title: Functional role of the KLF6 tumour suppressor gene in gastric cancer.
abstract: Gastric cancer is the second most common cancer and a leading cause of cancer-related death worldwide. The Kruppel-like factor 6 (KLF6) tumour suppressor gene had been previously shown to be inactivated in a number of human cancers through loss of heterozygosity (LOH), somatic mutation, decreased expression and increased alternative splicing into a dominant negative oncogenic splice variant, KLF6-SV1. In the present study, 37 gastric cancer samples were analysed for the presence of loss of heterozygosity (LOH) of the KLF6 locus and somatic mutation. In total, 18 of 34 (53%) of the gastric cancer samples analysed demonstrated KLF6 locus specific loss. Four missense mutations, such as T179I, R198G, R71Q and S180L, were detected. Interestingly, two of these mutations R71Q and S180L have been identified independently by several groups in various malignancies including prostate, colorectal and gastric cancers. In addition, decreased wild-type KLF6 (wtKLF6) expression was associated with loss of the KLF6 locus and was present in 48% of primary gastric tumour samples analysed. Functional studies confirmed that wtKLF6 suppressed proliferation of gastric cancer cells via transcriptional regulation of the cyclin-dependent kinase inhibitor p21 and the oncogene c-myc. Functional characterisation of the common tumour-derived mutants demonstrated that the mutant proteins fail to suppress proliferation and function as dominant negative regulators of wtKLF6 function. Furthermore, stable overexpression of the R71Q and S180L tumour-derived mutants in the gastric cancer cell line, Hs746T, resulted in an increased tumourigenicity in vivo. Combined, these findings suggest an important role for the KLF6 tumour suppressor gene in gastric cancer development and progression and identify several highly cancer-relevant signalling pathways regulated by the KLF6 tumour suppressor gene.
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, NY, United States.
authors.forename: Jaya
authors.initials: J
authors.lastname: Sangodkar
authors.forename: Jiayan
authors.initials: J
authors.lastname: Shi
authors.forename: Analisa
authors.initials: A
authors.lastname: DiFeo
authors.forename: Rachel
authors.initials: R
authors.lastname: Schwartz
authors.forename: Romina
authors.initials: R
authors.lastname: Bromberg
authors.forename: Aisha
authors.initials: A
authors.lastname: Choudhri
authors.forename: Kim
authors.initials: K
authors.lastname: McClinch
authors.forename: Raheleh
authors.initials: R
authors.lastname: Hatami
authors.forename: Elias
authors.initials: E
authors.lastname: Scheer
authors.forename: Sigal
authors.initials: S
authors.lastname: Kremer-Tal
authors.forename: John A
authors.initials: JA
authors.lastname: Martignetti
authors.forename: Alex
authors.initials: A
authors.lastname: Hui
authors.forename: W K
authors.initials: WK
authors.lastname: Leung
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
authors.forename: Goutham
authors.initials: G
authors.lastname: Narla
mesh_terms: D000368:Aged; D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D009368:Neoplasm Transplantation; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: C105465:KLF6 protein, human; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins