SOCS6 suppresses cell growth and is frequently inactivated in human gastrointestinal cancers Free

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Members of SOCS (suppressor of cytokine-induced signaling) family proteins are negative regulators of cytokine-induced signaling pathways. Transcriptional silencing of SOCS1 and SOCS3 has been implicated in the pathogenesis of a variety of human cancer. In this study, we report that SOCS6 works as a tumor suppressor, and the mechanisms leading to its inactivation in human gastric cancer (GC) are elucidated. We showed that SOCS6 expression is frequently down-regulated in human gastric cancer (GC) and colorectal cancer. Loss of heterozygosity (LOH) of SOCS6 locus is detected in 41% (18/41) sporadic GC, with significant association with GC of expanding type by Ming’s criteria (P < 0.001) and expansive (INFα) growth pattern (P = 0.03). To examine the possible involvement of epigenetic modification as the second hit in SOCS6 inactivation, we defined the region of functional SOCS6 promoter and showed that this promoter was aberrantly methylated in 89% (16/18) of the GC displaying SOCS6 LOH. In addition, a missense mutation in SOCS6 coding region was identified in one of the remaining two LOH-positive GC. These data demonstrate that inactivation of SOCS6 in GC, complying with Knudson’s two-hit model, was ascribed to the deletion of the wild-type allele accompanied with point mutation in the second allele or epigenetic silencing of its promoter. Most importantly, we showed that ectopic expression of SOCS6 suppresses cell growth by inducing programmed cell death. Taken together, these findings support a suppressive role of SOCS6 and its inactivation may contribute to the pathogenic development of gastrointestinal cancers.