Genetic variations of microRNAs in human cancer and their effects on the expression of miRNAs.
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the posttranscriptional level to lead to mRNA degradation or repressed protein production. The expression of miRNA is deregulated in many types of cancers. To determine whether genetic alterations in miRNA genes are associated with cancers, we have systematically screened sequence variations in several hundred human miRNAs from >100 human tumor tissues and 20 cancer cell lines. We identified 8 new single-nucleotide polymorphisms (SNPs) and 14 novel mutations (or very rare SNPs) that specifically present in human cancers. These mutations/SNPs are distributed in the regions of pri-, pre- and even mature miRNAs, respectively. Importantly, whereas most of the mutations did not exert detectable effects on miRNA function, a G --> A mutation at 19 nt downstream of miRNA let-7e led to a significant reduction of its expression in vivo, indicating that miRNA mutation could contribute to tumorigenesis. These data suggest that further screening for genetic variations in miRNA genes from a wide variety of human cancers should increase the discovery and identification of molecular diagnostic and therapeutic targets and complement the mutation analysis of consensus coding sequences in human cancers.
Wu
Meiqun
M
Department of Medicine, McGill University, Montréal, Québec H3G 1A4, Canada.
Jolicoeur
Normand
N
Li
Zhen
Z
Zhang
Linhua
L
Fortin
Yves
Y
L'Abbe
Denis
D
Yu
Zhenbao
Z
Shen
Shi-Hsiang
SH
D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D015152:Blotting, Northern; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy; D009690:Nucleic Acid Conformation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012322:RNA Precursors / Q000235:genetics* / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D014408:Biomarkers, Tumor; D035683:MicroRNAs; D012322:RNA Precursors; D012333:RNA, Messenger; D012334:RNA, Neoplasm