Suppressor of cytokine signalling-2 controls hepatic gluconeogenesis and hyperglycemia by modulating JAK2/STAT5 signalling pathway

Zhang, Xu; Zhuang, Yuan; Qin, Tian; Chang, Meijia; Ji, Xuetao; Wang, Ning; Zhang, Zhilei; Zhou, Hongwen; Wang, Qian; Li, John

doi:10.1016/j.metabol.2021.154823

Cited by 10 publications

(8 citation statements)

References 38 publications

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“…It has been shown that the SOCS family plays an important role in the regulation of cellular responses to cytokines and growth factors, and that the SOCS family is a major negative regulator of a number of signaling pathways, including JAK/STAT pathway [3,20,21] . More and more studies suggested that the SOCS family genes were the key factors in the occurrence, development, invasion and angiogenesis of malignant tumors [2,22] .…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that PIK3R3/STAT3 pathway may play an important role in the regulation of embryonic development, hematopoiesis, in ammatory response and stem cell maintenance [21] . The abnormally activated PIK3R3/STAT3 signaling pathway is critical for many cancers [20,21] . SOCS family genes, as important regulators of the PIK3R3/STAT3 signal, can be developed molecularly targeted drugs to inhibit PIK3R3/STAT3 signalling in a variety of cancers with unique modes of action [25] .…”

Section: Discussionmentioning

confidence: 99%

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Expression characteristics, immune signature, and prognostic value of the SOCS family identified by multiomics integrative analysis in liver cancer

Dong

Dai

Fang

et al. 2023

Preprint

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Objective Hepatocellular carcinoma is one of the most common malignancies in the world, and the death rate is very high. The members of the SOCS family are the key factors in the regulation of various cytokines and growth factors. It is not clear, however, whether the level of the SOCS family will affect the prognosis in patients with HCC. Methods Firstly, we studied the expression levels of the SOCS family genes in the HCC and the relationship between the expression level of the SOCS family and different clinicopathological characteristics. Then the public database was used to analyze the changes of expression, potential function, transcription factors and immune invasion of SOCS family members. Finally, we analyzed the prognostic value of the patients with SOC family with HCC and the correlation with SOC family and ferroptosis-related genes. Results The expression of SOCS2-7 and CISH was downregulated in HCC. The SOCS4, SOCS5 and SOCS7 genes were all related to the clinicopathological features of HCC patients. SOCS family genes are mainly related to PIK3R3, GHR, TNS4, TNS4 pathway. We found that STAT3, PPAR-gamma 2 and IRF-2 are important transcription factors in regulating SOCS family members. We also confirmed that the expression level of SOCS family members are closely related to the immune infiltration of liver cancer. Then, we clarified that SOCS2 and SOCS4 are risk-related gene in predicting the prognosis of patients with liver cancer. Finally, we found that SOCS2 gene may be involved in the development and progression of hepatocellular carcinoma, but the mechanism needs further experimental verification. Conclusion Our study may expand upon the understanding of SOCS gene function in liver cancer and help clinicians select appropriate drugs and predict the prognosis of patients with liver cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Expression characteristics, immune signature, and prognostic value of the SOCS family identified by multiomics integrative analysis in liver cancer

Dong

Dai

Fang

et al. 2023

Preprint

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“…34 SOCS2 overexpression inhibits gluconeogenesis in mouse primary hepatocytes and the liver of mice. 35 The effects of SOCS3 on gluconeogenesis, however, are controversial. studies reported that overexpression of SOCS3 gluconeogenic gene expression, while knockdown of has the opposite effects in mouse primary hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

“…11 Overexpression of SOCS3 in skeletal muscles aggravates systemic insulin resistance, 43 while SOCS3 knockout in skeletal muscle improves systemic insulin sensitivity. 44 However, hepatic overexpression of SOCS2 improves insulin sensitivity in db/db mice, 35 and HFDimpaired insulin resistance is worsen in SCOS2 deficient mice. 45 These data and our observations on CISH demonstrate that the impacts of each SOCS protein on insulin sensitivity are different.…”

