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Abstract
Colorectal cancer (CRC) is a common malignant tumor, in which the inflammatory microenvironment
plays an important role. STAT3 signaling pathway is regarded as the "bridge" between
inflammation and cancer, and involved in the development of CRC. SOCS3 is a key negative
feedback regulator of JAK/STAT signaling pathway. Studies about SOCS3 gene in CRC
are rarely reported. The purpose of this study is to determine the expression of SOCS3
in CRC tissue and its correlation with the clinical pathological characteristics and
prognosis of colorectal cancers. The effects of SOCS3 on biological behavior such
as apoptosis, proliferation, migration, invasion and tumor formation in nude mice
were studied. We observed that SOCS3 expression was down-regulated in CRC tissues,
while IL-6, pSTAT3 were up-regulated. Inflammatory cytokines IL-6 can promote the
expression of STAT3 signaling pathways while inhibit the expression of SOCS3 by promoting
hypermethylation of SOCS3 gene promoters. 5-Aza-cdR treatment can reverse IL-6/STAT3
signaling pathway mediated down-regulation of SOCS3 in colorectal cancer cells. Low
expression of SOCS3 was correlated with lymph node metastasis and advanced clinical
stage. Patients with high expression of SOCS3 in colorectal cancers often indicated
a relatively good prognosis. Overexpression of SOCS3 inhibited proliferation, migration,
invasion and tumorigenic ability of CRC cells while increased cell apoptosis. This
study demonstrated that IL-6/STAT3 signaling activation negatively regulated SOCS3
expression, which led to imbalance and sustained activation of STAT3 signaling pathway.
Reduced expression of SOCS3 promoted the growth and metastasis of colorectal cancer.
Thus, targeting IL-6/STAT3/SOCS3 signaling pathway may become an important treatment
strategy of colorectal cancer.