title: Reduced expression and novel splice variants of ING4 in human gastric adenocarcinoma.
abstract: ING4, a new member of the ING (inhibitor of growth) family of tumour suppressor genes, has been found to be deleted or down-regulated in gliomas, breast tumours, and head and neck squamous cell carcinomas. The goal of the present study was to investigate whether the expression and alternative splicing of ING4 transcripts are involved in the initiation and progression of stomach adenocarcinoma. ING4 mRNA and protein expression was examined in gastric adenocarcinoma tissues and human gastric adenocarcinoma cell lines by RT-PCR, real-time RT-PCR, tissue microarray immunohistochemistry, and western blot analysis. Alterations in ING4 transcripts were determined through sequence analysis of ING4 cDNA. Our data showed that ING4 mRNA and protein were dramatically reduced in stomach adenocarcinoma cell lines and tissues, and significantly less in female than in male patients. We also found that reduced ING4 mRNA expression correlated with the stage of the tumour. Interestingly, by sequence analysis, we discovered five novel aberrantly spliced variant forms of ING4_v1 and ING4_v2. These variants cause a codon frame-shift and, eventually, deletion of the NLS or PHD domain contributing to the mislocalization of p53 and/or HAT/HDAC complexes and, subsequently, altered gene expression in gastric adenocarcinoma. These results suggest that attenuated and aberrant ING4 expression may be involved in the initiation and progression of stomach adenocarcinoma.
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
authors.forename: Wen-jing
authors.initials: WJ
authors.lastname: Sun
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Jing
authors.initials: J
authors.lastname: Bai
authors.forename: Dan-dan
authors.initials: DD
authors.lastname: Tong
authors.forename: Ji-ping
authors.initials: JP
authors.lastname: Qi
authors.forename: Jin-rong
authors.initials: JR
authors.lastname: Du
authors.forename: Jing-shu
authors.initials: JS
authors.lastname: Geng
authors.forename: Qi
authors.initials: Q
authors.lastname: Huang
authors.forename: Xiao-yi
authors.initials: XY
authors.lastname: Huang
authors.forename: Yun
authors.initials: Y
authors.lastname: Huang
authors.forename: Fei-fei
authors.initials: FF
authors.lastname: Han
authors.forename: Xiang-ning
authors.initials: XN
authors.lastname: Meng
authors.forename: Jesusa L
authors.initials: JL
authors.lastname: Rosales
authors.forename: Ki-Young
authors.initials: KY
authors.lastname: Lee
authors.forename: Song-bin
authors.initials: SB
authors.lastname: Fu
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000032:analysis / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000032:analysis / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; C483230:ING4 protein, human; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins