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20197313
Regulation of fibroblast growth factor-2 by an endogenous antisense RNA and by argonaute-2.

Mol Endocrinol, 2010/4;24(4):800-12.

MacFarlane LA[1], Gu Y, Casson AG, Murphy PR

Affiliations

PMID: 20197313DOI: 10.1210/me.2009-0367

Abstract
We have previously reported that elevated fibroblast growth factor-2 (FGF-2) expression is associated with tumor recurrence and reduced survival after surgical resection of esophageal cancer and that these risks are reduced in tumors coexpressing an endogenous antisense (FGF-AS) RNA. In the present study, we examined the role of the endogenous FGF-AS transcript in the regulation of FGF-2 expression in the human lung adenocarcinoma cell line Seg-1. FGF-2 and FGF-AS were temporally and spatially colocalized in the cytoplasm of individual cells, and knockdown of either FGF-2 or FGF-AS by target-specific siRNAs resulted in dose-dependent up-regulation of the complementary transcript and its encoded protein product. Using a luciferase reporter system, we show that these effects are mediated by interaction of the endogenous antisense RNA with the 3'-untranslated region of the FGF-2 mRNA. Deletion mapping identified a 392-nucleotide sequence in the 5823-nucleotide FGF-2 untranslated tail that is targeted by FGF-AS. Small interfering RNA-mediated knockdown of either FGF-AS or FGF-2 significantly increased the stability of the complementary partner mRNA, demonstrating that these mRNAs are mutually regulatory. Knockdown of FGF-AS also resulted in reduced expression of argonaute-2 (AGO-2) and a number of other elements of the endogenous micro-RNA/RNA interference pathways. Conversely, small interfering RNA-mediated knockdown of AGO-2 significantly increased the stability of the FGF-2 mRNA transcript and the steady-state levels of both FGF-2 mRNA and protein, suggesting a role for AGO-2 in the regulation of FGF-2 expression.
MeSH terms
3' Untranslated Regions; Argonaute Proteins; Blotting, Western; Cell Line, Tumor; Eukaryotic Initiation Factor-2; Fibroblast Growth Factor 2; Humans; Models, Genetic; Oligonucleotide Array Sequence Analysis; RNA, Antisense; RNA, Messenger; RNA, Small Interfering; Reverse Transcriptase Polymerase Chain Reaction
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