title: Identification of novel subregions of LOH in gastric cancer and analysis of the HIC1 and TOB1 tumor suppressor genes in these subregions.
abstract: Previously, we identified 3 overlapping regions showing loss of heterozygosity (LOH, R(1)-R(3) from 11 to 30 cM) on chromosome 17 in 45 primary gastric cancers (GCs). The data indicated the presence of tumor suppressor genes (TSGs) on chromosome 17 involved in GC. Among the putative TSGs in these regions, HIC1 (in SR(1)) and TOB1 (in SR(3)) remain to be examined in GC. By immunohistochemistry (IHC), methylation-specific PCR (MSP) and western blot, we evaluated the expression and regulation status for HIC1 and TOB1 protein in GC. We narrowed down the deletion intervals on chromosome 17 and defined five smaller LOH subregions, SR(1)-SR(5) (0.54 to 3.42 cM), in GC. We found that HIC1 had downregulated expression in 86% (91/106) and was methylated in 87% (26/30) of primary GCs. Of the primary GCs showing downregulation of HIC1 protein, 75% (18/24) had methylated HIC1 gene. TOB1 was either absent or expressed at reduced levels in 75% (73/97) of the GC samples. In addition, a general reduction was found in total and the ratio of unphosphorylated to phosphorylated TOB1 protein levels in the differentiated GC cell lines. Further analysis revealed significant simultaneous downregulation of both HIC1 and TOB1 protein in GC tissue microarray samples (67%, 52/78) and in primary GCs (65%, 11/17). These results indicate that silencing of HIC1 and TOB1 expression is a common occurrence in GC and may contribute to the development and progression of the disease.
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China.
authors.forename: Jingcui
authors.initials: J
authors.lastname: Yu
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Cui
authors.forename: Yu
authors.initials: Y
authors.lastname: Sui
authors.forename: Guohua
authors.initials: G
authors.lastname: Ji
authors.forename: Rongwei
authors.initials: R
authors.lastname: Guan
authors.forename: Donglin
authors.initials: D
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Ji
authors.forename: Fangli
authors.initials: F
authors.lastname: Liu
authors.forename: An
authors.initials: A
authors.lastname: Liu
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
authors.forename: Jing
authors.initials: J
authors.lastname: Bai
authors.forename: Jingshu
authors.initials: J
authors.lastname: Geng
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Xue
authors.forename: Jiping
authors.initials: J
authors.lastname: Qi
authors.forename: Ki-Young
authors.initials: KY
authors.lastname: Lee
authors.forename: Songbin
authors.initials: S
authors.lastname: Fu
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002886:Chromosomes, Human, Pair 17 / Q000737:chemistry* / Q000235:genetics; D019175:DNA Methylation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D040081:Protein Array Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C499808:HIC1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; C098669:TOB1 protein, human; D025521:Tumor Suppressor Proteins