Wnt–β-catenin signalling in liver development, health and disease

Perugorria, María J.; Olaizola, Paula; Labiano, Ibone; Esparza-Baquer, Aitor; Marzioni, Marco; Marin, José J.G.; Bujanda, Luís; Bañales, Jesús M.

doi:10.1038/s41575-018-0075-9

Cited by 423 publications

(367 citation statements)

References 186 publications

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“…Such functionality of the E-cadherin in controlling cell maturation and movement is attributable to its predominant interactions with p120-catenin proteins, in order to regulate the activity of cognate genes [38]. Among them, -catenin is a key component of the Wnt signaling, that is important for normal development, growth and disease (e.g., cancer) [39,50,51]. When required for biological cues, -catenin is allowed for release from physical interaction with E-cadherin to translocate the nucleus and acts as a co-activator to bind one of its partner transcription factors LEF or TCF (including TCF1, TCF3 or TCF4).…”

Section: Activation Of -Catenin and Other Critical Genes For The Malmentioning

confidence: 99%

“…It is of crucial significance to note the involvement of the epithelial-mesenchymal transition (EMT) in cancer invasion and metastasis, which is modulated by cadherins, -and -catenins (encoded by CTNNA1 and CTNNB1). The latter -catenin is a versatile player of the Wnt signaling involved in liver development, health, and disease [38][39][40].…”

Section: Introductionmentioning

confidence: 99%

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Nrf1 is endowed with a dominant tumor-repressing effect onto the Wnt/β-Catenin-dependent and -independent signaling networks in the human liver cancer

Chen

Wang

et al. 2019

Preprint

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Our previous work revealed that Nrf1 exerts a tumor-repressing effect because its genomic loss (to yield Nrf1 −/− ) results in oncogenic activation of Nrf2 and target genes. Interestingly, -catenin is concurrently activated by loss of Nrf1 in a way similar to -catenin-driven liver tumor. However, a presumable relationship between Nrf1 and -catenin is not as yet established. Here, we demonstrate that Nrf1 enhanced ubiquitination of -catenin for targeting to proteasomal degradation. Conversely, knockdown of Nrf1 by its short-hairpin RNA (shNrf1) caused accumulation of -catenin so as to translocate the nucleus, allowing activation of a subset of Wnt−-catenin signaling responsive genes, which leads to the epithelial-mesenchymal transition (EMT) and related cellular processes. Such silencing of Nrf1 resulted in malgrowth of human hepatocellular carcinoma, along with malignant invasion and metastasis to the lung and liver in xenograft model mice. Further transcriptomic sequencing unraveled significant differences in the expression of both Wnt/-catenin-dependent and -independent responsive genes implicated in the cell process, shape and behavior of the shNrf1-expressing tumor. Notably, we identified that -catenin is not a target gene of Nrf1, but this CNC-bZIP factor contributes to differential or opposing expression of other critical genes, such as CDH1, Wnt5A, Wnt11A, FZD10, LEF, TCF4, SMAD4, MMP9, PTEN, PI3K, JUN and p53, each of which depends on the positioning of distinct cis-regulatory sequences (e.g., ARE and/or AP-1 binding sites) in the gene promoter contexts. In addition, altered expression profiles of some Wnt−-catenin signaling proteins were context-dependent, as accompanied by decreased abundances of Nrf1 in the clinic human hepatomas with distinct differentiation. Together, these results corroborate the rationale that Nrf1 acts as a bona fide dominant tumor-repressor, by its intrinsic inhibition of Wnt−-catenin signaling and relevant independent networks in cancer development and malignant progression.repressors Bach1 (BTB and CNC homology 1) and Bach2 [6,7], together with the recently-identified Nach (Nrf and CNC homology) proteins existing in marine bacteria to early diverging metazoans [3,4]. These CNC/Nach-bZIP family members share a common evolutionary ancestor with the Maf (musculoaponeurotic fibrosarcoma oncogene) family, including sMaf (small Maf) proteins [4]. They play a host of vital, and even indispensable, roles in regulating distinct subsets of target genes involved in antioxidant, detoxification, redox metabolism, proteasomal degradation, adaptive cytoprotection, and other physio-pathological responses to diverse cellular stresses [6][7][8]. Such genes are regulated transcriptionally by a functional heterodimer of each CNC-bZIP factor (except Skn-1) with a cognate partner sMaf or another bZIP protein, which directly binds the antioxidant and electrophile response elements (AREs/EpREs) and/or other cis-regulatory homologues (e.g., AP-1 binding site) within the gene promoter reg...

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Section: Activation Of -Catenin and Other Critical Genes For The Malmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nrf1 is endowed with a dominant tumor-repressing effect onto the Wnt/β-Catenin-dependent and -independent signaling networks in the human liver cancer

Chen

Wang

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…The Wnt/β-catenin signaling pathway is fundamental in liver development, health, disease, and regeneration. (8) Among others, this molecular pathway promotes hepatocyte proliferation, and its defects result in delayed liver regeneration. (9) In order to investigate whether the liver-specific loss of β-catenin expression in combination with CDE diet-induced liver injury impairs hepatocyte proliferation, and this triggers ductular reaction, authors used Albumin-Cre Ctnnb1 knock-out (KO) mice, which lack β-catenin expression in both hepatocytes and BECs.…”

Section: See Article On Page 742mentioning

confidence: 99%

“…In this issue of Hepatology , Russell et al have investigated BEC‐to‐hepatocyte transdifferentiation, performing sophisticated lineage‐tracing studies in conditional β‐catenin knockout mouse models following CDE diet–induced injury, with the aim of studying the potential contribution of BECs to the restoration of hepatocyte mass after chronic liver injury when hepatocyte proliferation is impaired. The Wnt/β‐catenin signaling pathway is fundamental in liver development, health, disease, and regeneration . Among others, this molecular pathway promotes hepatocyte proliferation, and its defects result in delayed liver regeneration .…”

mentioning

confidence: 99%

Cholangiocyte‐to‐Hepatocyte Differentiation: A Context‐Dependent Process and an Opportunity for Regenerative Medicine

Olaizola

2018

Hepatology

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“…In addition, the following two mechanisms are possible reasons for zone 3 steatosis: (i) a perivenous occurrence of glycolysis, which results in high acetyl‐CoA level; and (ii) an increased perivenous activity of lipogenesis‐related enzymes, including fatty acid synthase, by refeeding a high‐carbohydrate diet . Furthermore, Wnt–β‐catenin signaling was recently reported to be involved in the establishment of metabolic zonation through modulation of the sinusoidal oxygen gradient and hypoxia‐inducible factor‐1α‐mediated glycolysis and lipogenesis …”

mentioning

confidence: 99%

Branched chain amino acids: A factor for zone 3 steatosis in non‐alcoholic fatty liver disease

Kawaguchi

Torimura

2019

Hepatology Research

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Wnt–β-catenin signalling in liver development, health and disease

Cited by 423 publications

References 186 publications

Nrf1 is endowed with a dominant tumor-repressing effect onto the Wnt/β-Catenin-dependent and -independent signaling networks in the human liver cancer

Nrf1 is endowed with a dominant tumor-repressing effect onto the Wnt/β-Catenin-dependent and -independent signaling networks in the human liver cancer

Cholangiocyte‐to‐Hepatocyte Differentiation: A Context‐Dependent Process and an Opportunity for Regenerative Medicine

Branched chain amino acids: A factor for zone 3 steatosis in non‐alcoholic fatty liver disease

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