoter...
November 15, 2016: Oncotarget
https://www.readbyqxmd.com/read/27863385/gli1-promotes-colorectal-cancer-metastasis-in-a-foxm1-dependent-manner-by-activating-emt-and-pi3k-akt-signaling
#9
Chuan Zhang, Yong Wang, YiFei Feng, Yue Zhang, Bing Ji, Sen Wang, Ye Sun, Chunyan Zhu, Dongsheng Zhang, Yueming Sun
Colorectal cancer(CRC) is one of the most commonly diagnosed cancers in human beings and metastasis is the main death reason. Recently, Gli1 has been reported to be a key regulator of various cancer biologies and genes expressions. However, the detailed molecular mechanism of Gli1 in CRC metastasis remains largely unknown. In this study, we aimed to investigate the role of Gli1 in CRC metastasis. We used qRT-PCR, Immunohistochemistry and Western blot to test the expression levels of Gli1, Foxm1 and other target genes in the tissues and cells; Lentivirus stable transfection to change the expression levels of Gli1 and Foxm1; Wound-healing, cell invasion, migration assays and tail vein metastatic assay to test the role of Gli1 in CRC metastasis in vitro and vivo...
November 15, 2016: Oncotarget
https://www.readbyqxmd.com/read/27862693/gli1-a-master-regulator-of-the-hallmark-of-pancreatic-cancer
#10
REVIEW
Kenji Kasai
Hedgehog signaling is highly conserved across species and governs proper embryonic development. Germline gene mutations that reduce this signaling activity cause a variety of developmental abnormalities such as holoprosencephaly, while those that enhance Hedgehog signaling activity induce a tumor-predisposition condition Nevoid basal cell carcinoma syndrome. Furthermore, dysregulated activation of Hedgehog signaling has been recognized in various sporadic malignancies, including pancreatic adenocarcinoma. Pancreatic adenocarcinoma develops through a multistep carcinogenesis starting with oncogenic mutation of the KRAS gene...
December 2016: Pathology International
https://www.readbyqxmd.com/read/27853247/six2crefrs2%C3%AE-knockout-mice-are-a-novel-model-of-renal-cystogenesis
#11
Pawan Puri, Daniel Bushnell, Caitlin M Schaefer, Carlton M Bates
Six2cre-mediated deletion of Frs2α (Six2creFrs2αKO), a major fibroblast growth factor receptor (Fgfr) docking protein in mouse nephron progenitors results in perinatal renal hypoplasia; however, postnatal Six2creFrs2αKO kidneys develop cysts. We sought to determine the pathogenesis of Six2creFrs2αKO cyst formation. We performed histological assays, Western blots, and quantitative PCR (qPCR). While embryonic day (E) 18.5 Six2Frs2αKO kidneys were hypoplastic and not cystic, postnatal day (P) 7 mutants had proximal tubular-derived cysts that nearly replaced the renal parenchyma by P21...
November 17, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27849569/suppressor-of-fused-chaperones-gli-proteins-to-generate-transcriptional-responses-to-sonic-hedgehog-signaling
#12
Ziyu Zhang, Longyan Shen, Kelvin Law, Zengdi Zhang, Xiaotong Liu, Hu Hua, Sanen Li, Huijie Huang, Shen Yue, Chi-Chung Hui, Steven Y Cheng
Cellular responses to the graded Sonic hedgehog (Shh) morphogenic signal are orchestrated by three Gli genes that give rise to both transcription activators and repressors. An essential downstream regulator of the pathway, encoded by the tumor suppressor gene Suppressor of fused (Sufu), plays critical roles in the production, trafficking and function of Gli proteins, but the mechanism remains controversial. Here, we show that Sufu is up-regulated in active Shh responding tissues and accompanies Gli activators translocating into and Gli repressors out of the nucleus...
