title: KLF4 is a novel candidate tumor suppressor gene in pancreatic ductal carcinoma.
abstract: Ductal pancreatic carcinoma (DPC) is a deadly disease with an incidence of 9 cases in 100,000 people per year and a mortality rate close to 100%. Allelic losses in the long arm of chromosome 9 are commonly encountered in many human malignancies but no data are yet available about DPC. We screened 40 laser-microdissected DPC samples and 6 pre-invasive lesions for 9 microsatellite mapping markers of region 9q21.3 through 9q34.2. A small overlapping region of deletion, spanning 8 million base pairs, was identified between D9S127 and D9S105. Two genes, RSG3 and KLF4, mapped to 9q31.1 through 9q32, were further investigated. A highly significant association was found between KLF4 gene expression levels and genomic status. Similarly, absence of immunohistochemical expression of KLF4 protein was found in 86.8% cases of DPC (33/38). Overexpression of KLF4 in a human pancreatic carcinoma cell line induced a significant decrease in the proliferation associated with up-regulation of p21 and the down-regulation of cyclin D1. In conclusion, we identified a novel oncosuppressor region located at the 9q 31.1-3 locus that is lost in DPC at high frequency. Loss of KLF4 expression is closely related to the genomic loss, and its restoration inhibits cancer cell proliferation, suggesting a key suppressor role in pancreatic tumorigenesis.
authors.affiliation: Department of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Zammarchi
authors.forename: Mariangela
authors.initials: M
authors.lastname: Morelli
authors.forename: Michele
authors.initials: M
authors.lastname: Menicagli
authors.forename: Claudio
authors.initials: C
authors.lastname: Di Cristofano
authors.forename: Katia
authors.initials: K
authors.lastname: Zavaglia
authors.forename: Alessandra
authors.initials: A
authors.lastname: Paolucci
authors.forename: Daniela
authors.initials: D
authors.lastname: Campani
authors.forename: Paolo
authors.initials: P
authors.lastname: Aretini
authors.forename: Ugo
authors.initials: U
authors.lastname: Boggi
authors.forename: Franco
authors.initials: F
authors.lastname: Mosca
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavazzana
authors.forename: Luca
authors.initials: L
authors.lastname: Cartegni
authors.forename: Generoso
authors.initials: G
authors.lastname: Bevilacqua
authors.forename: Chiara Maria
authors.initials: CM
authors.lastname: Mazzanti
mesh_terms: D001483:Base Sequence; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D002470:Cell Survival; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D019204:GTP-Binding Proteins / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D019656:Loss of Heterozygosity; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D014176:Protein Biosynthesis / Q000235:genetics; D020710:RGS Proteins
chemical_list: D020690:GTPase-Activating Proteins; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D020710:RGS Proteins; C485898:RGS3 protein, human; D019204:GTP-Binding Proteins