title: Loss of function of the candidate tumor suppressor prox1 by RNA mutation in human cancer cells.
abstract: The importance of genetic mutations in carcinogenesis has been recognized, and it has been proposed that aberrant mutation of mRNA may represent a novel oncogenic principle. Here we report that the mRNA of a homeobox gene prox1, a candidate tumor suppressor, suffers adenosine-to-inosine nucleotide conversion and loses tumor-suppressive functions in a subset of human cancers. Expression of Prox1 was reduced in pancreatic cancers, and the extent of reduction correlated with progression of tumor differentiation. A-to-G base change was found in prox1 cDNA taken from human cancer cells, but not in corresponding genomic DNA. We mapped four common mutation sites in prox1 gene, and the same four sites were mutated in human clinical samples from several cancers. Tetracycline-induced wild-type (wt) Prox1 in tumor cells inhibited transforming activity and cellular proliferation. However, mutant Prox1 with the four common sites altered from A to G lost these inhibitory functions. In mice, xenografts of tumor cells with tetracycline-induced wt-Prox1 formed tumor masses significantly more slowly than control tumors, whereas mutated Prox1 had no effect. These findings may point to a pivotal role of the RNA mutation of prox1 gene in the pathogenesis of human cancer progression.
authors.affiliation: Molecular and Cancer Research Unit, HMRO, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Meiko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Takanobu
authors.initials: T
authors.lastname: Yoshimoto
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimoda
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kono
authors.forename: Masayuki
authors.initials: M
authors.lastname: Koizumi
authors.forename: Shujiro
authors.initials: S
authors.lastname: Yazumi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimada
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Doi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
authors.forename: Hajime
authors.initials: H
authors.lastname: Kubo
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D018450:Disease Progression; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics* / Q000502:physiology; D012334:RNA, Neoplasm / Q000235:genetics* / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D018398:Homeodomain Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein