Carcinogenesis Advance Access originally published online on August 11, 2008
Carcinogenesis 2008 29(11):2073-2077; doi:10.1093/carcin/bgn187
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let-7 regulates Dicer expression and constitutes a negative feedback loop
1 Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer
2 Department of Surgical Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya 466-8550, Japan
* To whom correspondence should be addressed. Tel: +81 52 744 2454; Fax: +81 52 744 2457; Email: tak{at}med.nagoya-u.ac.jp
microRNAs (miRNA) are small, endogenously expressed non-coding RNAs that are sequentially processed by Drosha and Dicer from primary transcripts, by negatively regulating the expression of protein-coding genes through either translational repression or RNA degradation. Their expression patterns are developmentally regulated and/or tissue specific, while altered expressions of certain miRNAs are frequently observed in human cancers, though the underlying regulatory mechanism is largely unknown. Herein, we show that Dicer expression was inversely correlated with expression levels of mature let-7 in a panel of human cancer cell lines, showing association with cell growth and cell cycle phases. Overexpression of let-7 significantly reduced the expression of Dicer at both the protein and messenger RNA levels, whereas antisense-mediated reduction of let-7 expression conversely increased Dicer at both levels. A luciferase assay using a reporter carrying a putative target site in the 3' untranslated region of Dicer revealed that let-7 directly affects Dicer expression. Downregulation of Dicer resulted in a reduced expression of mature let-7. Furthermore, overexpression of let-7 decreased the levels of expression of other mature miRNAs, while knockdown of let-7 increased those levels. Taken together, these findings strongly suggest the possible existence of a novel regulatory loop, in which let-7 may play a role as a key miRNA for implementing the tightly regulated, equilibrated state of Dicer and various miRNAs.
Abbreviations: AS, antisense oligonucleotides; miRNA, microRNA; mRNA, messenger RNA; PCR, polymerase chain reaction; siRNA, small interfering RNA; UTR, untranslated region
Received April 11, 2008; revised July 22, 2008; accepted August 3, 2008.
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