Abstract
The aim of the present study was to explore mechanisms by which let-7c suppresses NSCLC cell proliferation. The expression level of let-7c was quantified by qRT-PCR. A549 and H1299 cells were transfected with let-7c mimics to restore the expression of let-7c. The effects of let-7c were then assessed by cell proliferation, colony formation and cell cycle assay. Mouse experiments were used to confirm the effect of let-7c on tumorigenicity in vivo. Luciferase reporter assays and Western blotting were performed to identify target genes for let-7c. HOXA1 was identified as a novel target of let-7c. MTS, colony formation and flow cytometry assays demonstrated that forced expression of let-7c inhibited NSCLC cell proliferation by inducing G1 arrest in vitro, consistent with inhibitory effects induced by knockdown of HOXA1. Mouse experiments demonstrated that let-7c expression suppressed tumorigenesis. Furthermore, we found that let-7c could regulate the expression of HOXA1 downstream effectors CCND1, CDC25A and CDK2. Collectively, these results demonstrate let-7c inhibits NSCLC cell proliferation and tumorigenesis by partial direct targeting of the HOXA1 pathway, which suggests that restoration of let-7c expression may thus offer a potential therapeutic intervention strategy for NSCLC.
Highlights
MicroRNAs represent a class of endogenous, single-strand and highly conserved noncoding small RNAs
HOXA1 was identified as a novel target of let-7c
We demonstrated that let-7c inhibited NSCLC cell proliferation and tumorigenesis by directly targeting the 3’UTR of HOXA1 mRNA, which subsequently reduced the expression of CCND1, CDC25A and CDK2
Summary
MicroRNAs (miRNAs) represent a class of endogenous, single-strand and highly conserved noncoding small RNAs. MicroRNAs (miRNAs) represent a class of endogenous, single-strand and highly conserved noncoding small RNAs They post-transcriptionally regulate protein expression by directly binding the 3’-UTR of target genes and play critical roles in numerous biological processes, including development, apoptosis, life span and metabolism (Bartel, 2004). Let-7 was the second miRNA to be identified after lin-4 in Caenorhabditis elegans (Pasquinelli et al, 2000). Thirteen members of the let-7 family have been identified in the human genome (Pasquinelli et al, 2000; Roush et al, 2008). Restoration of its expression prevented tumor growth by targeting various oncogenes, including Ras, C-myc and HMGA2 (Johnson et al, 2007; Mayr et al, 2007; Kumar et al, 2008; Kim et al, 2009)
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