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Fold increase in cell number in IEC-6 and Caco2 cells grown in serum at 1–3 days after transfection of SOCS3 expression plasmid or empty vector. SOCS3 overexpression reduced cell proliferation (=P<0.05 vs empty vector).
Source publication
Intestinal injury or chronic inflammation induce cytokines that promote crypt regeneration and mucosal repair. If excessive or prolonged, such mechanisms may increase colon cancer risk. Factors that terminate or limit cytokine action in intestinal epithelial cells (IEC) may protect against crypt hyperplasia and neoplasia. We hypothesized that suppr...
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... were transfected with empty vector or SOCS3 expression plasmid and cell number was evaluated over a 3-day culture period, in serum. The numbers of empty vector-transfected cells increased over the 3-day culture period, whereas cells transfected with SOCS3 expression plasmid showed no increase in cell number (Figure 1). ...
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Citations
... In lung cancer, SOCS3 inhibited tumor cell proliferation and angiogenesis in small-cell lung cancer cells via inhibiting HIF-1a (12) and promoted apoptosis and cell proliferation in non-small-cell lung cancer through its methylation (13). Mouse model research illustrated that SOCS3 mediated the proliferation and hyperplasia of the crypt and the transformation of inflammation into cancer in the colon (14). Altered SOCS3 combined with chemotherapy or targeted therapy has been demonstrated to sensitize tumors and inhibit tumor progression (15). ...
Background
The suppressor of cytokine signaling 3 (SOCS3) is the negative feedback regulator of the JAK-STAT signaling pathway. The purpose of our study was to investigate the SOCS3 status in colon primary tumor and lung metastasis and its relationship with macrophages.
Methods
The SOCS3 expression pattern and its relationship with the immune response in pan-cancer was investigated using multiple methods. Samples and corresponding clinical information of 32 colon cancer patients with lung metastasis were collected, and the CD68, CD163, and SOCS3 status were conducted using immunohistochemistry (IHC). The relationship between SOCS3 status and macrophage markers was analyzed. Besides, we explored the molecular mechanisms of SOCS3 in lung metastasis via the TCGA database.
Results
High SOCS3 expression was more inclined to poor prognosis and was positively correlated with main immune cell infiltration in almost each cancer type, especially in colon cancer. Compared with the colon primary tumor, lung metastasis harbored higher CD163 and SOCS3 expression, and high SOCS3 expression was more likely to be associated with high CD163 expression in lung metastasis. Besides, the exceptional differentially expressed genes in lung metastasis significantly enriched in immune responses and regulations.
Conclusions
SOCS3 possessed value as a prognostic marker and target for immunotherapeutic intervention in different tumors and might be a potential target of tumor progression and tumor immunotherapy in colon cancer.
... Apart from the intrinsic regulatory mechanisms, stem cell activity is also modulated by extrinsic cues such as inflammation. Previous studies have shown that in non-neural tissues, inflammation negatively affects tissue restoration (Mourkioti and Rosenthal 2005;Keshav 2006;Rigby et al. 2007;Koning et al. 2013). Hence, elucidating the connection between inflammation and NSC activity is necessary to understand how the NSCs respond to alcohol intoxication. ...
Alcohol consumption is known to cause several brain anomalies. The pathophysiological changes associated with alcohol intoxication are mediated by various factors, most notable being inflammation. Alcohol intoxication may cause inflammation through several molecular mechanisms in multiple organs, including the brain, liver and gut. Alcohol-induced inflammation in the brain and gut are intricately connected. In the gut, alcohol consumption leads to the weakening of the intestinal barrier, resulting in bacteria and bacterial endotoxins permeating into the bloodstream. These bacterial endotoxins can infiltrate other organs, including the brain, where they cause cognitive dysfunction and neuroinflammation. Alcohol can also directly affect the brain by activating immune cells such as microglia, triggering the release of pro-inflammatory cytokines and neuroinflammation. Since alcohol causes the death of neural cells, it has been correlated to an increased risk of neurodegenerative diseases. Besides, alcohol intoxication has also negatively affected neural stem cells, affecting adult neurogenesis and causing hippocampal dysfunctions. This review provides an overview of alcohol-induced brain anomalies and how inflammation plays a crucial mechanistic role in alcohol-associated pathophysiology.
