|Year : 2017 | Volume
| Issue : 2 | Page : 337-345
Significance of expression of suppressor of cytokine signaling proteins: Suppressor of cytokine signaling-1, suppressor of cytokine signaling-2, and suppressor of cytokine signaling-3 in papillary thyroid cancer
Toral Pundrik Kobawala, Trupti I Trivedi, Kinjal Kevin Gajjar, Girish H Patel, Nandita R Ghosh
Division of Molecular Endocrinology, Department of Cancer Biology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
|Date of Web Publication||23-Jun-2017|
Nandita R Ghosh
Division of Molecular Endocrinology, Department of Cancer Biology, Gujarat Cancer and Research Institute, New Civil Hospital Compound, Asarwa, Ahmedabad - 380 016, Gujarat
Source of Support: None, Conflict of Interest: None
Purpose: Uncontrolled cytokine signal transduction largely associated with oncogene activation, can have disastrous biological consequences. The suppressor of cytokine signaling (SOCS) proteins represent one of the mechanisms by which this rampant signaling can be dissipated. Thus, we aimed to study the expression of SOCS-1, SOCS-2, and SOCS-3 in patients having benign thyroid disease and papillary thyroid cancer.
Materials and Methods: SOCS protein expression was studied in 45 patients with benign thyroid disease and in 83 papillary thyroid cancer patients by immunohistochemistry and their association with clinicopathological characteristics and overall survival in cancer patients were analyzed using SPSS software.
Results: Expressions of SOCS proteins were significantly higher in papillary thyroid cancer than in patients having benign disease. SOCS-1 expression was predominantly higher in males (P = 0.004), unilateral tumors (P = 0.030), and noninflammatory conditions (P = 0.028). SOCS-1 expression was also able to predict poor overall survival in subgroup of papillary thyroid cancer patients having larger tumor size (P = 0.013) and advanced stage disease (P = 0.033). Expression of SOCS-2 significantly correlated with tumor size (P = 0.017), extrathyroidal extension (P = 0.000), residual disease (P = 0.043), and treatment (P = 0.007), while preponderance of SOCS-3 expression was observed in males (P = 0.030) and in patients having extrathyroidal extension (P = 0.011) and absence of metastasis (P = 0.032).
Conclusion: Expression of the studied SOCS proteins may be a consequence of activation of Janus kinase-signal transducers and activators of transcription and other pathways supporting growth and survival of cancer cells that are sustained by several cytokines. Thus, SOCS-1, SOCS-2, and SOCS-3 proteins may directly or indirectly, have important roles in development and pathogenesis of papillary thyroid cancer.
Keywords: Immunohistochemistry, papillary thyroid cancer, suppressor of cytokine signaling, suppressor of cytokine signaling-1, suppressor of cytokine signaling-2, suppressor of cytokine signaling-3
|How to cite this article:|
Kobawala TP, Trivedi TI, Gajjar KK, Patel GH, Ghosh NR. Significance of expression of suppressor of cytokine signaling proteins: Suppressor of cytokine signaling-1, suppressor of cytokine signaling-2, and suppressor of cytokine signaling-3 in papillary thyroid cancer. J Can Res Ther 2017;13:337-45
|How to cite this URL:|
Kobawala TP, Trivedi TI, Gajjar KK, Patel GH, Ghosh NR. Significance of expression of suppressor of cytokine signaling proteins: Suppressor of cytokine signaling-1, suppressor of cytokine signaling-2, and suppressor of cytokine signaling-3 in papillary thyroid cancer. J Can Res Ther [serial online] 2017 [cited 2022 Aug 19];13:337-45. Available from: https://www.cancerjournal.net/text.asp?2017/13/2/337/174172
| > Introduction|| |
Thyroid cancer is the most common endocrine malignancy and has a relatively small contribution to overall burden of cancer accounting for about 1–1.5% of all newly diagnosed cancer cases. The National Cancer Institute indicates that thyroid cancer is the most common type of endocrine-related cancer and estimates 62,980 new cases in 2014. Thyroid cancer represents approximately 3.8% of all new cancer cases. Moreover, it has been estimated that a much greater number of patients develop clinically significant thyroid nodules by 60 years of age. Because of this high prevalence of benign and malignant thyroid disease worldwide, the exploration of underlying mechanisms and potential risk factors has become a major scientific interest.
Thyroid diseases have been closely associated with inflammation, even though their precise relationship remains to be elucidated. Experimental and clinical evidence suggests that thyroid cancer growth and progression are largely mediated by oncogene activation. Further this oncogene activation appears to be mainly associated with the production of various cytokines having proinflammatory properties.,,,,,, These inflammatory mediators are the hallmarks of cancer-related inflammation that induce the remodeling of tumor tissue and stimulate angiogenesis and thus enhance tumor progression.,
Cytokines are secreted proteins that regulate diverse biological functions by binding to receptors at the cell surface to activate complex signal transduction pathways. The pathways by which cytokines exert their biologic effects have been under extensive investigation over past few years. Cytokines bind to multi subunit receptor complexes and activate Janus kinases (JAKs), which in turn phosphorylate many downstream pathways including signal transducers and activators of transcription (STATs), mitogen-activated protein kinases, and phosphoinositol 3-kinase (PI3K). In fact, the JAK-STAT pathway is one of the most important mechanisms by which cytokines activate gene transcription. When cytokines bind to receptors on the cell surface, they cause receptor oligomerization, which in turn induces JAK activation. The activated JAKs, in turn, phosphorylate the cytokine receptors, leading to the recruitment and subsequent activation of other signaling molecules such as STAT family proteins. The activated STAT proteins form dimmers and translocate into the nucleus where they influence transcription of various target genes.
Rampant cytokine signal transduction can have disastrous biological consequences such as over proliferation, differentiation, survival, and functional activation. Hence, subsequent dissipation of this signaling is essential to ensure that response of the cell does not become pathogenic. The suppressor of cytokine signaling (SOCS) proteins represent one key mechanism by which this level of control is achieved., There are eight mammalian SOCS family members; SOCS1-7 and cytokine-inducible SH2-containing protein. Individual SOCS proteins negatively regulate signaling by several mechanisms: They can recognize cytokine receptors or the associated JAKs and attenuate signal transduction either by direct interference with signaling or by targeting the receptor complex for ubiquitin-mediated proteasomal degradation and prevention of nuclear translocation of key signaling molecules.,
Among all, SOCS1-3 are most often associated with the cytokine signaling through JAK-STAT pathway. All the three SOCS proteins: SOCS-1, SOCS-2, and SOCS-3 are known to be induced by cytokine receptors and serve to extinguish signaling from the same receptor, providing a classical negative feedback loop. This occurs via activation of receptor associated JAKs, which phosphorylate tyrosine residues on the receptor complex to recruit signaling molecules such as STAT proteins. These also become phosphorylated, form dimmers and then are translocated into the nucleus, where they stimulate transcription of target genes. These target genes include SOCSgenes, the encoded proteins of which are able to inhibit receptor signaling, creating a negative feedback loop. SOCS-1 and SOCS-3 can directly inhibit JAK kinases, whereas SOCS-2 and SOCS-3 inhibit signaling through their ability to bind to phosphotyrosine residues on receptors and can thereby block access of other SH2-containing signaling molecules. In addition, there are several observations showing a relationship between dysregulated levels of SOCS proteins and cancer development. In thyroid cancer cells, the real time PCR analysis showed that the mRNA expressions of SOCS-1 and SOCS-3 were lower than that demonstrated in normal thyrocytes. Recently, De Santis et al. also reported that SOCS-1 was markedly down-regulated in tumor tissue of papillary thyroid cancer compared to surrounding normal host tissue. However, the present study is novel in terms of determining the protein expression of SOCS-1, SOCS-2, and SOCS-3 by immunohistochemical analysis for 1st time, in papillary thyroid cancer. Hence, we aimed to explore the occurrence of these SOCS proteins and their potential relationship with various clinicopathological parameters and also to assess their prognostic values in papillary thyroid carcinoma patients.
