Multilayered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/βcatenin signaling activation (Review)
βcatenin/CTNNB1 is an intracellular scaffold protein that interacts with adhesion molecules (Ecadherin/CDH1, Ncadherin/CDH2, VEcadherin/CDH5 and αcatenins), transmembranetype mucins (MUC1/CD227 and MUC16/CA125), signaling regulators (APC, AXIN1, AXIN2 and NHERF1/EBP50) and epigenetic or transcriptional regulators (BCL9, BCL9L, CREBBP/CBP, EP300/p300, FOXM1, MED12, SMARCA4/BRG1 and TCF/LEF). Gainoffunction CTTNB1 mutations are detected in bladder cancer, colorectal cancer, gastric cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer and uterine cancer, whereas lossoffunction CTNNB1 mutations are also detected in human cancer. ABCB1, ALDH1A1, ASCL2, ATF3, AXIN2, BAMBI, CCND1, CD44, CLDN1, CTLA4, DKK1, EDN1, EOMES, FGF18, FGF20, FZD7, IL10, JAG1, LEF1, LGR5, MITF, MSX1, MYC, NEUROD1, NKD1, NODAL, NOTCH2, NOTUM, NRCAM, OPN, PAX3, PPARD, PTGS2, RNF43, SNAI1, SP5, TCF7, TERT, TNFRSF19, VEGFA and ZNRF3 are representative βcatenin target genes. βcatenin signaling is involved in myofibroblast activation and subsequent pulmonary fibrosis, in addition to other types of fibrosis. βcatenin and NFκB signaling activation are involved in field cancerization in the stomach associated with Helicobacter pylori (H. pylori) infection and in the liver associated with hepatitis C virus (HCV) infection and other etiologies. βcatenintargeted therapeutics are functionally classified into βcatenin inhibitors targeting upstream regulators (AZ1366, ETC159, G007LK, GNF6231, ipafricept, NVPTNKS656, rosmantuzumab, vantictumab, WNTC59, WNT974 and XAV939), βcatenin inhibitors targeting proteinprotein interactions (CGP049090, CWP232228, E7386, ICG001, LF3 and PRI724), βcatenin inhibitors targeting epigenetic regulators (PKF118310), βcatenin inhibitors targeting mediator complexes (CCT251545 and cortistatin A) and βcatenin inhibitors targeting transmembranetype transcriptional outputs, including CD44v6, FZD7 and LGR5. Eradicating H. pylori and HCV is the optimal approach for the firstline prevention of gastric cancer and hepatocellular carcinoma (HCC), respectively. However, βcatenin inhibitors may be applicable for the prevention of organ fibrosis, secondline HCC prevention and treating βcatenindriven cancer. The multilayered prevention and treatment strategy of βcateninrelated human diseases is necessary for the practice of personalized medicine and implementation of precision medicine.
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Document Type: Research Article
Affiliations: Department of Omics Network, National Cancer Center, Chuo Ward, Tokyo 1040045, Japan
Publication date: January 1, 2018
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- The International Journal of Molecular Medicine is a monthly, peer-reviewed journal devoted to the publication of high quality studies related to the molecular mechanisms of human disease. The journal welcomes research on all aspects of molecular and clinical research, ranging from biochemistry to immunology, pathology, genetics, human genomics, microbiology, molecular pathogenesis, molecular cardiology, molecular surgery and molecular psychology.
The International Journal of Molecular Medicine aims to provide an insight for researchers within the community in regard to developing molecular tools and identifying molecular targets for the diagnosis and treatment of a diverse number of human diseases.
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