Comprehensive analysis of β-catenin target genes in colorectal carcinoma cell lines with deregulated Wnt/β-catenin signaling
Andreas Herbst,Vindi Jurinovic,Stefan Krebs,Susanne E. Thieme,Helmut Blum,Burkhard Göke,Frank T. Kolligs +6 more
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TLDR
DLD1 and SW480 colon carcinoma cell lines are suitable model systems to study Wnt/β- catenin signaling and associated colorectal carcinogenesis and the confirmed and the newly identified potential β-catenin target genes are useful starting points for further studies.Abstract:
Deregulation of Wnt/β-catenin signaling is a hallmark of the majority of sporadic forms of colorectal cancer and results in increased stability of the protein β-catenin. β-catenin is then shuttled into the nucleus where it activates the transcription of its target genes, including the proto-oncogenes MYC and CCND1 as well as the genes encoding the basic helix-loop-helix (bHLH) proteins ASCL2 and ITF-2B. To identify genes commonly regulated by β-catenin in colorectal cancer cell lines, we analyzed β-catenin target gene expression in two non-isogenic cell lines, DLD1 and SW480, using DNA microarrays and compared these genes to β-catenin target genes published in the PubMed database and DNA microarray data presented in the Gene Expression Omnibus (GEO) database. Treatment of DLD1 and SW480 cells with β-catenin siRNA resulted in differential expression of 1501 and 2389 genes, respectively. 335 of these genes were regulated in the same direction in both cell lines. Comparison of these data with published β-catenin target genes for the colon carcinoma cell line LS174T revealed 193 genes that are regulated similarly in all three cell lines. The overlapping gene set includes confirmed β-catenin target genes like AXIN2, MYC, and ASCL2. We also identified 11 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that are regulated similarly in DLD1 and SW480 cells and one pathway – the steroid biosynthesis pathway – was regulated in all three cell lines. Based on the large number of potential β-catenin target genes found to be similarly regulated in DLD1, SW480 and LS174T cells as well as the large overlap with confirmed β-catenin target genes, we conclude that DLD1 and SW480 colon carcinoma cell lines are suitable model systems to study Wnt/β-catenin signaling and associated colorectal carcinogenesis. Furthermore, the confirmed and the newly identified potential β-catenin target genes are useful starting points for further studies.read more
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Genetic Mechanisms of Immune Evasion in Colorectal Cancer
Catherine S. Grasso,Marios Giannakis,Marios Giannakis,Daniel K. Wells,Tsuyoshi Hamada,Xinmeng Jasmine Mu,Xinmeng Jasmine Mu,Michael J. Quist,Michael J. Quist,Jonathan A. Nowak,Reiko Nishihara,Zhi Rong Qian,Kentaro Inamura,Teppei Morikawa,Katsuhiko Nosho,Gabriel Abril-Rodriguez,Charles M. Connolly,Helena Escuin-Ordinas,Milan S. Geybels,William M. Grady,William M. Grady,Li Hsu,Siwen Hu-Lieskovan,Jeroen R. Huyghe,Yeon Joo Kim,Paige Krystofinski,Mark D.M. Leiserson,Dennis Montoya,Brian B. Nadel,Matteo Pellegrini,Colin C. Pritchard,Cristina Puig-Saus,Elleanor H. Quist,Benjamin J. Raphael,Stephen J. Salipante,Daniel Sanghoon Shin,Eve Shinbrot,Brian H. Shirts,Sachet A. Shukla,Sachet A. Shukla,Sachet A. Shukla,Janet L. Stanford,Janet L. Stanford,Wei Sun,Jennifer Tsoi,Alexander Upfill-Brown,David A. Wheeler,Catherine J. Wu,Catherine J. Wu,Ming Yu,Syed H.E. Zaidi,Jesse M. Zaretsky,Stacey Gabriel,Eric S. Lander,Levi A. Garraway,Levi A. Garraway,Thomas J. Hudson,Thomas J. Hudson,Charles S. Fuchs,Antoni Ribas,Shuji Ogino,Ulrike Peters,Ulrike Peters +62 more
TL;DR: This large-scale genomic analysis of colorectal cancer demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration and, furthermore, that coloreCTal cancer tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion.
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lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/β-catenin signaling
Yuanyuan Lu,Xiaodi Zhao,Xiaodi Zhao,Qi Liu,Cunxi Li,Ramona Graves-Deal,Zheng Cao,Bhuminder Singh,Jeffrey L. Franklin,Jing Wang,Huaying Hu,Tian-Ying Wei,Mingli Yang,Timothy J. Yeatman,Ethan Lee,Kenyi Saito-Diaz,Scott Hinger,James G. Patton,Christine H. Chung,Stephan Emmrich,Jan-Henning Klusmann,Daiming Fan,Robert J. Coffey,Robert J. Coffey +23 more
TL;DR: These findings identify a clinically actionable, epigenetic cause of cetuximab resistance, and describe a double-negative feedback loop between MIR100HG and the transcription factor GATA6, whereby Gata6 represses MIR 100HG, but this repression is relieved by miR-125b targeting of GATA 6.
Journal ArticleDOI
Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex.
Youn Sang Jung,Jae Il Park +1 more
TL;DR: The Wnt inhibitors currently being used in clinical trials are discussed and how additional cancer-specific regulators could be utilized to treat Wnt signaling-associated cancer are suggested.
Journal ArticleDOI
WNT Signaling in Cardiac and Vascular Disease
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TL;DR: A general picture is emerging that excessive stimulation of WNT signaling adversely affects cardiovascular pathology, and a rapidly increasing collection of drugs interfering at different levels of W NT signaling will allow the evaluation of therapeutic interventions in the pathway in relevant animal models of cardiovascular diseases and eventually in patients in the near future.
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MIBI-TOF: A multiplexed imaging platform relates cellular phenotypes and tissue structure
Leeat Keren,Marc Bosse,Steve Thompson,Tyler Risom,Kausalia Vijayaragavan,Erin McCaffrey,Diana M. Marquez,Roshan Angoshtari,Noah F. Greenwald,Harris G. Fienberg,Jennifer Y. Wang,Neeraja Kambham,David Kirkwood,Garry P. Nolan,Thomas J. Montine,Stephen J. Galli,Robert B. West,Sean C. Bendall,Michael Angelo +18 more
TL;DR: MIBI-TOF (multiplexed ion beam imaging by time of flight) is described, an instrument that uses bright ion sources and orthogonal time-of-flight mass spectrometry to image metal-tagged antibodies at subcellular resolution in clinical tissue sections to interrogate intrapatient heterogeneity in tumor organization in triple-negative breast cancer.
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TL;DR: The c-MYC oncogene is identified as a target gene in this signaling pathway and shown to be repressed by wild-type APC and activated by beta-catenin, and these effects were mediated through Tcf-4 binding sites in the c- MYC promoter.
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