| > Materials and Methods|| |
Total 83 untreated patients with histologically confirmed papillary thyroid cancer and 45 patients with benign thyroid disease (e.g. - goiter, follicular adenoma, thyroiditis), who underwent surgery between 2008 and 2012 at the Department of Surgical Oncology of our institute, were enrolled in this study. Written consent of the patients was obtained prior to primary tumor tissue collection. The clinicians of the institute decided the treatment strategies. The clinical and histopathological details of all the patients were noted from the case files maintained at the Medical Record Department of the institute. Histological classification of the tumors was in accordance with the WHO classification. The disease was staged according to the American Joint Committee on Cancer tumor node metastasis (TNM) staging system. As in this staging system, patients are staged on the basis of their age (< 45/≥ 45 years), we have also grouped our patients into a younger (< 45 years) and an older group (≥ 45 years) [Table 1]. The patients were followed for a period of 4 years or until death within that period. For survival analysis, complete follow-up details was obtained in 76 out of total 83 papillary thyroid carcinoma patients. This study has been approved by the Institutional Review Board and Ethics Committee.
|Table 1: Clinicopathological parameters of papillary thyroid cancer patients|
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For immunohistochemistry, paraffin embedded tissue blocks were obtained from the Histopathology Department and 4 μm thick tissue sections were mounted on 3-aminopropyltriethoxysilane–coated glass slides. The immunohistochemical analysis was carried out using MACH4 universal horseradish peroxidase-polymer detection system from Biocare Medical, USA; as per manufacturer's protocol recommendations. Rabbit polyclonal primary antibodies for immunostaining of SOCS-1 (H-93), SOCS-2 (H-74), and SOCS-3 (H-103) from Santa Cruz Biotechnology, CA, USA, at dilution of 1:50 in Tris buffer saline (pH 8), were used. The antigen retrieval was carried out by heating the tissue sections in 10 mM citrate buffer (pH 6.0) for 20 min in a pressure cooker, prior to application of the respective primary antibodies.
All the sections were scored independently by two individual observers in a blinded fashion. A semi quantitative immunoreactive score (IRS) method of Remmele and Stegner was implemented. Staining positivity was scored as 0 for no stained cells, 1 for staining in 11–30% of cells, 2 for staining in 31–50% of cells, 3 for staining in 50–80% of cells, and 4 for staining in >80% of cells; whereas the staining intensity was scored as 0 for no staining, 1 for weak/faint staining, 2 for moderate staining, and 3 for intense/dark staining intensity. The IRS score was then obtained by multiplying the staining positivity and the staining intensity and therefore, theoretically the scores could range from 0 to 12 with 6.5 as the median score. An IRS score below the median score, i.e., for scores ranging from 0 to 6 the expression was considered as weak, whereas for scores ranging from 7 to 12, the expression was considered as strong.
The data were analyzed statistically using the SPSS software (SPSS Base 10; SPSS Inc., Chicago, IL, USA, 1999). To compare the expression of proteins in benign and carcinoma patients, independent samples t-test and two sided Fisher's exact test were used. The two-tailed Chi-square test was used to assess associations between the SOCS proteins and clinicopathological parameters of carcinoma patients and correlation between two parameters was calculated using Spearman's correlation coefficient (r). Overall survival curves were generated with the Kaplan–Meier survival function. Differences in survival were tested for statistical significance using the log-rank statistic. P≤ 0.05 were considered significant.
| > Results|| |
Incidence of suppressor of cytokine signaling protein expression in benign versus papillary thyroid carcinoma patients
Cytoplasmic protein expression of SOCS-1, SOCS-2, and SOCS-3 was observed in both benign as well as papillary thyroid carcinoma patients. The independent samples t-test revealed that the expression of all the three SOCS proteins was significantly higher in papillary thyroid carcinoma patients (mean ± standard error [SE] of IRS score: SOCS-1 = 6.58 ± 0.42, SOCS-2 = 7.20 ± 0.37, and SOCS-3 = 5.02 ± 0.42) as compared to that of patients with benign thyroid disease (mean ± SE of IRS score: SOCS-1 = 2.98 ± 0.47, SOCS-2 = 4.27 ± 0.52, and SOCS-3 = 2.80 ± 0.41) (SOCS-1: P= 0.000, SOCS-2: P= 0.000, and SOCS-3: P= 0.001) [Figure 1]. Further, when patients were subgrouped as having weak expression (IRS score ≤ 6) and strong expression (IRS score > 6), in papillary thyroid carcinoma patients, strong SOCS-1, SOCS-2, and SOCS-3 expression was observed in 37.3%, 45.8% and 28.9% patients, respectively, as compared to only 11.1%, 24.4%, and 8.9% patients with benign thyroid disease showing strong expression for SOCS-1, SOCS-2, and SOCS-3, respectively. This indicates that the incidence of strong SOCS protein expression was significantly higher in papillary thyroid carcinoma than that in patients with benign thyroid disease (SOCS-1: P= 0.002, SOCS-2: P= 0.022, and SOCS-3: P= 0.013) [Table 2].