Section: Discussionmentioning

confidence: 99%

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Hepatic cytokine‐inducible SH2 ‐containing protein ( CISH ) regulates gluconeogenesis via cAMP ‐responsive element binding protein ( CREB )

et al. 2022

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Impairment of gluconeogenesis is a key factor responsible for hyperglycemia in patients with type 2 diabetes. As an important member of the suppressors of cytokine signaling (SOCS) protein family, many physiological functions of cytokine‐inducible SH2‐containing protein (CISH) have been described; however, the role of hepatic CISH in gluconeogenesis is poorly understood. In the present study, we observed that hepatic CISH expression was reduced in fasted wild‐type (WT) mice. Overexpression of CISH decreased glucose production in mouse primary hepatocytes, while silencing of CISH had the opposite effects. In addition, adenovirus‐mediated hepatic CISH overexpression resulted in improved glucose tolerance and decreased gluconeogenesis in WT and leptin receptor‐deficient diabetic (db/db) mice. In contrast, adenovirus‐mediated hepatic CISH knockdown impaired glucose tolerance and increased gluconeogenesis in WT mice. We also generated liver‐specific CISH knockout (LV‐CISH KO) mice and discovered that these mice had a similar phenotype in glucose tolerance and gluconeogenesis as mice injected with adenoviruses that knockdown CISH expression. Mechanistically, we found that CISH overexpression decreased and CISH knockdown increased the mRNA and protein levels of glucose‐6‐phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase 1 (PEPCK), two key enzymes involved in gluconeogenesis, in vitro, and in vivo. Moreover, we discovered that the phosphorylation of cAMP‐responsive element binding protein 1 (CREB), a transcription factor of G6pase and Pepck, was required for regulating gluconeogenesis by CISH. Taken together, this study identifies hepatic CISH as an important regulator of gluconeogenesis. Our results also provide important insights into the metabolic functions of the SOCS protein family and the potential targets for the treatment of diabetes.

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Expression Characteristics, Immune Signature, and Prognostic Value of the SOCS Family Identified by Multiomics Integrative Analysis in Liver Cancer

Dong,

Dai,

et al. 2024

Cancer Reports

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BackgroundHepatocellular carcinoma (HCC) is a prevalent malignancy with a high mortality rate worldwide. Suppressor of cytokine signaling (SOCS) family members play important roles in the proliferation, metabolism, and immunity of HCC cells by regulating cytokines and growth factors. However, it remains uncertain whether the level of SOCS family members can affect the prognosis of HCC patients.AimsThis study aimed to comprehensively assess the role and mechanisms of SOCS family members in the development of HCC and to guide clinical selection.MethodsWe investigated the expression levels of SOCS family genes in HCC patients and their associations with various clinicopathological characteristics. We also utilized a public database to analyze the changes in the expression, potential functions, transcription factors, and immune invasion of SOCS family members. Additionally, we examined the prognostic value of the SOC family for HCC and its correlation with the SOC family and ferroptosis‐related genes.ResultsThis study revealed that the expression of SOCS2‐7, and CISH was downregulated in HCC. The SOCS4, SOCS5, and SOCS7 genes were associated with the clinicopathological features of HCC patients. SOCS family genes are mainly related to the PIK3R3, GHR, and TNS4 pathways. Additionally, this study revealed that STAT3, PPAR‐gamma 2, and IRF‐2 are important transcription factors that regulate SOCS family members. The expression levels of SOCS family members are closely related to immune infiltration in liver cancer. The study also indicated that SOCS2 and SOCS4 are risk‐related genes for predicting the prognosis of patients with liver cancer. Finally, this study suggested that the SOCS2 gene may be involved in the development and progression of HCC.ConclusionOur study enhances the current understanding of SOCS gene function in liver cancer and can help clinicians select appropriate drugs and predict the prognosis of HCC patients.

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Suppressor of cytokine signalling-2 controls hepatic gluconeogenesis and hyperglycemia by modulating JAK2/STAT5 signalling pathway

Cited by 10 publications

References 38 publications

Expression characteristics, immune signature, and prognostic value of the SOCS family identified by multiomics integrative analysis in liver cancer

Expression characteristics, immune signature, and prognostic value of the SOCS family identified by multiomics integrative analysis in liver cancer

Hepatic cytokine‐inducible SH2 ‐containing protein ( CISH ) regulates gluconeogenesis via cAMP ‐responsive element binding protein ( CREB )

Expression Characteristics, Immune Signature, and Prognostic Value of the SOCS Family Identified by Multiomics Integrative Analysis in Liver Cancer

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