| Summary: | 博士 === 國立陽明大學 === 藥理學研究所 === 98 === Members of the SOCS (suppressor of cytokine-induced signaling) family are negative regulators of cytokine/growth factor signaling pathways. In this thesis, I demonstrated that SOCS6 can act as a tumor suppressor in gastric cancer (GC). SOCS6 was initially identified as one of the genes down-regulated in human GC in this laboratory by means of differential display. Lowered expression of SOCS6 was detected in 15 of 24 (62.5%) primary tumors as assessed by real-time PCR. Loss of heterozygosity (LOH) of SOCS6 gene was detected in 51.6% (16/31) of GC. Moreover, hypermethylation of SOCS6 promoter in several GC cell lines was found, in which expression could be restored by treatment of a methyltransferase inhibitor. In order to assess the methylation status of SOCS6 promoter in vivo, the genomic structure of human SOCS6 gene was established. SOCS6 gene constitutes of two exons and an intron of 35 kb on chromosome 18q22.2, with the coding region lying in exon 2 which can translate a protein of 535 amino acids. Aberrant methylation was observed in 68.8% (11/16) of the LOH tumors, suggesting the biallelic inactivation of SOCS6 gene in primary GC. Re-introduction of SOCS6 into cell lines suppressed tumor cell growth by inducing programmed cell death through intrinsic apoptotic pathway, accompanied with a decrease of mitochondrial membrane potential and an increase of reactive oxygen species (ROS). Moreover, ectopically expressed SOCS6 was found to be localized in mitochondria and facilitated mitochondrial fragmentation. Taken together, this study provides molecular and functional data supporting the importance of loss-of-function of SOCS6 as a frequent event in gastric tumorigenesis.
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