Suppressor of cytokine signaling 1 expression is affected by various cytokines and hormones. SOCS1 displays a potent antiproliferative effect on tumor cells and is dependent on the inhibition of STAT3 and on other signaling proteins (31). In non-small cell lung cancer cells, SOCS-1 inhibits the activity of FAK-dependent signaling pathway, except for JAK/STAT signaling, by suppressing the phosphorylation of FAK tyrosine (32, 33) and promoting polyubiquitination and the degradation of FAK in a SOCS box-dependent manner (21). In prostate cancer, SOCS1 expression decreases after androgen-deprivation treatments and is elevated in recurrent patients to inhibit cell proliferation. SOCS1 also exerts a growth-inhibitory function through downregulation of cyclin D1, cyclin-dependent kinases2 (CDK2), and CDK4, in prostate cancer (34). Furthermore, SOCS1 inhibits the invasion and migration of colorectal tumors by preventing the epithelial–mesenchymal transition and promoting the mesenchymal–epithelial transition by increasing E-cadherin and decreasing ZEB1 observed in cell lines and mouse xenograft models (35). SOCS1 expression exhibits a correlation with the clinical stages of colorectal tumors. Tumors at stages II–IV express lower levels of SOCS1 mRNA than those of tumors at stage I; additionally, SOCS1 protein is highly expressed in all of the well-differentiated adenocarcinomas (35). Thus, SOCS1 can be regarded as a molecular marker of the disease progression of colorectal tumors. SOCS1 expression in breast tumor tissues and cell lines might be caused by proinflammatory cytokine, growth hormone, and prolactin in the tumor microenvironment (36, 37), which result in the loss of sensitivity to subsequent prolactin stimulus (38). Breast cancer patients with positive expression of SOCS1 protein exhibit a decreased risk of detectable circulating tumor cells in the peripheral blood. Therefore, SOCS1 is critical for the successful control of tumor dissemination (39). High expression level of SOCS1 mRNA is associated with early tumor stages and improved clinical outcomes in breast cancer (40). SOCS1 expression in chronic myeloid leukemia correlates with poor cytogenetic response to IFN-α and short progression-free survival time (41). Evidence indicated that SOCS1 downregulates the biological functions of IFN (42, 43). Hence, aberrant SOCS1 expression might induce the resistance against IFN-α therapy and cause poor prognosis, which implied that SOCS1 might be a negative prognostic biomarker in the chronic myeloid leukemia treated with IFN-α.

Taken together, SOCS1 shows an antitumor effect in most of tumors through inhibiting tumor proliferation, attenuating tumor invasion, and reducing the sensitivity of tumor cells to cytokines or hormones. The expression of SOCS1 is associated with clinical stages of tumor. In tumors at early stage, elevated SOCS1 is frequently observed compared with those tumors at advanced stage, which could be regarded as a molecular marker of cancer progression. However, the concrete molecular mechanisms regulating the expression of SOCS1 in different stages of tumors have not been fully elucidated.

Suppressor of cytokine signaling 3 can act either as an oncogene or a tumor suppressor, depending on cellular context. SOCS3 is frequently silenced in cancer, thereby leading to a growth advantage for cancer cells. Similar to SOCS1, SOCS3 significantly diminishes the cell cycle regulatory proteins CDK2 and CDK4, cyclin E, and cyclin D1 in prostate tumor (44). The overexpression of SOCS3 induces apoptosis and partial G0/G1 arrest by inhibiting JAK1, ERK, and FAK signaling pathways in malignant pleural mesothelioma EHMES-1 and H226 cell lines. Furthermore, SOCS3 exhibits antitumor activity in a mesothelioma xenograft model, such as reducing tumor volume and tumor nodule weight and inducing tumor apoptosis (45).

Suppressor of cytokine signaling 3 can potentially hinder the receptor recruitment of the SH2 domain-containing tyrosine phosphatase to Tyr759 of gp130, which results in inhibition of ERK activation (9, 46). Methylation silencing of SOCS3 increases the IL-6/JAK/STAT3 and FAK phosphorylation in human hepatocellular carcinoma (9). The restoration of SOCS3 decreases STAT3 and FAK phosphorylation and FAK protein level, thereby inhibiting cell migration and growth (9). SOCS3 can also negatively control the STAT3/NF-κB signaling pathway in a triple-negative breast cancer model. Downregulation of SOCS3 correlates with increased level of IL-6 (47). The molecular and mutational analyses of breast cancers revealed that inactivation of tumor suppressors, p53, and PTEN is accompanied with downregulation of SOCS3, which is forcefully associated with the development and progression of triple-negative breast cancer (47). Additionally, the knockdown of p53 and PTEN in MCF10 cells promotes the downregulation of SOCS3 at translational/posttranslational level; such action is attributed to the proteasomal degradation after the activation of proinflammatory IL-6/STAT3/NF-κB signaling pathway rather than DNA methylation in colorectal and hepatocellular carcinomas (9, 48). This study provided a new understanding regarding the mechanism of SOCS3 silencing. SOCS3 can be also detected in breast cancer tissue samples because the number of analyzed samples is relatively small (3 normal breast tissues, 6 in situ ductal carcinomas, and 11 infiltrating ductal carcinomas) (37). Increasing the number of samples may be necessary to validate this contradictory result. Melanoma cells abnormally express high levels of SOCS3, which influences the responsiveness of melanoma cells to IFN-α and IFN-γ and consequently reduces the efficiency of immunotherapy (49). This study demonstrated that the expression of SOCS3 in melanoma is a disadvantage.

Suppressor of cytokine signaling 3 regulates numerous tumors through inhibition of various signaling pathways and functioning as a tumor suppressor gene. Similar to SOCS1, the expression and function of SOCS3 vary significantly among different tumor types. SOCS3 also promotes the progression of melanoma and attenuates the therapeutic efficacy of IFN-α and IFN-γ treatments. Therefore, a comprehensive understanding of the functions and mechanisms regulating the expression of SOCS1 and SOCS3 might facilitate their future clinical applications, either as diagnostic or prognostic biomarkers.

Suppressor of cytokine signaling 1 is critical in the regulation of the function of DCs (11). SOCS1-silenced DCs can induce an enhanced antigen-specific CTL response and antitumor activity (50). SOCS1 can maintain the self-tolerance of DCs at the host level through the constraint of IL-12 and downstream cytokine signaling cascade (51). Immunization with SOCS1^−/− DCs induces hyper Th1 immune responses and antitumor activities (52). During DCs differentiation, the STAT pathway is developmentally regulated; considerable increases of SOCS1, SOCS2, and SOCS3 are correlated with the downregulation of STAT6 (53) and regulate DCs maturation. In addition to the regulation of phosphokinase, SOCS3 can also regulate the metabolic enzyme in DCs. Indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme in the catabolic process of tryptophan, which is an essential amino acid for T-cell proliferation and activation (54). IDO⁺ DCs are a subset of human tolerogenic DCs that play a pivotal role in establishing an immunosuppressive microenvironment. The degradation of IDO in CD8⁺ DCs is mediated by SOCS3. SOCS3 binds mouse IDO, recruits the Elongin–Cullin–SOCS E3 ligase, and targets the IDO/SOCS3 complex for proteasomal degradation (55). Moreover, the IL-6-dependent upregulation of SOCS3 is responsible for inhibiting the IFN-driven transcriptional expression of IDO (56). Thus, an inverse relationship exists in DCs between SOCS3 and IDO. Furthermore, SOCS3 can bind to pyruvate kinase type M2 (M2-PK) in DCs. M2-PK is a key enzyme in glycolysis. The interaction of SOCS3 with M2-PK reduces the ATP production and weakens the curative effect of antitumor immune therapy, which indicates that SOCS3 manipulates the activation and function of DCs in the tumor microenvironment (57) (Figure 1A). Hence, depending on the regulated enzymes, SOCS3 is probably both a promoter and an inhibitor for the function of DCs.

Macrophages express SOCS1 and SOCS3 (58, 59), and they are both rapidly inducible and present potent but distinct inhibitory roles. The increased infiltrating numbers of macrophages express SOCS3 in tumors with complete responses compared with those without response to chemotherapy (60). Given that SOCS3 inhibits the STAT3 signaling that is responsible for the inflammatory cytokine section of macrophage and that STAT3 signaling is highly activated in M1 macrophages, the expression of SOCS3 significantly regulates the macrophage differentiation and its proinflammatory properties (61).

