Expression Of SOCS-3 Gene In Renal Carcinoma And Determination Of Its Methylation

Renal carcinoma is the leading cause of cancer death in the world, but the molecular mechanisms for its development have not been well characterized. The suppressors of cytokine signaling (SOCS) are inhibitors of cytokine signaling that function via the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. Eight SOCS proteins with similar structures have been identified so far. SOCS family members, however, have distinct mechanisms of inhibition of JAK/STAT signaling. Abnormalities of the JAK/STAT pathway are associated with cancer. Inhibition of signaling results in growth suppression in various cell types. Recently, the involvement of SOCS-1 in carcinogenesis has been reported. Here, we report identification of frequent hypermethylation in CpG islands of the functional SOCS-3 promoter that correlates with its transcription silencing in cell lines (lung cancer, breast cancer, and mesothelioma) and primary renal carcinoma tissue samples. Restoration of SOCS-3 in renal carcinoma cells where SOCS-3 was methylation silenced resulted in the down- regulation of active STAT3, induction of apoptosis, and growth suppression. Our results suggest that methylation silencing of SOCS-3 is one of the important mechanisms of constitutive activation of the JAK/STAT pathway in cancer pathogenesis. The data also suggest that SOCS-3 therapy may be useful in the treatment of cancer. The Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling plays important roles in a number of important biologic responses, including immune function, cellulargrowth,differentiation,and hematopoieses. Eight proteins, cytokine-inducible SH2-domain-containing protein (CIS) and suppressors of cytokine signaling 1-7 (SOCS-1-7), have been identified in the SOCS family so far. They contain a central SH2 domain, a conserved C terminus (the SOCS box), and a unique N terminus. Expression of SOCS-1-3 and CIS is induced by cytokine or growth factor stimulation, which directly antagonizes STAT activation as part of a classic feedback loop.SOCS family members have distinct mechanisms of inhibition of JAK/STAT signaling. For example, CIS is believed to antagonize signaling by blocking STAT receptor recruitment. SOCS-1 is believed to inhibit signaling through direct interaction with JAK activation. SOCS-3 can bind both the cytokine receptor and the JAK and isrecruited to the tyrosine-phosphorylated receptor, facilitating inhibition of the JAK. Another possible mechanism by which SOCS proteins attenuate signaling is to promote protein degradation.It has been reported that abnormalities of the JAK/STAT pathway are associated with cancer. For example, constitutive activation of the JAK was found in T cell childhood acute lymphoblastic leukemia. Transfection of a constitutively activated STAT3 results in tumorige nicity in nude mice. Constitutive activation of STAT3 correl- ates with cell proliferation in breast carcinoma and non-small-cell lung cancer (NSCLC) and also inhibits apoptosis. On the other hand, inhibition of JAK/STAT signaling results in suppression of cancer cell growth and induces apoptosis in various cancer types. These results suggest the significance of JAK/STAT activation in oncogenesis.Aberrant hypermethylation of promoter regions in CpG islands has been shown to be associated with transcriptiona silencing of the genes in various cancers. Recently, involvement of SOCS-1 in carcinogenesis has also been reported. SOCS-1 was found frequent lysilenced by hypermethylation in hepatocellular carcinoma (HCC), multiple myeloma, and hepatoblastomas.SOCS-1 appears to have tumor suppressor activity, and restoration of the SOCS-1 gene in HCC cells causes growth suppression and induction of apoptosis. However, silencing of SOCS-3 by promoter methylation in human renal carcinoma has not been reported. In this study, we demonstrate the correlation of methylation of the SOCS-3 promoter and its transcription silencing as well as growth-suppression activity of SOCS-3 in Renal carcinoma.In our study, we get out renal carcinoma tissues RNA.To make use of RT-PCR determine SOCS-3 appearance and contract with normal renal tissues, peri carcinoma.To approach the expression of SOCS-3 in renal carcinoma Objective: To investigate the expressions level of suppressors of cytokine signaling-3(SOCS-3) in renal carcinoma of human.Methods: The expression level of SOCS-3 was detected by RT-PCR, including ten human normal renal tissues, fifteen specimens peri tumor tissues, fifteen renal carcinoma tissues of human,and through the methalytion specificity PCR detect SOCS-3 methylation state.Results:1. In this experiment condition, compared to the normal renal specimens , the expression level of SOCS-3 in renal carcinoma was significantly lower or can't be detected (p<0. 05) .2.Through the methalytion specificity PCR detect SOCS-3 methylation state. We discover thirteen specimens tumor tissues SOCS-3 promotor methylation abnormality.Conclusion: This result show that the deletion of suppressor of cytokine signaling 3 is associated to the development and progress of renal carcinoma.