Accumulating experimental evidence indicates that microRNAs play important roles in various biological processes, such as cell differentiation, proliferation, metabolism and apoptosis. In addition, several reports concluded that altered expression of specific microRNA genes contributes to the initiation and progression of cancer. Here, we summarize the current knowledge about aberrant expression of various microRNAs in human solid cancers (e.g., lung, breast, and gastric cancers), their target proteins, and the relationship between their expression and response to chemotherapies. We also review the potential for using microRNAs as biomarkers for the diagnosis and cancer therapy. The development of treatment strategies against human solid cancers based on the profile and/or certain features of microRNAs is promising.
What is microRNA?MicroRNAs are noncoding, single-stranded RNAs, 18-25 nucleotides long, and were first reported in Caenorhabditis elegans in 1993. 1 Subsequent studies led to the identification of microRNAs in human RNA, 2 as well as to the understanding of their mechanisms of action. Most human miRNAs are found within introns of either protein-coding or noncoding mRNA transcripts, 3 and they do not code for any protein although they are RNA sequences.MicroRNA genes are generally transcribed by RNA polymerase II in the nucleus to form pri-miRNA transcripts. These are processed into pre-miRNAs by a microprocessor complex, which contains the Rnase III enzyme Drosha 4 and DGCR8.5 Exportin5 and a RanGTP 6 transport the pre-miRNAs from the nucleus to the cytoplasm, where they are further processed by the RNAase III enzyme Dicer. 7 The mature miRNA is retained in RISC (RNA-induced silencing complex) 8 and it is currently understood that microRNAs mainly bind to the 3' untranslated region (UTR) of their target mRNAs. However, recent studies have reported that microRNAs do not only bind to 3'UTR but also to 5'UTR 9,10 or open reading frame (ORF) 11,12 of the target mRNA. By binding to the 3'UTRs, 5'UTR or ORF of target mRNAs, microRNAs regulate the translation of proteins from mRNA or degrade the mRNA itself.
13While microRNAs are thought to repress the translation of target mRNAs, recent results demonstrated that microRNAs can activate the expression of the target genes.14 In the same study, microRNA was reported to be essential for translation activation under growth arrest conditions. Regulation of translation by microRNAs might change from repression to activation depending on the cell cycle.In addition, because microRNA can bind even to mRNA that is not partially complementary, 15 microRNA and mRNA do not correspond one-to-one, 16 such that one microRNA may regulate several mRNAs or one mRNA may be regulated by several microRNAs. For example, in human gliomas, miR-34a inhibits the expression of multiple oncogenes (e.g., c-Met, Notch-1/Notch-2 and CDK6) by binding to their 3'-UTR and suppressing tumor growth.17 Thus, these microRNAs potentially regulate approximately 30% of all genes encoding h...