|Figure 1: Expression of suppressor of cytokine signaling proteins in benign thyroid disease versus papillary thyroid carcinoma patients|
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|Table 2: Incidence of suppressor of cytokine signaling protein expression in benign versus papillary thyroid carcinoma patients|
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Correlation of suppressor of cytokine signaling protein expression with clinicopathological parameters of papillary thyroid carcinoma patients
The relation of SOCS immunoreactivity with clinicopathological parameters is depicted in [Table 3].
|Table 3: Correlation of expression of suppressor of cytokine signaling proteins with clinicopathological characteristics of papillary thyroid carcinoma patients|
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Preponderance of SOCS-1 expression was found in male patients (χ2 = 8.210, r = 0.315, P= 0.004), in unilateral tumors (χ2 = 4.700, r = −0.238, P= 0.030) and in noninflammatory conditions (χ2 = 4.840, r = −0.241, P= 0.028) when compared to their respective counterparts. No such significant correlation was observed with other clinicopathological parameters.
Predominant positive correlations of SOCS-2 protein expression were established with the tumor size (χ2 = 5.697, r = 0.262, P= 0.017), extrathyroidal extension of the tumors (χ2 = 12.643, r = 0.390, P= 0.000) and presence of residual disease (χ2 = 4.132, r = 0.223, P= 0.043). SOCS-2 expression was also found to be significantly higher in the majority of the patients who were postoperatively treated with both radioiodine ablation (RIA) therapy and radiotherapy, rather than in patients who were treated only by surgery or surgery followed by RIA therapy (χ2 = 7.117, r = 0.293, P= 0.007).
Stronger expression of SOCS-3 was found to be significantly higher in males (χ2 = 4.695, r = 0.238, P= 0.030), absence of distant metastasis (χ2 = 4.625, r = −0.236, P= 0.032), and presence of extrathyroidal extension of the tumors (χ2 = 6.353, r = 0.277, P= 0.011) when compared to that in females, presence of distant metastasis, and absence of extrathyroidal extension, respectively. Significant correlations were not observed with the other clinicopathological parameters [Table 3].
Survival analysis in papillary thyroid cancer patients in relation to suppressor of cytokine signaling protein expression
In total patients with papillary thyroid carcinoma, univariate analysis revealed that none of the studied SOCS proteins were able to predict overall survival (SOCS-1: Log-rank = 2.588, df = 1, P= 0.108; SOCS-2: Log-rank = 0.014, df = 1, P= 0.907; and SOCS-3: Log-rank = 1.149, df = 1, P= 0.284). Further, when subgrouped according to clinicopathological parameters, the Kaplan–Meier survival curve demonstrated that high SOCS-1 expression was remarkably associated with poor overall survival in patients with larger tumor size (log-rank = 6.204, df = 1, P= 0.013) [Figure 2], as well as in those having advanced stage of the disease (log-rank = 4.206, df = 1, P= 0.040) [Figure 3]. In subgroup of patients with larger tumor size, within a period of 48 months, 31% (5/16) of patients showing stronger expression for SOCS-1 protein died as compared to only 4% (1/27) patients with weak SOCS-1 expression. Within the same period, 42% (5/12) of advanced stage patients exhibiting stronger expression for SOCS-1, died in comparison to only 9% (2/21) advanced stage patients with weak SOCS-1 expression. Whereas no association of SOCS-1 expression was observed with overall survival in subgroup of patients with smaller tumor size or early stage papillary thyroid carcinoma patients [Table 4]. SOCS-2 and SOCS-3 expressions were not able to predict survival even in any of the clinicopathological subgroups of patients with papillary thyroid carcinoma.
