Down regulation of c-Myc and induction of an angiogenesis inhibitor, thrombospondin-1, by 5-FU in human colon cancer KM12C cells.
5-FU is commonly used for treatment of various solid tumors including colon carcinoma. We have previously demonstrated that Egr-1 induced by 5-FU enhanced TSP-1 expression in human colon cancer KM12C cells. In this study, a Genechip analysis of KM12C cells treated with 5-FU revealed down-regulation of 924 genes and up-regulation of 460 genes. The decreased expression of c-Myc mRNA and phosphorylated c-Myc were detected and confirmed by RT-PCR and immunoblotting. Since 5-FU induced the expression of TSP-1, we examined the effect of c-Myc on the TSP-1 promoter. Deletion of the TSP-1 promoter region in which binding sites for c-Myc reside had no effect on the TSP-1 promoter activity induced by 5-FU. Meanwhile, 5-FU dose-dependently decreased the expression of miR-17-92 cluster. These findings suggest that 5-FU decreased the expression of c-Myc and consequently miR-17-92 cluster and increased the expression of TSP-1 mRNA.
Zhao
Hong-Ye
HY
Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, Japan.
Ooyama
Akio
A
Yamamoto
Masatatsu
M
Ikeda
Ryuji
R
Haraguchi
Misako
M
Tabata
Sho
S
Furukawa
Tatsuhiko
T
Che
Xiao-Fang
XF
Iwashita
Ken-ichi
K
Oka
Toshinori
T
Fukushima
Masakazu
M
Nakagawa
Masayuki
M
Ono
Mayumi
M
Kuwano
Michihiko
M
Akiyama
Shin-ichi
S
D020533:Angiogenesis Inhibitors / Q000235:genetics*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015536:Down-Regulation; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016259:Genes, myc; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D019700:Thrombospondin 1 / Q000235:genetics*
D020533:Angiogenesis Inhibitors; D000964:Antimetabolites, Antineoplastic; C524941:MIRN17 microRNA, human; D035683:MicroRNAs; D019700:Thrombospondin 1; D005472:Fluorouracil