Suppressor of cytokine signaling 3 is an important controller of macrophage phases and functions, which could regulate macrophage polarization. In macrophages, SOCS3 is knocked down by siRNA-prevented M1 activation; consequently, STAT3 activity is enhanced and the syntheses of NO and IL-6 is decreased, thereby suggesting that SOCS3 is necessary for development of M1 macrophages (13, 62). Recently, SOCS3 deficiency in macrophages exhibits a remarkable bias toward M2-like population and results in resistance to LPS-induced endotoxic shock. Conversely, SOCS2 deficiency enriches the M1-like phenotype. The SOCS3 in the macrophages suppresses M2 by inhibiting IL-4- and IL-12-induced STAT6 phosphorylation (63). Thus, SOCS3 is an essential controller of macrophage polarization and function, thereby promoting anti-inflammatory responses in the case of SOCS3 deficiency. Nevertheless, some studies proposed conflicting opinions. Some reports demonstrated that SOCS3 deficiency promotes M1 macrophage polarization in tumors (64, 65). In glioma, SOCS3-deficient bone marrow-derived macrophages display enhanced and prolonged expression of proinflammatory M1 cytokines, which contradicts the observation in inflammation (65). Suppression of SOCS3 (specific SOCS3 conditional knockout) in macrophages prevents cancer metastasis by modifying macrophage phase and inducing the production of antitumorigenic chemokine MCP2/CCL8 (61). These results implied that SOCS3 exerts remarkably different effects on macrophage differentiation and promotes M1 polarization in tumor deficiency of SOCS3. Inflammation overexpression of SOCS3 confers similar effects. The difference between these two phenomena might be attributed to the different microenvironments.

The genetic deletion of SOCS3, specifically in myeloid cells, significantly enhances tumor growth, which correlates with elevated levels of MDSCs in the tumor microenvironment. SOCS3 negatively regulates the G-CSF-induced generation of Gr-1⁺CD11b⁺ cells by inhibiting the JAK/STAT3 activation (66). The loss of SOCS3 in myeloid cells promotes the differentiation of BM-derived progenitor cells into Gr-1⁺CD11b⁺ MDSCs and the generation of immunosuppressive microenvironment (66). Their findings clearly demonstrated the importance of SOCS3 in restricting MDSC-mediated immunosuppression activity in tumor (Figures 1B,C). Further work should be performed to verify the critical function of SOCS3 as a negative regulator of MDSCs development and function in tumor environment.

The inhibition of Th1 differentiation by IL-6 is mediated by SOCS1. IL-6 upregulates the SOCS1 expression in activated CD4⁺ T cells, thereby interfering with the STAT1 phosphorylation and blocking Th1 differentiation (67). SOCS3 regulates the activation and differentiation of naive CD4⁺ T cells, preferentially promoting Th2 and inhibiting Th1 differentiation through the inhibition of IL-12-mediated STAT4 activation (68). SOCS1 and SOCS3 function contradictory in Th1 differentiation. SOCS1-deficient naive CD4⁺ T cells are predominantly differentiated into Th1 and poorly into Th17 in vitro. A large amount of IFN-γ in SOCS1-deficient T cells suppresses Th17 differentiation, which can be explained by the SOCS3-induced STAT3 suppression after STAT1 activation in SOCS1-deficient T cells (69). The TGF-β-mediated SMAD transcriptional activity is severely inhibited in SOCS1-deficient cells in the presence of IFN-γ. Therefore, SOCS1 is necessary for Th17 differentiation by suppressing the antagonistic effect of IFN-γ on both STAT3 and SMAD (69). SOCS1 promotes Th17 differentiation through upregulating STAT3 and SMAD signaling. Moreover, targeting SOCS1 in the T-cell compartment could represent a novel means to enhance the antitumor activity of exogenously administered IFN-α in melanoma (70). The overexpression of SOCS1 and SOCS3 in T cells inhibits IFN-α-induced phosphorylated STAT1 and the transcription of IFN-stimulated genes (3). Unlike the T-helper cells, Tregs are deficient in SOCS3 expression. The in vitro overexpression of SOCS3 in Tregs decreases their proliferation and Foxp3 expression. Similarly, some research found that SOCS3 removal in T-lymphocytes upregulates CTLA-4 expression, which shows that SOCS3 negatively regulates CTLA-4 level in T cells and provides a mechanistic explanation for the expansion of Tregs (71). IL-12 permits the conversion of mouse IL-17-producing CD8⁺ T (Tc17) cells to IL-17/IFN-γ-double producing CD8⁺ T (Tc17/IFN-γ) cells by the prohibitive epigenetic modifications of the SOCS3 gene promoters (72). This conversion mechanism for therapeutic tumor immunity can be manipulated because these Tc17/IFN-γ cells exhibit potent antitumor activities (Figure 1D).

