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https://www.readbyqxmd.com/read/28098170/targeting-the-pi3k-akt-pathway-via-gli1-inhibition-enhanced-the-drug-sensitivity-of-acute-myeloid-leukemia-cells
#1
Hui Liang, Qi-Li Zheng, Peng Fang, Jian Zhang, Tuo Zhang, Wei Liu, Min Guo, Christopher L Robinson, Shui-Bing Chen, Xiao-Ping Chen, Fang-Ping Chen, Hui Zeng
Combination targeted therapy is commonly used to treat acute myeloid leukemia (AML) patients, particularly in refractory/relapse (RR) population. However, concerns have been raised regarding the safety and patient tolerance of combination chemotherapy. It is critical to choose the appropriate treatment for precision therapy. We performed genome-wide RNA profiling using RNA-Seq to compare the RR group and the complete remission (CR) group (a total of 42 adult AML patients). The Hedgehog (Hh) and PI3K/AKT pathways were upregulated in the RR population, which was further confirmed by western blot and/or qPCR...
January 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28069799/ikbke-is-required-during-kras-induced-pancreatic-tumorigenesis
#2
Mihir Rajurkar, Kyvan Dang, Maite G Fernandez-Barrena, Xiangfan Liu, Martin E Fernandez-Zapico, Brian C Lewis, Junhao Mao
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies lacking effective therapeutic strategies. Here, we show that the noncanonical IκB-related kinase, IKBKE, is a critical oncogenic effector during KRAS-induced pancreatic transformation. Loss of IKBKE inhibits the initiation and progression of pancreatic tumors in mice carrying pancreatic-specific KRAS activation. Mechanistically, we demonstrate that this protumoral effect of IKBKE involves the activation of GLI1 and AKT signaling and is independent of the levels of activity of the NF-κB pathway...
January 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28052321/canonical-hedgehog-signaling-regulates-hepatic-stellate-cell-mediated-angiogenesis-in-liver-fibrosis
#3
Feng Zhang, Meng Hao, Huanhuan Jin, Zhen Yao, Naqi Lian, Li Wu, Jiangjuan Shao, Anping Chen, Shizhong Zheng
BACKGROUND AND PURPOSE: Hepatic stellate cells (HSCs) are liver-specific pericytes regulating angiogenesis during liver fibrosis. We aimed to elucidate the mechanisms by which hedgehog signaling regulated HSC angiogenic properties and to validate the therapeutic implications. EXPERIMENTAL APPROACH: Rats and mice were intoxicated with carbon tetrachloride for in vivo evaluation of hepatic angiogenesis and fibrotic injury. Diversified molecular approaches including real-time PCR, Western blot, luciferase reporter assay, chromatin immunoprecipitation, electrophoretic mobility shift assay, and co-immunoprecipitation were used to investigate the underlying mechanisms in vitro...
January 4, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28035348/nek2a-sufu-feedback-loop-regulates-gli-mediated-hedgehog-signaling-pathway
#4
Fen Zhou, Dengliang Huang, Yong Li, Guanghui Hu, Hai Rao, Quqin Lu, Shiwen Luo, Yao Wang
Suppressor of Fused (SuFu), one of the most conserved components of the Hedgehog (Hh) signaling, binds Gli transcription factors and impedes activation of target gene expression in mammalian cells. Despite the central importance of SuFu in the Hh pathway, little is known about SuFu regulation. In a previous study, we identified NIMA-related expressed kinase 2A (Nek2A) as a SuFu-interacting protein. Here, we show that Nek2A stabilizes SuFu through impairing ubiquitin/proteasome degradation of SuFu. In addition, Nek2A negatively regulates target genes of Hh signaling as well as Gli2 transcriptional activity...
February 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28030801/the-embryonic-type-of-spp1-transcriptional-regulation-is-re-activated-in-glioblastoma
#5
Magdalena Kijewska, Marta Kocyk, Michal Kloss, Karolina Stepniak, Zbigniew Korwek, Renata Polakowska, Michal Dabrowski, Anna Gieryng, Bartosz Wojtas, Iwona A Ciechomska, Bozena Kaminska
Osteopontin (SPP1, a secreted phosphoprotein 1) is primarily involved in immune responses, tissue remodelling and biomineralization. However, it is also overexpressed in many cancers and regulates tumour progression by increasing migration, invasion and cancer stem cell self-renewal. Mechanisms of SPP1 overexpression in gliomas are poorly understood. We demonstrate overexpression of two out of five SPP1 isoforms in glioblastoma (GBM) and differential isoform expression in glioma cell lines. Up-regulated SPP1 expression is associated with binding of the GLI1 transcription factor to the promoter and OCT4 (octamer-binding transcription factor 4) to the first SPP1 intron of the SPP1 gene in human glioma cells but not in non-transformed astrocytes...
December 22, 2016: Oncotarget
https://www.readbyqxmd.com/read/28030567/tumor-derived-suppressor-of-fused-mutations-reveal-hedgehog-pathway-interactions
#6
Nicole M Urman, Amar Mirza, Scott X Atwood, Ramon J Whitson, Kavita Y Sarin, Jean Y Tang, Anthony E Oro
The Hedgehog pathway is a potent regulator of cellular growth and plays a central role in the development of many cancers including basal cell carcinoma (BCC). The majority of BCCs arise from mutations in the Patched receptor resulting in constitutive activation of the Hedgehog pathway. Secondary driver mutations promote BCC oncogenesis and occur frequently due to the high mutational burden resulting from sun exposure of the skin. Here, we uncover novel secondary mutations in Suppressor of Fused (SUFU), the major negative regulator of the Hedgehog pathway...
2016: PloS One
https://www.readbyqxmd.com/read/27939373/molecular-classification-of-hepatocellular-adenoma-associates-with-risk-factors-bleeding-and-malignant-transformation
#7
Jean Charles Nault, Gabrielle Couchy, Charles Balabaud, Guillaume Morcrette, Stefano Caruso, Jean-Frederic Blanc, Yannick Bacq, Julien Calderaro, Valérie Paradis, Jeanne Ramos, Jean-Yves Scoazec, Viviane Gnemmi, Nathalie Sturm, Catherine Guettier, Monique Fabre, Eric Savier, Laurence Chiche, Philippe Labrune, Janick Selves, Dominique Wendum, Camilla Pilati, Alexis Laurent, Anne De Muret, Brigitte Le Bail, Sandra Rebouissou, Sandrine Imbeaud, Paulette Bioulac-Sage, Eric Letouzé, Jessica Zucman-Rossi
BACKGROUND & AIMS: Hepatocellular adenomas (HCA) are benign liver tumors that can be assigned to molecular subtypes based on inactivating mutations in HNF1A, activating mutations in β-catenin, or activation of inflammatory signaling pathways. We aimed to update the classification system for HCA and associate the subtypes with disease risk factors and complications. METHODS: We analyzed expression levels of 20 genes and sequenced exon regions of 8 genes (HNF1A, IL6ST, CTNNB1, FRK, STAT3, GNAS, JAK1, and TERT) in 607 samples of 533 HCAs from 411 patients, collected from 28 centers mainly in France from 2000 and 2014...
December 7, 2016: Gastroenterology
https://www.readbyqxmd.com/read/27936185/hedgehog-signaling-overcomes-an-ezh2-dependent-epigenetic-barrier-to-promote-cholangiocyte-expansion
#8
Nidhi Jalan-Sakrikar, Thiago M De Assuncao, Jie Lu, Luciana L Almada, Gwen Lomberk, Martin E Fernandez-Zapico, Raul Urrutia, Robert C Huebert
BACKGROUND & AIMS: Developmental morphogens play an important role in coordinating the ductular reaction and portal fibrosis occurring in the setting of cholangiopathies. However, little is known about how membrane signaling events in ductular reactive cells (DRCs) are transduced into nuclear transcriptional changes to drive cholangiocyte maturation and matrix deposition. Therefore, the aim of this study was to investigate potential mechanistic links between cell signaling events and epigenetic regulators in DRCs...
2016: PloS One
https://www.readbyqxmd.com/read/27905054/crosstalk-between-shh-and-stemness-state-signaling-pathways-in-esophageal-squamous-cell-carcinoma
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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...
January 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/27877222/hedgehog-signaling-non-canonical-activated-by-pro-inflammatory-cytokines-in-pancreatic-ductal-adenocarcinoma
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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