p53 and MicroRNA-34 Are Suppressors of Canonical Wnt Signaling

Abstract

Although loss of p53 function and activation of canonical Wnt signaling cascades are frequently coupled in cancer, the links between these two pathways remain unclear. We report here that p53 transactivates miRNA-34 (miR-34), which suppresses the transcriptional activity of β-catenin-T-cell factor/lymphoid enhancer factor (TCF/LEF) complexes by targeting the untranslated regions (UTRs) of a set of highly-conserved targets in a network of Wnt pathway-regulated genes. Loss of p53 function increases canonical Wnt signaling through miR-34-specific interactions with target UTRs, whereas miR-34 depletion relieves p53-mediated Wnt repression. Further, gene expression signatures reflecting the status of β-catenin-TCF/LEF transcriptional activity in breast cancer and pediatric neuroblastoma patients are closely associated with p53 and miR-34 functional status. Loss of p53 or miR-34 contributed to neoplastic progression by triggering the Wnt-dependent, tissue-invasive activity of colorectal cancer cells. Further, during development, miR-34 interactions with the β-catenin UTR determine Xenopus body axis polarity and Wnt-dependent gene patterning. These data provide insight into the mechanisms by which a p53-miR-34 network restrains canonical Wnt signaling cascades in developing organisms and human cancer.

MicroRNA therapy inhibits hepatoblastoma growth in vivo by targeting β‐catenin and Wnt signaling

“…Interestingly, miR‐1205 and let‐7i are positively regulated by p53,29, 30 and miR‐885‐5p and miR‐449b activate the p53 pathway 31, 32. Therefore, our results further strengthen the idea that the regulation of beta‐catenin by miRNAs is linked to p53 signaling 17. We noticed that the exon 3 deletion in HepG2 cells made mutated beta‐catenin more resistant to miRNAs, confirming previous data with miR‐483‐3p in colon cancer cells 18.…”

“…2D). Very surprisingly, several previously reported miRNAs with a regulatory effect on beta‐catenin, such as miR‐34a and miR‐200a,16, 17 had no such regulatory effect in HBL cells (Fig. 2).…”

“…2A‐D; Supporting Fig. S2, dark gray bars) 16, 17. Nine out of 26 miRNA candidates significantly decreased beta‐catenin protein expression in Huh6 cells, which carry the beta‐catenin missense G34V mutation (Fig.…”

“…This characteristic of miRNAs is an advantage for cancer therapy since tumors display specific signaling pathway alterations that can be controlled by single miRNAs 11, 12. Many miRNAs have been reported to target beta‐catenin: mature miRNA (miR)‐200a in human meningioma,16 members of the miR‐34 family in lung and breast carcinomas,17 miR‐483‐3p in breast and colon cancers,18 and miR‐214 in HCC 19. However, it is unknown if one of these miRNAs targets beta‐catenin in HBL.…”

Circulating microRNA signature of genotype‐by‐age interactions in the long‐lived Ames dwarf mouse

“…We reason that circulating miRNAs may be downregulating Wnt signaling in target tissues prone to uncontrolled cell proliferation and development of cancer. Indeed, several genes in the Wnt/β‐catenin signaling network have been found negatively correlated with age and tightly regulated by miRNAs (e.g., miR‐34 family; Kim et al ., 2011). …”