The epigenetic dysregulation of SOCS family genes frequently occurs in cancer and causes gene silence, protein downregulation, and inactivation in relatively large number of tumor cells. The methylation status of SOCS genes varies in different types of tumors (73). SOCS3 hypermethylation is observed in cholangiocarcinoma (74, 75), head and neck squamous cell carcinoma (8), and lung cancer (76). SOCS1 hypermethylation is detected in myeloid leukemia (77–79), lymphoma (80), Barrett’s adenocarcinoma (81), and breast cancer (73). However, SOCS1 hypermethylation shows no correlation with clinical features, OS, and PFS in acute myeloid leukemia patients (79). Both phenomena can be detected in hepatocellular carcinoma (9, 82). miR-29b induces the demethylation of the SOCS1 gene promoter, which results in SOCS1 protein upregulation that is associated with reduced STAT3 phosphorylation and impaired NF-κB activity (83). The acetylation status of SOCS genes also influences the expression and function of SOCS proteins. Histone deacetylase inhibitor, that is, sodium butyrate, increases the transcript and protein expression levels of SOCS1 and SOCS3 by triggering the histone acetylation of SOCS1 and SOCS3 gene promoters in myeloproliferative neoplasm (84). Trichostatin A (TSA), a histone deacetylase inhibitor, suppresses JAK2/STAT3 signaling by increasing the expression of SOCS1 and SOCS3 in human colorectal cancer cells (85) and manipulates the expression of SOCS proteins in tumors. The somatic hypermutation of SOCS1 in lymphocyte-predominant Hodgkin lymphoma (lpHL) is accompanied with high JAK2 expression and STAT6 activation (86). Furthermore, the genomic deletions of the region encompassing SOCS1 are frequent in lpHL and affect the expression of SOCS1 (87). Several genomic single nucleotide polymorphisms within the locus of SOCS1 are associated with the dysfunction of SOCS1 in leukemia (88).

microRNAs are small non-coding RNAs that bind to complementary sequences on target mRNAs to induce gene silence and manipulate gene functions (89). miRNA-155 can modulate the differentiation and function of Th17 cells by targeting SOCS1. Pre-miR-155 inhibits the expression of SOCS1 and enhances the phosphorylation of STAT3 and STAT5 proteins (90). miR-19a and miR-19b could downregulate the expression of SOCS1 and SOCS3 in various tumors. miR-19a directly binds the 3′-UTR of the SOCS1 and regulates its expression in NSCLC cells; the transfection with miR-19a mimics significantly decreases the mRNA and protein levels of SOCS1 (91). Similarly, miR-19a significantly decreases SOCS3 mRNA and protein, whereas a miR-19a antagonist specifically reverses the inhibitory effect of miR-19a to SOCS3 (92). Furthermore, the miR-19a-mediated reduction of SOCS3 enhances the IFN-α and IL-6 signal transductions through STAT3 (92). The overexpression of miR-19b in human colon cancer cell line HT-29 cells downregulates the protein level of SOCS3, but not that of the SOCS3 mRNA. The downregulation of SOCS3 by miR-19b causes the phosphorylation of STAT3 and induces the expression of cyclinD1, which could promote cell proliferation by the transition from G1 phase to S and G2 phases (93). miR-221 directly inhibits the expression of SOCS3 and sensitizes prostate cancer cells to IFN-γ-mediated growth inhibition (94). Therefore, although few references have reported that miRNA-induced dysregulation of SOCS expression and function exerts significant influence on the clinical outcome of cancer patients, some miRNAs, such as miR-155, miR-19a, miR-19b, and miR-221, might be promising biomarker candidates in predicting and evaluating the clinical prognosis of certain tumor types.