SOCS, inflammation, and cancer

Inagaki–Ohara, Kyoko; Kondo, Taisuke; Ito, Minako; Yoshimura, Akihiko

doi:10.4161/jkst.24053

Cited by 149 publications

(152 citation statements)

References 105 publications

(127 reference statements)

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“…Given that SOCS protein expression has been shown to be STAT-dependent, and SOCS genes are target genes of STATs and get induced by active JAK-STAT signaling [21], altered SOCS3 expression was expected and is indicative of a regulatory role of SOCS3 in CDH. In many pathological circumstances, increased expression of SOCS proteins coincides with the activation of JAK/STAT pathways [21,[49][50][51]. Collectively, our data provide the first evidence for a previously unappreciated regulatory mechanism occurring in the pathological development of experimental CDH.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 51%

STATs in Lung Development: Distinct Early and Late Expression, Growth Modulation and Signaling Dysregulation in Congenital Diaphragmatic Hernia

Piairo

Moura

Baptista

et al. 2017

Cell Physiol Biochem

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Key Words Signal transducer and activator of transcription (STAT) • Suppressor of cytokine signaling (SOCS) • Congenital diaphragmatic hernia (CDH) • Lung development • NitrofenAbstract Background: Congenital diaphragmatic hernia (CDH) is a life-threatening developmental anomaly, intrinsically combining severe pulmonary hypoplasia and hypertension. During development, signal transducers and activators of transcription (STAT) are utilized to elicit cell growth, differentiation, and survival. Methods: We used the nitrofen-induced CDH rat model. At selected gestational time points, lungs were divided into two experimental groups, i.e., control or CDH. We performed immunohistochemistry and western blotting analysis to investigate the developmental expression profile of the complete family of STATs (STAT1-6), plus specific STATs activation (p-STAT3, p-STAT6) and regulation by SOCS (SOCS3) in normal lungs against those of diseased lungs. The normal fetal lung explants were treated with piceatannol (STAT3 inhibitor) in vitro followed by morphometrical analysis. Results: Molecular profiling of STATs during the lung development revealed distinct early and late expression signatures. Experimental CDH altered the STATs expression, activation, and regulation in the fetal lungs. In particular, STAT3 and STAT6 were persistently over-expressed and early over-activated. Piceatannol treatment dose-dependently stimulated the fetal lung growth. Conclusion: These findings suggest that STATs play an important role during normal fetal lung development and CDH pathogenesis. Moreover, functionally targeting STAT signaling modulates fetal lung growth, which highlights that STAT3 and STAT6 signaling might be promising therapeutic targets in reducing or preventing pulmonary hypoplasia in CDH.

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Section: Cellular Physiology and Biochemistrymentioning

confidence: 51%

STATs in Lung Development: Distinct Early and Late Expression, Growth Modulation and Signaling Dysregulation in Congenital Diaphragmatic Hernia

Piairo

Moura

Baptista

et al. 2017

Cell Physiol Biochem

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“…Even though SOCS proteins are well-known regulators of cytokine receptors that signal via the JAK-STAT pathway, it is becoming increasingly clear that they also attenuate signaling via receptor tyrosine kinases (RTKs) such as c-KIT and receptors for epidermal growth factor, fibroblast growth factor and hepatocyte growth factor (HGF), which are implicated in oncogenesis. 3,4 We have previously shown that SOCS1-deficient hepatocytes show increased HGF signaling via the MET receptor. 5 Increased MET expression and aberrant MET signaling occur in many cancers including HCC.…”

Section: Introductionmentioning

confidence: 99%

Regulation of MET receptor tyrosine kinase signaling by suppressor of cytokine signaling 1 in hepatocellular carcinoma

et al. 2015

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Suppressor of cytokine signaling 1 (SOCS1) is considered as a tumor suppressor protein in hepatocellular carcinoma (HCC), but the underlying mechanisms remain unclear. Previously, we have shown that SOCS1-deficient hepatocytes displayed increased responsiveness to hepatocyte growth factor (HGF) due to enhanced signaling via the MET receptor tyrosine kinase. As aberrant MET activation occurs in many tumors including HCC, here we elucidated the mechanisms of SOCS1-mediated regulation. SOCS1 attenuated HGF-induced proliferation of human and mouse HCC cell lines and their growth as tumors in NOD.scid.gamma mice. Tumors formed by SOCS1 expressing HCC cells showed significantly reduced MET expression, indicating that SOCS1 not only attenuates MET signaling but also regulates MET expression. Mechanistically, SOCS1 interacted with MET via the Src homology 2 domain and this interaction was promoted by MET tyrosine kinase activity. The SOCS1-mediated reduction in MET expression does not require the juxtamembrane Y1003 residue implicated in Cbl-mediated downmodulation. Moreover, the proteasome inhibitor MG-132, but not the inhibitors of lysosomal degradation bafilomycin and chloroquine, reversed the SOCS1-mediated reduction in MET expression, indicating that this process is distinct from Cbl-mediated downmodulation. Accordingly, SOCS1 promoted polyubiquitination of MET via K48-dependent but not K63-mediated ubiquitin chain elongation. Furthermore, siRNA-mediated downmodulation of Cbl did not abolish SOCS1-mediated reduction in MET expression in HCC cells. SOCS1-dependent ubiquitination of endogenous MET receptor occurred rapidly following HGF stimulation in HCC cells, leading to proteasomal degradation of phosphorylated MET receptor. These findings indicate that SOCS1 mediates its tumor suppressor functions, at least partly, by binding to MET and interfering with downstream signaling pathways as well as by promoting the turnover of the activated MET receptor. We propose that loss of this control mechanism due to epigenetic repression of SOCS1 could contribute to oncogenic MET signaling in HCC and other cancers, and that MET inhibitors might be useful in treating these patients.

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“…Excessive JAK / STAT activity has been found in tumor tissue samples derived from a large number of patients across a range of tumor types, suggesting that JAK/STAT inhibitors may be effective chemotherapeutic agents [3]. Consistent with this hypothesis, in a preclinical study, AZD1480, an ATP-competitive inhibitor of JAK1/2, was found to inhibit the growth of subcutaneous tumors and increase survival of mice bearing intracranial glioblastoma tumors [6].…”

mentioning

confidence: 84%

JAK Inhibition: A new therapeutic strategy for management of chronic diseases

Yu¹

2016

J Biomol Res Ther

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SOCS, inflammation, and cancer

Cited by 149 publications

References 105 publications

STATs in Lung Development: Distinct Early and Late Expression, Growth Modulation and Signaling Dysregulation in Congenital Diaphragmatic Hernia

STATs in Lung Development: Distinct Early and Late Expression, Growth Modulation and Signaling Dysregulation in Congenital Diaphragmatic Hernia

Regulation of MET receptor tyrosine kinase signaling by suppressor of cytokine signaling 1 in hepatocellular carcinoma

JAK Inhibition: A new therapeutic strategy for management of chronic diseases

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