Carcinogenesis Advance Access published online on August 11, 2008
Carcinogenesis, 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, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
2 Department of Surgical Oncology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
Correspondence: T Takahashi, Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Phone: 81-52-744-2454; FAX: 81-52-744-2457; E-mail: tak{at}med.nagoya-u.ac.jp
microRNAs are small, endogenously expressed noncoding 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 microRNAs 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 mRNA 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’ UTR 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 microRNAs, 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 microRNA for implementing the tightly regulated, equilibrated state of Dicer and various microRNAs.
Key Words: miRNA • let-7 • Dicer • lung cancer
Received April 11, 2008; revised July 22, 2008; accepted August 3, 2008.
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