November 14, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27836001/galectin-1-from-cancer-associated-fibroblasts-induces-epithelial-mesenchymal-transition-through-%C3%AE-1-integrin-mediated-upregulation-of-gli1-in-gastric-cancer
#13
Yang Chong, Dong Tang, Qingquan Xiong, Xuetong Jiang, Chuanqi Xu, Yuqin Huang, Jie Wang, Huaicheng Zhou, Youquan Shi, Xiaoqing Wu, Daorong Wang
BACKGROUND: Gastric cancer (GC) is characterized by the excessive deposition of extracellular matrix, which is thought to contribute to this tumor's malignant behavior. Epithelial-mesenchymal transition (EMT) is regarded as a crucial contributing factor to cancer progression. Galectin-1 (Gal-1), a β-galactoside-binding protein abundantly expressed in activated cancer-associated fibroblasts (CAFs), has been reported to be involved in GC progression and metastasis by binding to β1 integrin, which, in turn, can bind to matrix proteins and activate intracellular cascades that mediate EMT...
November 11, 2016: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/27826729/pharmacodynamic-study-of-the-oral-hedgehog-pathway-inhibitor-vismodegib-in-patients-with-metastatic-castration-resistant-prostate-cancer
#14
Benjamin L Maughan, Daniel L Suzman, Brandon Luber, Hao Wang, Stephanie Glavaris, Robert Hughes, Rana Sullivan, Rana Harb, Karim Boudadi, Channing Paller, Mario Eisenberger, Angelo Demarzo, Ashely Ross, Emmanuel S Antonarakis
PURPOSE: Hedgehog (Hh) pathway signaling has been implicated in prostate cancer tumorigenesis and metastatic development and may be upregulated even further in the castration-resistant state. We hypothesized that antagonism of the Hh pathway with vismodegib in men with metastatic castration-resistant prostate cancer (mCRPC) would result in pathway engagement, inhibition and perhaps induce measurable clinical responses in patients. METHODS: This is a single-arm study of oral daily vismodegib in men with mCRPC...
November 8, 2016: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/27825128/activation-of-the-basal-cell-carcinoma-pathway-in-a-patient-with-cns-hgnet-bcor-diagnosis-consequences-for-personalized-targeted-therapy
#15
Claudia Paret, Johanna Theruvath, Alexandra Russo, Bettina Kron, Khalifa El Malki, Nadine Lehmann, Arthur Wingerter, Marie A Neu, Aslihan Gerhold-Ay, Wolfgang Wagner, Clemens Sommer, Torsten Pietsch, Larissa Seidmann, Jörg Faber
High grade neuroepithelial tumor of the central nervous system with BCOR alteration (CNS HGNET-BCOR) is a recently described new tumor entity with a dismal prognosis. The objective of this study was to identify and validate pathways deregulated in CNS HGNET-BCOR as basis for targeted therapy approaches.We characterized the BCOR alteration in a pediatric patient with CNS HGNET-BCOR diagnosis by Sanger sequencing and demonstrated an elevated BCOR expression by qRT-PCR and western blot. By whole transcriptome sequencing and Ingenuity Pathway Analysis, we identified the activation of the Sonic Hedgehog (SHH) and of the WNT signaling pathway in two different regions of the primary tumor and of one inoculation metastasis compared to normal brain...
November 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27819521/microrna-326-sensitizes-human-glioblastoma-cells-to-curcumin-via-the-shh-gli1-signaling-pathway
#16
Shi Yin, Wenzhong Du, Feng Wang, Bo Han, Yuqiong Cui, Dongbo Yang, Hui Chen, Daming Liu, Xing Liu, Chuanlu Jiang
Glioblastoma multiforme is the most malignant and common brain tumor in adults and is characterized by poor survival and high resistance to chemotherapy and radiotherapy. Among the new chemotherapy drugs, curcumin, a popular dietary supplement, has proven to have a potent anticancer effect on a variety of cancer cell types; however, it remains difficult to achieve a satisfactory therapeutic effect with curcumin using the traditional single-drug treatment. In this study, we found that expression of miR-326, a tumor suppressor microRNA in various tumor types, resulted in a marked increase of curcumin-induced cytotoxicity and apoptosis and a decrease of proliferation and migration in glioma cells...