Graphical Abstract
... The Socs3 down-regulation was observed only in activated SMRT KD cDC1 after 6h activation, which suggested that the initial events of IL-10 and STAT3 decrease through downregulation of mTOR activity are somehow leading to SOCS3 decrease. To our surprise, we found that SOCS3 and STAT3 both are down regulated in SMRT KD cDC1, as in several reports it has been documented that decreased SOCS3 favors enhanced STAT3 (49). We hypothesize that it could be due to the dynamic time dependent regulation of STAT3 and SOCS3 in CpG activated SMRT KD cells. ...
Dendritic cell (DC) fine-tunes inflammatory versus tolerogenic responses to protect from immune-pathology. However, the role of co-regulators in maintaining this balance is unexplored. NCoR1-mediated repression of DC immune-tolerance has been recently reported. Here we found that depletion of NCoR1 paralog SMRT (NCoR2) enhanced cDC1 activation and expression of IL-6, IL-12 and IL-23 while concomitantly decreasing IL-10 expression/secretion. Consequently, co-cultured CD4⁺ and CD8⁺ T-cells depicted enhanced Th1/Th17 frequency and cytotoxicity, respectively. Comparative genomic and transcriptomic analysis demonstrated differential regulation of IL-10 by SMRT and NCoR1. SMRT depletion represses mTOR-STAT3-IL10 signaling in cDC1 by down-regulating NR4A1. Besides, Nfkbia and Socs3 were down-regulated in Ncor2 (Smrt) depleted cDC1, supporting increased production of inflammatory cytokines. Moreover, studies in mice showed, adoptive transfer of SMRT depleted cDC1 in OVA-DTH induced footpad inflammation led to increased Th1/Th17 and reduced tumor burden after B16 melanoma injection by enhancing oncolytic CD8⁺ T-cell frequency, respectively. We also depicted decreased Ncor2 expression in Rheumatoid Arthritis, a Th1/Th17 disease.
... The Socs3 down-regulation was observed only in activated SMRT KD cDC1 after 6h activation, which suggested that the initial events of IL-10 and STAT3 decrease through downregulation of mTOR activity are somehow leading to SOCS3 decrease. To our surprise, we found that SOCS3 and STAT3 both are down regulated in SMRT KD cDC1, as in several reports it has been documented that decreased SOCS3 favors enhanced STAT3 [51]. We hypothesize that it could be due to the dynamic time dependent regulation of STAT3 and SOCS3 in CpG activated SMRT KD cells. ...
Dendritic cell (DC) fine-tunes inflammatory versus tolerogenic responses to protect from immune-pathology. However, the role of co-regulators in maintaining this balance is unexplored. NCoR1-mediated repression of DC immune-tolerance has been recently reported. Here we found that depletion of NCoR1 paralog SMRT (NCoR2) enhanced cDC1 activation and expression of IL-6, IL-12 and IL-23 while concomitantly decreasing IL-10 expression/secretion. Consequently, co-cultured CD4 ⁺ and CD8 ⁺ T-cells depicted enhanced Th1/Th17 frequency and cytotoxicity, respectively. Comparative genomic and transcriptomic analysis demonstrated differential regulation of IL-10 by SMRT and NCoR1. SMRT depletion represses mTOR-STAT3-IL10 signaling in cDC1 by down-regulating NR4A1. Besides, Nfkbia and Socs3 were down-regulated in Ncor2 ( Smrt ) knockdown cDC1, supporting increased production of inflammatory cytokines. Moreover, studies in mice showed, adoptive transfer of SMRT knockdown cDC1 in OVA-DTH induced footpad inflammation led to increased Th1/Th17 and reduced tumor burden after B16 melanoma injection by enhancing oncolytic CD8 ⁺ T-cell frequency, respectively. We also depicted decreased Ncor2 expression in Rheumatoid Arthritis, a Th1/Th17 disease.
... This was mediated by tumor-derived G-CSF driven proliferation of myeloid-derived suppressor cells in the tumor microenvironment via STAT3, which suppressed CD8+ T cell responses against the tumor (245). In mice models of colitis associated cancer, SOCS3 deletion in intestinal epithelial cells (IEC) exacerbated the development of cancer through constitutive STAT3 activation leading to IEC proliferation (246,247). Furthermore, downregulation of SOCS3 was also observed in patients where colitis resulted in carcinogenesis, suggesting that loss of inhibition on STAT3 promotes the development of cancer during colitis (248). ...
