Activation of the Transcription Factor GLI1 by WNT Signaling Underlies the Role of SULFATASE 2 as a Regulator of Tissue Regeneration

Nakamura, Ikuo; Fernández‐Barrena, Maite G.; Ortiz-Ruiz, Maria C.; Almada, Luciana L.; Hu, Chunling; Elsawa, Sherine F.; Mills, Lisa D.; Romecín, Paola; Gulaid, Kadra H; Moser, Catherine D.; Han, Jing; Vrabel, Anne M.; Hanse, Eric A.; Akogyeram, Nicholas A.; Albrecht, Jeffrey H.; Monga, Satdarshan P.; Sanderson, Schuyler O.; Prìeto, Jesús; Roberts, Lewis R.; Fernández-Zapico, Martín E.

doi:10.1074/jbc.m112.443440

Cited by 34 publications

(25 citation statements)

References 37 publications

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“…17 What was intriguing was that the Wnt5a increase occurred almost immediately after b-catenin activation and relatively early during LR, but did not precede b-catenin activation, which is evident at 1 to 6 hours after PH in mice. 10,27 Although there was a modest increase in Wnt5a evident in LR at 1 and 12 hours, there was either no change or, in fact, down-regulation of Frizzled-2 expression at these times. It was only at 24 hours that Wnt5a and Frizzled-2 were simultaneously induced significantly after PH.…”

Section: Discussionmentioning

confidence: 98%

WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

Yang

Cusimano

Monga

et al. 2015

The American Journal of Pathology

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Activation of Wnt/b-catenin signaling during liver regeneration (LR) after partial hepatectomy (PH) is observed in several species. However, how this pathway is turned off when hepatocyte proliferation is no longer required is unknown. We assessed LR in liver-specific knockouts of Wntless (Wls-LKO), a protein required for Wnt secretion from a cell. When subjected to PH, Wls-LKO showed prolongation of hepatocyte proliferation for up to 4 days compared with littermate controls. This coincided with increased b-catenineT-cell factor 4 interaction and cyclin-D1 expression. Wls-LKO showed decreased expression and secretion of inhibitory Wnt5a during LR. Wnt5a expression increased between 24 and 48 hours, and Frizzled-2 between 24 and 72 hours, after PH in normal mice. Treatment of primary mouse hepatocytes and liver tumor cells with Wnt5a led to a notable decrease in b-catenineT-cell factor activity, cyclin-D1 expression, and cell proliferation. Intriguingly, Wnt5a-LKO did not display any prolongation of LR because of compensation by other cells. In addition, Wnt5a-LKO hepatocytes failed to respond to exogenous Wnt5a treatment in culture because of a compensatory decrease in Frizzled-2 expression.In conclusion, we demonstrate Wnt5a to be, by default, a negative regulator of b-catenin signaling and hepatocyte proliferation, both in vitro and in vivo. We also provide evidence that the Wnt5a/Frizzled-2 axis suppresses b-catenin signaling in hepatocytes in an autocrine manner, thereby contributing to timely conclusion of the LR process. (Am J Pathol 2015, 185: 2194e2205; http:// dx

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Section: Discussionmentioning

confidence: 98%

WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

Yang

Cusimano

Monga

et al. 2015

The American Journal of Pathology

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“…SULF2, a heparan sulfate 6-O-sulfatase, releases growth factors from extracellular storage sites and facilitates tumor progression (28–31). But its role in modulating angiogenesis in HCC has not been studied before.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Induction of Periostin by a Sulfatase 2–TGFβ1–SMAD Signaling Axis Mediates Tumor Angiogenesis in Hepatocellular Carcinoma

et al. 2017

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Existing anti-angiogenic approaches to treat metastatic hepatocellular carcinoma (HCC) are weakly effectual, prompting further study of tumor angiogenesis in this disease setting. Here we report a novel role for the sulfatase 2 (SULF2) in driving HCC angiogenesis. Sulf2-deficient mice (Sulf2 KO) exhibited resistance to diethylnitrosamine-induced HCC and did not develop metastases like wild-type mice (Sulf2 WT). The smaller and less numerous tumors formed in Sulf2 KO mice exhibited a markedly lower microvascular density. In human HCC cells, SULF2 overexpression increased proliferation, adhesion, chemotaxis and endothelial tube formation in a paracrine fashion. Mechanistic analyses identified the extracellular matrix protein periostin (POSTN), a ligand of αvβ3/5 integrins, as an effector function in SULF2-induced angiogenesis. POSTN silencing in HCC cells attenuated SULF2-induced angiogenesis and tumor growth in vivo. The TGFβ1-SMAD pathway was identified as a critical signaling axis between SULF2 and upregulation of POSTN transcription. In clinical specimens of HCC, elevated levels of SULF2 correlated with increased microvascular density, POSTN levels and relatively poorer patient survival. Together, our findings define an important axis controlling angiogenesis in HCC and a mechanistic foundation for rational drug development.

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“…Wnt2 is highly relevant in activating β-catenin signaling, and HGF can also activate β-catenin in addition to stimulating other mitogenic cascades relevant in LR. Additionally, as previously mentioned, sulfatase 2, a heparan sulfate 6-O-endosulfatase that releases growth factors from extracellular storage sites, was shown to be essential for Wnt3a release after PH that in turn led to activation of β-catenin, GLI1 expression, and upregulation of cyclin-D1 (69). Yet another recent study showed an important role of long noncoding RNA (lncRNA), which was termed as an lncRNA associated with LR or lnc-RNA-LALR1 (70).…”

Section: β-Catenin Signaling In Liver Regenerationmentioning

confidence: 94%

Role and Regulation of β-Catenin Signaling During Physiological Liver Growth

Monga

2014

gene expr

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Wnt/β-catenin signaling plays key roles not only during development but also in adult tissue homeostasis. This is also evident in liver biology where many temporal roles of β-catenin have been identified during hepatic development, where, in hepatic progenitors or hepatoblasts, it is a key determinant of proliferation and eventually differentiation to mature hepatocytes, while also playing an important role in bile duct homeostasis. β-Catenin signaling cascade is mostly quiescent in hepatocytes in an adult liver except in the centrizonal region of a hepatic lobule. This small rim of hepatocytes around the central vein show constitutive β-catenin activation that in turn regulates expression of genes whose products play an important role in ammonia and xenobiotic metabolism. Intriguingly, β-catenin can also undergo activation in hepatocytes after acute liver loss secondary to surgical or toxicant insult. Such activation of this progrowth protein is observed as nuclear translocation of β-catenin and formation of its complex with the T-cell factor (TCF) family of transcription factors. Expression of cyclin-D1, a key inducer of transition from the G1 to S phase of cell cycle is regulated by β-catenin-TCF complex. Thus β-catenin activation is absolutely critical in the normal regeneration process of the liver as shown by studies in several models across various species. In the current review, the temporal role and regulation of β-catenin in liver development, metabolic zonation in a basal adult liver, and during the liver regeneration process, will be discussed. In addition, the probability of therapeutically regulating β-catenin activity as a possible future treatment strategy for liver insufficiency will also be discussed.

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Activation of the Transcription Factor GLI1 by WNT Signaling Underlies the Role of SULFATASE 2 as a Regulator of Tissue Regeneration

Cited by 34 publications

References 37 publications

WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

Transcriptional Induction of Periostin by a Sulfatase 2–TGFβ1–SMAD Signaling Axis Mediates Tumor Angiogenesis in Hepatocellular Carcinoma

Role and Regulation of β-Catenin Signaling During Physiological Liver Growth

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