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Smad3 signaling in the regenerating liver: implications for the regulation of IL-6 expression.

ABSTRACT: Liver regeneration is vital for graft survival and adequate organ function. Smad activation regulates hepatocyte proliferation and macrophage function. The aim of the current study was to evaluate the impact of Smad3 signaling during liver regeneration in the mouse. Male C57Bl/6 wild-type (wt) mice or mice deficient in Smad3 (Smad3(-/-) ) were subjected to a 70% partial hepatectomy (pHx) or sham surgery and sacrificed 24, 42, or 48 h later. Tissue was analyzed for TGF-? signaling, the mitogenic cytokine response [i.e., tumor necrosis factor alpha, TNF-?; interleukin (IL)-6], and liver regeneration. Partial hepatectomy stimulated a strong regenerative response measured by proliferating cell nuclear antigen-positive hepatocytes 42 and 48 h post-pHx in conjunction with an increased expression of IL-6, TNF-?, and Smad2/3 phosphorylation 24 h post-pHx in both hepatocytes and nonparenchymal cells. Surprisingly, Smad3 deficiency led to reduced hepatocyte proliferation 42 h post-pHx which recovered by 48 h, a process that correlated with and was preceded by significant reductions in IL-6 expression and signal transducer and activator of transcription 3 phosphorylation, and cyclin D1 induction 24 h post-pHx. Loss of Smad3 signaling suppresses the expression of key mitogenic cytokines and delays hepatocellular regeneration. Therapies directed at finely regulating Smad3 activation early within the regenerating liver may prove useful in promoting liver cell proliferation and restoration of liver mass.

SUBMITTER: Kremer M

PROVIDER: S-EPMC4057977 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Smad3 signaling in the regenerating liver: implications for the regulation of IL-6 expression.

Kremer Michael M Son Gakuhei G Zhang Kun K Moore Sherri M SM Norris Amber A Manzini Giulia G Wheeler Michael D MD Hines Ian N IN

Transplant international : official journal of the European Society for Organ Transplantation 20140522 7

Liver regeneration is vital for graft survival and adequate organ function. Smad activation regulates hepatocyte proliferation and macrophage function. The aim of the current study was to evaluate the impact of Smad3 signaling during liver regeneration in the mouse. Male C57Bl/6 wild-type (wt) mice or mice deficient in Smad3 (Smad3(-/-) ) were subjected to a 70% partial hepatectomy (pHx) or sham surgery and sacrificed 24, 42, or 48 h later. Tissue was analyzed for TGF-β signaling, the mitogenic ...[more]

PMID: 24649805

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Project description:The response to transforming growth factor-? (TGF-?) depends on cellular context. This context is changed in mitosis through selective inhibition of vesicle trafficking, reduction in cell volume and the activation of mitotic kinases. We hypothesized that these alterations in cell context may induce a differential regulation of Smads and TGF-? receptors. We tested this hypothesis in mesenchymal-like ovarian cancer cells, arrested (or not) in mitosis with 2-methoxyestradiol (2ME2). In mitosis, without TGF-? stimulation, Smad3 was phosphorylated at the C-terminus and linker regions and localized to the mitotic spindle. Phosphorylated Smad3 interacted with the negative regulators of Smad signaling, Smurf2 and Ski, and failed to induce a transcriptional response. Moreover, in cells arrested in mitosis, Smad3 levels were progressively reduced. These phosphorylations and reduction in the levels of Smad3 depended on ERK activation and Mps1 kinase activity, and were abrogated by increasing the volume of cells arrested in mitosis with hypotonic medium. Furthermore, an Mps1-dependent phosphorylation of GFP-Smad3 was also observed upon its over-expression in interphase cells, suggesting a mechanism of negative regulation which counters increases in Smad3 concentration. Arrest in mitosis also induced a block in the clathrin-mediated endocytosis of the type II TGF-? receptor (T?RII). Moreover, following the stimulation of mitotic cells with TGF-?, the proteasome-mediated attenuation of TGF-? receptor activity, the degradation and clearance of T?RII from the plasma membrane, and the clearance of the TGF-? ligand from the medium were compromised, and the C-terminus phosphorylation of Smad3 was prolonged. We propose that the reduction in Smad3 levels, its linker phosphorylation, and its association with negative regulators (observed in mitosis prior to ligand stimulation) represent a signal attenuating mechanism. This mechanism is balanced by the retention of active TGF-? receptors at the plasma membrane. Together, both mechanisms allow for a regulated cellular response to TGF-? stimuli in mitosis.

Project description:BackgroundHepatocellular carcinoma (HCC) is the leading cause of mortality worldwide. Phosphatase regenerating liver 3 (PRL-3) was associated with cancer metastasis. However, the significance of PRL-3 in the prognosis of HCC remains elusive. The aim of this study was to elucidate the role of PRL-3 in HCC metastasis and its prognosis.MethodsThe expressions of PRL-3 in cancer tissues isolated from 114 HCC patients, who underwent curative hepatectomy from May to November in 2008, were analyzed by immunohistochemistry, and its prognostic significance was evaluated. Thereafter, the migration, invasion, and metastatic alterations in MHCC97H cells with PRL-3 overexpression or knockdown were explored and compared with the tumor size and lung metastasis in orthotopic HCC model of nude mice derived from MHCC97H cells with PRL-3 overexpression or knockdown. The underlying mechanism involving PRL-3-mediated effect on HCC migration, invasion, and metastasis was further examined.ResultsUnivariate and multivariate analysis demonstrated PRL-3 overexpression was an independent prognostic factor for poor overall survival (OS) and progression-free survival (PFS) of the HCC patients. Increased PRL-3 expression in MHCC97H cells was in accordance with the enhanced metastasis potential. PRL-3 knockdown inhibited the migration, invasiveness, and clone forming ability in MHCC97H cells, whereas PRL-3 overexpression reverted the above behavior. The growth of xenograft tumor in the liver was suppressed, and the lung metastasis in nude mice was inhibited by PRL-3 downregulation. The knockdown of PRL-3 could downregulate the expressions of Integrinβ1 and p-Src (Tyr416), p-Erk (Thr202/Tyr204) activation, and reduce MMP9 expression. Both MEK1/2 inhibitor (U0126) and Src inhibitor could repress PRL-3-induced invasiveness and migration in MHCC97H cells.ConclusionsPRL-3 was significantly overexpressed and an independent prognostic factor to predict the death of HCC patients. Mechanically, PRL-3 plays a critical role in HCC invasive and metastasis via Integrinβ1/FAK-Src/RasMAPK signaling. Validation of PRL-3 as a clinical prediction marker in HCC warrants further research.

Dataset Information

Smad3 signaling in the regenerating liver: implications for the regulation of IL-6 expression.

Publications

Smad3 signaling in the regenerating liver: implications for the regulation of IL-6 expression.

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