November 7, 2016: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/27814475/a-gli-1-ttering-role-for-perivascular-stem-cells-in-blood-vessel-remodeling
#17
Andrew H Baker, Bruno Péault
Blood vessels significantly remodel in response to injury and pathologic conditions, although the contribution of stem cells to this process is unclear. Now in Cell Stem Cell, Kramann et al. (2016) show that Gli1+ perivascular cells in the outermost vessel layer are progenitors that substantially contribute to pathologic vessel remodeling.
November 3, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/27810405/anti-proliferation-of-breast-cancer-cells-with-itraconazole-hedgehog-pathway-inhibition-induces-apoptosis-and-autophagic-cell-death
#18
Xiaoya Wang, Sanhua Wei, Yong Zhao, Changhong Shi, Peijuan Liu, Caiqin Zhang, Yingfeng Lei, Bo Zhang, Bing Bai, Yong Huang, Hai Zhang
Itraconazole is a common antifungal which may have promise for treating various human cancers. We report that itraconazole was cytotoxic to MCF-7 and SKBR-3 breast cancer cell lines via apoptosis by altering mitochondria membrane potential, reducing BCL-2 expression and elevating caspase-3 activity. Itraconazole also induced autophagic cell death via LC3-II expression upregulation, P62/SQSTM1 degradation, autophagosome formation and increases in autophagic puncta. Itraconazole treatment inhibited hedgehog pathway key molecular expression, such as SHH and Gli1, resulting in promotion of apoptosis and autophagy The anti-proliferation effect of itraconazole-induced apoptosis and autophagy via hedgehog pathway inhibition was confirmed with Gli1 inhibitor GANT61 and SHH siRNA, GANT61 and SHH siRNA synergistically enhanced cytotoxicity induced by itraconazole...
October 31, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27801979/preaxial-polydactyly-following-early-gestational-exposure-to-the-smoothened-agonist-sag-in-c57bl-6j-mice
#19
Eric W Fish, Scott E Parnell, Kathleen K Sulik, Lorinda K Baker, Laura B Murdaugh, David Lamson, Kevin P Williams
BACKGROUND: While pharmacological activation of the Hedgehog (HH) signaling pathway may have therapeutic benefits for developmental and adult diseases, its teratogenic potential is of concern. The membrane molecule Smoothened (SMO) transduces HH signaling and can be acutely modulated by antagonists and agonists. The objective of the current experiments was to determine how maternal treatment with the Smo agonist, SAG, affects the developing limb. METHODS: Pregnant C57BL/6J mice received a single injection of SAG (15, 17, or 20 mg/kg, i...
November 1, 2016: Birth Defects Research. Part A, Clinical and Molecular Teratology
https://www.readbyqxmd.com/read/27799542/cilia-have-high-camp-levels-that-are-inhibited-by-sonic-hedgehog-regulated-calcium-dynamics
#20
Bryn S Moore, Ann N Stepanchick, Paul H Tewson, Cassandra M Hartle, Jin Zhang, Anne Marie Quinn, Thomas E Hughes, Tooraj Mirshahi
Protein kinase A (PKA) phosphorylates Gli proteins, acting as a negative regulator of the Hedgehog pathway. PKA was recently detected within the cilium, and PKA activity specifically in cilia regulates Gli processing. Using a cilia-targeted genetically encoded sensor, we found significant basal PKA activity. Using another targeted sensor, we measured basal ciliary cAMP that is fivefold higher than whole-cell cAMP. The elevated basal ciliary cAMP level is a result of adenylyl cyclase 5 and 6 activity that depends on ciliary phosphatidylinositol (3,4,5)-trisphosphate (PIP3), not stimulatory G protein (Gαs), signaling...
October 31, 2016: Proceedings of the National Academy of Sciences of the United States of America
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