|Figure 2: Kaplan–Meier survival curve of papillary thyroid cancer patients with larger tumor size in relation to suppressor of cytokine signaling-1 expression|
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|Figure 3: Kaplan–Meier survival curve of patients with advanced stage papillary thyroid carcinoma in relation to suppressor of cytokine signaling-1 expression|
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|Table 4: Univariate survival analysis (Kaplan–Meier survival function) of suppressor of cytokine signaling-1 expression|
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| > Discussion|| |
The SOCS proteins which have been identified as the negative feedback regulators of cytokine mediated signaling in various tissues have also been implicated to play critical roles in the oncogenesis of various solid tumors and hematological malignancies.,,,,,, However, little information exists regarding the significance of association of SOCS protein expressions with clinicopathological features and prognosis of thyroid cancer. Therefore, in this study, we sought to elucidate the expression of SOCS-1, SOCS-2, and SOCS-3 of the SOCS family members and reveal their association with clinicopathological parameters and overall survival in papillary thyroid cancer patients by immunohistochemistry.
In this study, we observed expression of all the three SOCS proteins in the cytoplasm of thyroid follicular cells of both benign and papillary thyroid cancer tissues. Wu et al. have also shown predominant cytoplasmic expression of SOCS-3 in the hepatic cells. Several observations showed a relationship between dysregulated levels of SOCS proteins and cancer development. Studies in hepatocellular carcinoma (HCC) and breast cancers have reported decreased expression of SOCS3 in the cancer cells as compared to respective adjacent nontumor tissues., Huang et al. found that SOCS-3 expression was higher in noninvasive urothelial carcinoma than in invasive urothelial carcinoma. SOCS-2 was also found to be significantly downregulated in colorectal cancer whereas SOCS-1 did not show statistically relevant difference in expression compared to normal mucosal tissue. Francipane et al. demonstrated that normal thyrocytes constitutively expressed SOCS-1 and SOCS-3 molecules, whereas their expressions were very low in thyroid cancer cells. In a study by De Santis et al., SOCS-1 was markedly downregulated in tumor tissue of papillary thyroid cancer compared to surrounding normal host tissue. Aberrant methylation of SOCS promoter genes has been reported in a variety of human cancers and strongly correlates with such reduced expression., 28, ,, Moreover, there is also a study which shows no significant difference between SOCS expressions in breast cancer specimens and in matched normal background tissues.
However, we observed significant higher expressions of the SOCS proteins in the studied papillary thyroid carcinoma patients as compared to the patients having benign disease. In accordance to our study, Yang et al. detected the expression of SOCS-3 in 87 HCC patients and observed that 67.8% of HCC lesions showed moderate to very strong SOCS-3 staining. In addition, Raccurt et al. described an increased SOCS-2 expression in cancerous ducts and reactive stroma as compared to normal breast tissues by in situ hybridization. Both SOCS-2 mRNA and protein expression were upregulated in prostate cancer tissues compared with those in noncancerous prostate tissues in a study by Zhu et al. Increased expression of SOCS-2 in malignancies such as chronicmyeloid leukemia , could contribute to transformation by negative interference with other SOCS molecules that normally would suppress tumor development. Moreover, persistent expression of SOCS-1 and/or SOCS-3 has also been observed in several haematological malignancies such as cutaneous T-cell lymphoma, chronicmyeloid leukemia, ALK+anaplastic large cell lymphoma, and some acute leukemia. In these circumstances, increased expression occurred with constitutive activation of JAK-STAT pathway.,,,, Moreover, a study in prostate cancer cell line showed increased expression of SOCS members on stimulation with interleukin-6. Thus, within the tumor microenvironment, cancer cells are sustained by several cytokines, which lead to activation of JAK-STAT and other pathways that support cancer cell growth and survival. Expression of SOCS proteins may be a consequenceof this, rather than a causing mechanism. In addition, there might be failure of other negative regulatory pathways acting upon the JAK-STAT pathway, inappropriate regulation of oncogene expression, or inappropriately enhanced oncogene function, which may overpower the capacity of SOCS proteins to reduce STAT activation. However, despite their overexpression in cancer cells, the inhibitory action of SOCS proteins may not have a significant impact on cancer cell proliferation and survival. Therefore, overall it can be suggested that increased SOCS expression may be a consequent mechanism of, rather than a factor contributing to, the cancer phenotype and malignant disease progression. The results of our study also support this concept for observation of high SOCS expression.
