Editors' ChoiceCancer

Noncoded Competition

Sci. Signal.  14 Jan 2014:
Vol. 7, Issue 308, pp. ec9
DOI: 10.1126/scisignal.2005071

Some RNAs can function as microRNA (miRNA) sponges, preventing the miRNA from repressing its other target transcripts. HMGA2, which encodes a nonhistone chromosomal protein, is highly expressed in non–small cell lung cancer (NSCLC) and is a target for the miRNA let-7. Kumar et al. found that NSCLC is promoted by the sponge-like activity of Hmga2 transcripts independently of Hmga2 protein. As expected, Hmga2 knockdown impaired the colony formation of murine NSCLC cell lines in soft agar. In control and Hmga2 knockdown cells, colony formation was increased by transfection with wild-type (WT) Hmga2 or Hmga2 missing the start codon (ATG/WT) compared with cells transfected with empty vector or Hmga2 mutant for all let-7 binding sites (m7 or ATG/m7). Mice injected intravenously with Hmga2-deficient NSCLC cells reconstituted with WT or ATG/WT Hmga2 had an incidence of lung tumor formation and metastasis and mortality rate similar to those observed in mice injected with wild-type NSCLC cells. RNA sequencing and Sylamer analysis, which detects miRNA seed sites in 3′ untranslated regions, revealed that the transcripts present in Hmga2 knockdown cells transfected with WT or ATG/WT Hmga2 were enriched for let-7 sites compared with those transfected with empty vector or either m7-mutant Hmga2, indicating that the presence of Hmga2 transcripts that can bind let-7 released let-7 targets from repression. Tgfbr3, which encodes a transforming growth factor–β (TGF-β) co-receptor, was identified as a let-7 target transcript that was increased in Hmga2-deficient metastatic NSCLC cells. In murine NSCLC cells, expression of WT or ATG/WT Hmga2, but neither m7-mutant Hmga2, increased the abundance of Tgfbr3 transcript and protein, the activity of a TGF-β reporter, and the phosphorylation of TGF-β pathway substrates, and it decreased the recruitment of Tgfbr3 transcripts to Argonaute, a component of the RNA silencing complex. Exogenous expression of let-7 impaired the ability of WT or ATG/WT Hmga2 to increase Tgfbr3 abundance. Analysis of two large, independent NSCLC data sets showed that HMGA2 and TGFBR3 expression positively correlated in patients. The findings suggest that HMGA2 transcripts may promote NSCLC by competing for let-7 occupancy, enabling the derepression of let-7 targets, such as those that encode components in the TGF-β pathway.

M. S. Kumar, E. Armenteros-Monterroso, P. East, P. Chakravorty, N. Matthews, M. M. Winslow, J. Downward, HMGA2 functions as a competing endogenous RNA to promote lung cancer progression. Nature 505, 212–217 (2014). [PubMed]