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2018 ; 42
(2
): 713-725
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Multi?layered prevention and treatment of chronic inflammation, organ fibrosis
and cancer associated with canonical WNT/??catenin signaling activation (Review)
#MMPMID29786110
Katoh M
Int J Mol Med
2018[Aug]; 42
(2
): 713-725
PMID29786110
show ga
??catenin/CTNNB1 is an intracellular scaffold protein that interacts with
adhesion molecules (E?cadherin/CDH1, N?cadherin/CDH2, VE?cadherin/CDH5 and
??catenins), transmembrane?type 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). Gain?of?function CTTNB1 mutations are detected in bladder cancer,
colorectal cancer, gastric cancer, liver cancer, lung cancer, pancreatic cancer,
prostate cancer and uterine cancer, whereas loss?of?function 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 ??catenin target genes. ??catenin signaling is involved in
myofibroblast activation and subsequent pulmonary fibrosis, in addition to other
types of fibrosis. ??catenin and NF??B 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. ??catenin?targeted therapeutics are functionally classified
into ??catenin inhibitors targeting upstream regulators (AZ1366, ETC?159,
G007?LK, GNF6231, ipafricept, NVP?TNKS656, rosmantuzumab, vantictumab, WNT?C59,
WNT974 and XAV939), ??catenin inhibitors targeting protein?protein interactions
(CGP049090, CWP232228, E7386, ICG?001, LF3 and PRI?724), ??catenin inhibitors
targeting epigenetic regulators (PKF118?310), ??catenin inhibitors targeting
mediator complexes (CCT251545 and cortistatin A) and ??catenin inhibitors
targeting transmembrane?type transcriptional outputs, including CD44v6, FZD7 and
LGR5. Eradicating H. pylori and HCV is the optimal approach for the first?line
prevention of gastric cancer and hepatocellular carcinoma (HCC), respectively.
However, ??catenin inhibitors may be applicable for the prevention of organ
fibrosis, second?line HCC prevention and treating ??catenin?driven cancer. The
multi?layered prevention and treatment strategy of ??catenin?related human
diseases is necessary for the practice of personalized medicine and
implementation of precision medicine.