Cytokine signaling represents one of the cornerstones of the immune system, mediating the complex responses required to facilitate appropriate immune cell development and function that supports robust immunity. It is crucial that these signals be tightly regulated, with dysregulation underpinning immune defects, including excessive inflammation, as well as contributing to various immune-related malignancies. A specialized family of proteins called suppressors of cytokine signaling (SOCS) participate in negative feedback regulation of cytokine signaling, ensuring it is appropriately restrained. The eight SOCS proteins identified regulate cytokine and other signaling pathways in unique ways. SOCS1–3 and CISH are most closely involved in the regulation of immune-related signaling, influencing processes such polarization of lymphocytes and the activation of myeloid cells by controlling signaling downstream of essential cytokines such as IL-4, IL-6, and IFN-γ. SOCS protein perturbation disrupts these processes resulting in the development of inflammatory and autoimmune conditions as well as malignancies. As a consequence, SOCS proteins are garnering increased interest as a unique avenue to treat these disorders.
... In some types of cancer, the role of SOCS3 seems controversial. Although there are reports of either increased or decreased SOCS3 expression in breast and prostate cancer, SOCS3 functions as a tumor suppressor in most cancer types including gastric cancer, HCC, and colon cancer (Rigby et al., 2007;Kershaw et al., 2013). It has been demonstrated that SOCS3 deletion in the liver resulted in hyperactivation of STAT3 and promoted chemical-induced liver fibrosis (Ogata et al., 2006a). ...
Modern diets, which often feature high levels of fat and charcoal-grilled meat, contribute to the pathogenesis of obesity and nonalcoholic fatty liver disease (NAFLD), resulting in liver cancer progression. Benzo(a)pyrene (B[a]P) is a common environmental and foodborne pollutant found in smoke and fire-grilled foods, which can have an adverse effect on human health. Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer and the second leading cause of cancer-related deaths worldwide. The epidemiological studies suggest that both environmental risk factors and chronic liver injury including NAFL are important for HCC development, but the precise mechanisms linking eating habits to hepato-carcinogenesis remain unclear. In the present study, we demonstrated that various miRNAs in B[a]P-exposed tumor cells contribute to tumor metastasis, among which miR-650 could be the most potent inducer. Furthermore, we found that suppressor of cytokine signaling 3 (SOCS3) is directly regulated by miR-650 and its suppression regulates the activation of the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) cascade. Our findings reveal a possible adverse outcome pathway of SOCS3/JAK/STAT3 regulation in B[a]P-induced HCC progress. These results provide a better understanding of the adverse effects of chronic exposure to B[a]P on human health.
... Inflammatory cytokines stimulate the activation of STAT3 signaling, which in turn contributes to promoted epithelial cell survival and resistance to apoptosis (5). STAT3 is critical for intestinal regeneration and tumorigenesis by regulating survival, cell cycle progression, and inflammation (50). Hyperactivation of STAT3 in epithelial cells has been linked to the development of CRC. ...
Receptor-interacting protein 3 (RIPK3), a member of the family of serine/threonine protein kinases, emerged as a critical regulator of necroptosis. Downregulated expression of RIPK3 is correlated with poor prognosis in multiple tumor types. Here, we show that RIPK3 is involved in the progression of spontaneous intestinal tumorigenesis. As a clinical correlate, reduced expression of RIPK3 is positively associated with histological grade, lymphatic metastasis and poor prognosis in CRC patients. RIPK3-deficient (Ripk3-/- ) mice exhibit increased tumor formation in Apcmin/+ spontaneous intestinal tumorigenesis. Apcmin/+Ripk3-/- tumors promote hyperactivation of IL-6/STAT3 signaling, which exacerbates proliferation and inhibits apoptosis. Blocking IL-6 signaling suppressed tumor formation and reduced STAT3 activation in Apcmin/+Ripk3-/- mice. Thus, our results reveal that RIPK3 is a tumor suppressor in spontaneous intestinal tumorigenesis, and implicate targeting the IL-6/STAT3 signaling axis as a potential therapeutic strategy for intestinal tumor patients with reduced RIPK3.
