Abstract
Suppressor of cytokine signaling (SOCS) family is an important negative regulator of cytokine signaling and deregulation of SOCS has been involved in many types of cancer. All cervical cancer cell lines tested showed lower expression of SOCS1, SOCS3, and SOCS5 than normal tissue or cell lines. The immunohistochemistry result for SOCS proteins in human cervical tissue also confirmed that normal tissue expressed higher level of SOCS proteins than neighboring tumor. Similar to the regulation of SOCS in other types of cancer, DNA methylation contributed to SOCS1 downregulation in CaSki, ME-180, and HeLa cells. However, the expression of SOCS3 or SOCS5 was not recovered by the inhibition of DNA methylation. Histone deacetylation may be another regulatory mechanism involved in SOCS1 and SOCS3 expression, however, SOCS5 expression was neither affected by DNA methylation nor histone deacetylation. Ectopic expression of SOCS1 or SOCS3 conferred radioresistance to HeLa cells, which implied SOCS signaling regulates the response to radiation in cervical cancer. In this study, we have shown that SOCS expression repressed by, in part, epigenetically and altered SOCS1 and SOCS3 expression could contribute to the radiosensitive phenotype in cervical cancer.
Highlights
Members of the suppressor of cytokine signaling (SOCS) family of proteins play key roles in the negative regulation of cytokine signal transduction
The mRNA level of SOCS1 (Fig 1A), SOCS3 (Fig 1B), and SOCS5 (Fig 1C) was significantly lower in all cervical cancer cells tested than in normal cervix tissue and established normal colon (CCD-18Co) or lung fibroblast (CCD-18Lu, WI-38) cell lines, To confirm that the lower expression of SOCS1, SOCS3, and SOCS5 in cervical cancer cells is a general phenomenon observed in human tumors, immunohistochemical staining of SOCS proteins was performed in human cervical cancer tissue and in the surrounding normal tissue as a control (Fig 2)
All these results led to the conclusion that SOCS1, SOCS3, and SOCS5 expression ishigher in normal tissue than in cervical cancer, and support the possibility that downregulation of SOCS might contribute to the tumorigenesis or maintenance of cervical cancer
Summary
Members of the suppressor of cytokine signaling (SOCS) family of proteins play key roles in the negative regulation of cytokine signal transduction. SOCS1 appears to have tumor suppressor activity [2] and restoration of SOCS1 gene expression causes growth suppression and induction of apoptosis in HCC cells [3]. Zhou et al suggested that targeting SOCS expression or function in glioblastoma cells may be a useful strategy to sensitize tumor cells to ionizing radiation. Other signaling pathways activated in the cell at the time of DNA damage can modulate the response and alter the output of DNA damage-induced signal transduction [12]. We show that altered SOCS1 and SOCS3 expression may contribute to the radiosensitive phenotype in cervical cancer
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