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Smad3 deficiency ameliorates hepatic fibrogenesis through the expression of senescence marker protein-30, an antioxidant-related protein.

ABSTRACT: Smad3 is a key mediator of the transforming growth factor (TGF)-?1 signaling pathway that plays central role in inflammation and fibrosis. In present study, we evaluated the effect of Smad3 deficiency in Smad3-/- mice with carbon tetrachloride (CCl4)-induced liver fibrosis. The animals were received CCl4 or olive oil three times a week for 4 weeks. Histopathological analyses were performed to evaluate the fibrosis development in the mice. Alteration of protein expression controlled by Smad3 was examined using a proteomic analysis. CCl4-induced liver fibrosis was rarely detected in Smad3-/- mice compared to Smad3+/+. Proteomic analysis revealed that proteins related to antioxidant activities such as senescence marker protein-30 (SMP30), selenium-binding proteins (SP56) and glutathione S-transferases (GSTs) were up-regulated in Smad3-/- mice. Western blot analysis confirmed that SMP30 protein expression was increased in Smad3-/- mice. And SMP30 levels were decreased in CCl4-treated Smad3+/+ and Smad3-/- mice. These results indicate that Smad3 deficiency influences the proteins level related to antioxidant activities during early liver fibrosis. Thus, we suggest that Smad3 deteriorate hepatic injury by inhibitor of antioxidant proteins as well as mediator of TGF-?1 signaling.

SUBMITTER: Jeong DH

PROVIDER: S-EPMC3876072 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Smad3 deficiency ameliorates hepatic fibrogenesis through the expression of senescence marker protein-30, an antioxidant-related protein.

Jeong Da-Hee DH Hwang Meeyul M Park Jin-Kyu JK Goo Moon-Jung MJ Hong Il-Hwa IH Ki Mi-Ran MR Ishigami Akihito A Kim Ah-Young AY Lee Eun-Mi EM Lee Eun-Joo EJ Jeong Kyu-Shik KS

International journal of molecular sciences 20131204 12

Smad3 is a key mediator of the transforming growth factor (TGF)-β1 signaling pathway that plays central role in inflammation and fibrosis. In present study, we evaluated the effect of Smad3 deficiency in Smad3-/- mice with carbon tetrachloride (CCl4)-induced liver fibrosis. The animals were received CCl4 or olive oil three times a week for 4 weeks. Histopathological analyses were performed to evaluate the fibrosis development in the mice. Alteration of protein expression controlled by Smad3 was ...[more]

PMID: 24304543

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Project description:BackgroundSenescence marker protein 30 (SMP30), which plays a pivotal role as a suppressor protein in cell proliferation, among other regulatory actions, is a marker of aging that shows decreased expression during senescence. Decreased SMP30 has been identified in several human cancers, but its expression and role in human non-small cell lung cancer (NSCLC) remain unclear.MethodsUsing tumor tissue and matched adjacent normal tissue from 341 patients with resected NSCLC, we assessed SMP30 expression using immunohistochemical methods. The relationship between SMP30 expression and clinicopathologic characteristics was investigated by Kaplan-Meier survival analysis and multivariate analysis. Cell viability assay, colony formation assay, EdU incorporation assay and in vivo tumor xenograft models were also performed to investigate NSCLC cell proliferation using A549 and H1299 cell lines. Recombinant lentivirus-meditated in vivo gene overexpression and Western blot were performed to clarify the underlying molecular mechanism of SMP30 inhibiting NSCLC proliferation.ResultsSMP30 expression was frequently downregulated in NSCLC tissue, as compared with adjacent non-tumor tissue. Kaplan-Meier survival analyses revealed NSCLC patients with low SMP30 expression had a significantly worse overall survival (OS), with median OS of 18 vs. 67 months in high SMP30 expression group. SMP30 overexpression significantly inhibited A549 and H1299 cell proliferation both in vitro and in tumor xenografts and downregulated the expression of c-Myc and CyclinD1 protein. Moreover, Western blot analyses confirmed that SMP30 overexpression significantly inhibited the histone deacetylase 4 (HDAC4) level in NSCLC cells, and HDAC4 overexpression reversed SMP30-mediated NSCLC repression both in vitro and in vivo.ConclusionsSMP30 inhibited NSCLC proliferation by reducing HDAC4 expression, and SMP30 and HDAC4 may serve as new prognostic biomarkers and future therapeutic targets for NSCLC.

Project description:The loss of mitochondrial function impairs intracellular energy production and potentially results in chronic liver disease. Increasing evidence suggests that mitochondrial dysfunction in hepatocytes contributes to the activation of hepatic stellate cells (HSCs), thereby resulting in hepatic fibrogenesis. High-temperature requirement protein A2 (HtrA2/Omi), a mitochondrial serine protease with various functions, is responsible for quality control in mitochondrial homeostasis. However, little information is available regarding its role in mitochondrial damage during the development of liver fibrosis. This study examined whether HtrA2/Omi regulates mitochondrial homeostasis in hepatocyte during the development of hepatic fibrogenesis. In this study, we demonstrated that HtrA2/Omi expression considerably decreased in liver tissues from the CCl4-induced liver fibrotic mice model and from patients with liver cirrhosis. Knockdown of HtrA2/Omi in hepatocytes induced the accumulation of damaged mitochondria and provoked mitochondrial reactive oxygen species (mtROS) stress. We further show that the damaged mtDNA isolated from HtrA2/Omi-deficient hepatocytes as a form of damage-associated molecular patterns can induce HSCs activation. Moreover, we found that motor neuron degeneration 2-mutant mice harboring the missense mutation Ser276Cys in the protease domain of HtrA2/Omi displayed altered mitochondrial morphology and function, which increased oxidative stress and promoted liver fibrosis. Conversely, the overexpression of HtrA2/Omi via hydrodynamics-based gene transfer led to the antifibrotic effects in CCl4-induced liver fibrosis mice model through decreasing collagen accumulation and enhancing anti-oxidative activity by modulating mitochondrial homeostasis in the liver. These results suggest that suppressing HtrA2/Omi expression promotes hepatic fibrogenesis via modulating mtROS generation, and these novel mechanistic insights involving the regulation of mitochondrial homeostasis by HtrA2/Omi may be of importance for developing new therapeutic strategies for hepatic fibrosis.

Dataset Information

Smad3 deficiency ameliorates hepatic fibrogenesis through the expression of senescence marker protein-30, an antioxidant-related protein.

Publications

Smad3 deficiency ameliorates hepatic fibrogenesis through the expression of senescence marker protein-30, an antioxidant-related protein.

Similar Datasets

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