... STAT3 (IL-6/STAT3, IL-22/STAT3 pathways): Various cytokine pathways leading to STAT3 activation have been implicated in IBD and CAC (in particular, IL-6/STAT3 signaling has been shown to have anti-apoptotic effects on T cells and anti-apoptotic and proproliferative effects on intestinal epithelial cells) [67 , 73 , 74] . The suppressor of cytokine signaling (SOCS) 3 protein is a key regulator of cytokine-mediated STAT3 signaling [75] , and has been shown to have a role in the pathogenesis of IBD and CAC [75][76][77] . In a mouse model of colitis and CRC, the anti-inflammatory cytokine, TGF-ß, was shown to have an anti-proliferative effect related to inhibition of the IL-6/STAT3 pathway [78] . ...
The risk of colorectal cancer (CRC) is higher in patients with inflammatory bowel disease (IBD). Population-based data from patients with ulcerative colitis (UC) estimate that the risk of CRC is approximately 2- to 3-fold that of the general population; patients with Crohn's disease appear to have a similar increased risk. However, the true extent of colitis-associated cancer (CAC) in undertreated IBD is unclear. Data suggest that the size (i.e., severity and extent) and persistence of the inflammatory process is largely responsible for the development of CRC in IBD. As patients with IBD and CRC have a worse prognosis than those without a history of IBD, the impact of current therapies for IBD on CAC is of importance. Chronic inflammation of the gut has been shown to increase the risk of developing CAC in both UC and CD. Therefore, control of inflammation is pivotal to the prevention of CAC. This review presents an overview of the current knowledge of CAC in IBD patients, focusing on the role of inflammation in the pathogenesis of CAC and the potential for IBD drugs to interfere with the process of carcinogenesis by reducing the inflammatory process or by modulating pathways directly involved in carcinogenesis.
... Here, KSHV infection is associated with an increase in IL-6 expression which results in increased expression of the suppressor of cytokine signaling 3 (SOCS3). SOCS3 is associated with inhibition of neutrophil recruitment to areas of inflammation by inhibition of mediators such as IL-1 and TNFα [26]. In HIV-associated KS patients, neutrophil function has been reported to be compromised [27]. ...
Kaposi's sarcoma (KS) is an angioproliferative malignancy whose associated etiologic agent is the Kaposi's sarcoma-associated herpesvirus (KSHV). KS is the most prevalent malignancy among HIV-infected individuals globally and is considered an AIDS-defining malignancy. The different forms of KS including HIV-associated KS, iatrogenic (immunosuppression-related) KS, and classical KS in elderly males suggest that immune cell dysregulation is among the key components in promoting KS development in KSHV-infected individuals. It is therefore expected that different cell types of the immune system likely play distinct roles in promoting or inhibiting KS development. This narrative review is focused on discussing cells of the innate and adaptive immune systems in KSHV infection and KS pathogenesis, including how these cells can be useful in the control of KSHV infection and treatment of KS.
... 39 Lack of SOCS3 contributes to accelerative intestinal crypt growth and facilitates tumour growth. 40 In the current study, OCA treatment increased the mRNA and protein levels of SOCS3. Similarly, restoration of SOCS3 by FXR agonist GW4064 is observed in hepatocellular inflammation and HCC, 41,42 indicating that FXR-SOCS3 axis may serve as a new potential target for the prevention and treatment of HCC. ...
Farnesoid X receptor (FXR, encoded by NR1H4), a bile acid-activated nuclear receptor, is widely implicated in human tumorigenesis. The FXR agonist obeticholic acid (OCA) has preliminarily displayed tumour suppressor potential. However, the anticancer effects of this agent on colorectal cancer (CRC) remain unclear. In this study, the treatment of colon cancer cells with OCA inhibited cell proliferation and invasion in vitro, retarded tumour growth in vivo and prevented the G0 /G1 to S phase transition. Moreover, the expression of active caspase-3, p21 and E-cadherin was up-regulated and the expression of cyclin D1, c-Myc, vimentin, N-cadherin and MMP9 was down-regulated in OCA-treated colon cancer cells. Mechanistic studies indicated that OCA treatment suppressed the activity of JAK2/STAT3 pathway by up-regulating SOCS3 expression. Colivelin, an agonist of JAK2/STAT3 pathway, antagonized the tumour-suppressive effect of OCA on colon cancer cells. Dual-luciferase reporter and quantitative chromatin immunoprecipitation (qChIP) assays further confirmed that OCA promoted SOCS3 transcription by enhancing the binding of FXR to the FXRE/IR9 of the SOCS3 promoter. In conclusion, our study demonstrates that targeting FXR and improving its function might be a promising strategy for CRC treatment.