In present study, SOCS-1 significantly correlated with the male patients while its expression showed markedly inverse correlation with bilaterality of tumors and presence of inflammation in patients with papillary thyroid cancer. This indicates that the presence of stronger expression of SOCS-1 was significant in male patients, in unilateral tumors and in patients who had absence of inflammation in their tumors. A study on SOCS-1 mRNA demonstrated a significant decrease in its expression with increasing TNM stage in breast cancer. Other studies show that in gastric cancer, loss of SOCS-1 may be involved in lymph node metastasis and tumor progression, whereas restoration of its expression suppressed development and progression of HCC cells.
Stronger SOCS-2 expression predominantly correlated positively with the tumor size, extrathyroidal extension, residual disease and treatment in the studied papillary thyroid cancer patients. Thus, there is an increase in SOCS-2 expression with increase in size of the tumor, with extension of tumor beyond the thyroid gland as well as with the presence of residual disease and more severe treatment. This reveals that SOCS-2 is evident in more advancing clinicopathological status of tumors and that its expression may be helpful in predicting treatment in the papillary thyroid cancer patients. Sasi et al. reported that the expression of SOCS-2 mRNA was found to significantly increasewith higher tumor grade in breast cancer tissues. Conversely, others have shown markedly inverse correlation of SOCS-2 expression with pathological grade in breast cancer patients, with metastasis and gleason score in prostate cancer patients.,
Moreover we have observed a significant positive correlation of SOCS-3 expression with male patients, with patients having extrathyroidal extensions of the tumors and a near positive correlation was observed with tumor size, while an inverse correlation between the expression of SOCS-3 protein and presence of metastasis was also significant. In a recent report, exogenous expression of SOCS-1 and SOCS-3 in the highly aggressive anaplastic thyroid cancer cells has been shown to reduce or abolish STAT3 and STAT6 phosphorylation and PI3K/AKT pathway activation and resulted in alteration in the balance of proapoptotic and antiapoptotic molecules and sensitization to chemotherapeutic drugs in vitro. Likewise, exogenous expression of SOCS-3 was found to significantly reduce tumour growth and potently enhance the efficacy of chemotherapy in vivo. Further, a study in breast carcinoma revealed that deficient expression of SOCS-3 was significantly associated with lymph node metastasis, blood vessel invasion and reduced disease-free survival. Moreover, Nakagawa et al. also demonstrated that decreased expression of SOCS-3 mRNA was correlated with tumor lymph node metastasis in breast carcinoma. Similarly, SOCS-3 may also be involved in the suppression of tumor growth and metastasis of several malignancies including lung cancer, hepatocellular cancer, and head and neck squamous cell carcinoma.,, These observations strongly suggested a highly significant negative correlation between SOCS proteins and advancing clinicopathological stage and poorer differentiation of breast carcinoma. However, Yang et al. showed that increased expression of SOCS-3 was positively associated with tumor vascular invasion.
None of the studied SOCS proteins could predict overall survival in papillary thyroid carcinoma patients. However, strong SOCS-1 expression was considerably associated with poor overall survival in subgroup of patients with larger tumor size and advanced stage cancer. This is in accordance with a study where a group of breast cancer patients with low SOCS-1 expression exhibited longer overall survival, but this association of low SOCS-1 expression and good prognosis reached borderline statistical significance (P = 0.07). In contrast to this, high SOCS-1 expression was of significant benefit in predicting better overall survival in breast cancer patients. On the other, SOCS-2 expressions have shown favorable prognostic value in breast cancer. In addition, high SOCS-3 expression could predict better overall survival in breast cancer and HCC patients., While another group of researchers have shown association of increased SOCS-3 expression with poor overall survival, and the multivariate analysis revealed SOCS-3 as a significant determinant of the overall survival for HCC.
| > Conclusion|| |
In general, our study suggests that the expression of SOCS-1, SOCS-2, and SOCS-3 proteins may directly or indirectly, have important roles in differentiating thyroid cancer patients from benign group and also in development and pathogenesis of papillary thyroid carcinoma. However, contradictions in the literature reflect a complex role of these proteins in different types of malignancies and thus require further investigations. Our data could be further used to validate a clear mechanism of the JAK/STAT/SOCS interactions and their role in thyroid cancer that may in turn be helpful in identifying new therapeutic applications.
Financial support and sponsorship
This study was financially supported by Gujarat Cancer Society.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]
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