HMGA2 functions as a competing endogenous RNA to promote lung cancer progression

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From: Nature(Vol. 505, Issue 7482)
Publisher: Nature Publishing Group
Document Type: Report
Length: 6,342 words
Lexile Measure: 1440L

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Non-small-cell lung cancer (NSCLC) is the most prevalent histological cancer subtype worldwide (1). As the majority of patients present with invasive, metastatic disease (2), it is vital to understand the basis for lung cancer progression. Hmga2 is highly expressed in metastatic lung adenocarcinoma, in which it contributes to cancer progression and metastasis (3-6). Here we show that Hmga2 promotes lung cancer progression in mouse and human cells by operating as a competing endogenous RNA (ceRNA) (7-11) for the let-7 microRNA (miRNA) family. Hmga2 can promote the transformation of lung cancer cells independent of protein-coding function but dependent upon the presence of let-7 sites; this occurs without changes in the levels of let-7 isoforms, suggesting that Hmga2 affects let-7 activity by altering miRNA targeting. These effects are also observed in vivo, where Hmga2 ceRNA activity drives lung cancer growth, invasion and dissemination. Integrated analysis of miRNA target prediction algorithms and metastatic lung cancer gene expression data reveals the TGF-[beta] co-receptor Tgfbr3 (ref. 12) as a putative target of Hmga2 ceRNA function. Tgfbr3 expression is regulated by the Hmga2 ceRNA through differential recruitment to Argonaute 2 (Ago2), and TGF-[beta] signalling driven by Tgfbr3 is important for Hmga2 to promote lung cancer progression. Finally, analysis of NSCLC-patient gene-expression data reveals that HMGA2 and TGFBR3 are coordinately regulated in NSCLC-patient material, a vital corollary to ceRNA function. Taken together, these results suggest that Hmga2 promotes lung carcinogenesis both as a protein-coding gene and as a non-coding RNA; such dual-function regulation of gene-expression networks reflects a novel means by which oncogenes promote disease progression.

The ceRNA hypothesis posits that specific RNAs can function as sinks for pools of active miRNAs, functionally liberating other transcripts targeted by that set of miRNAs (10). Downregulation of the transcription factor Nkx2.1 promotes lung adenocarcinoma progression partially through derepression of Hmga2 (ref. 6), a non-histone chromosomal high-mobility group protein. Intriguingly, Hmga2 has been described as a prototypic let-7 target transcript, with seven conserved sites in its 3' untranslated region (3' UTR) (13). Reduction of Hmga2 by RNA interference, which would deplete both Hmga2 protein and transcript, greatly reduces metastatic ability. Thus, it is possible that the transcript could operate independently of the protein in lung cancer progression.

To determine whether Hmga2 can operate as a ceRNA for the let-7 family, we generated an allelic series of Hmga2 expression constructs (Fig. 1a). In this series, we expressed the wild-type full-length Hmga2 complementary DNA (WT); Hmga2 with mutation of all seven predicted let-7 binding sites (13) (m7); Hmga2 with mutation of the single inframe start codon (ATG WT); or Hmga2 with mutation of both the start codon and the let-7 binding sites (ATG m7). We then examined these constructs in two lung cancer cell lines generated from the [Kras.sup.LSL-G12D]; Trp53flox/flox mouse model: a cell line derived from a non-metastatic lung tumour that expresses very low levels of Hmga2 (368T1); and a cell line derived from a lymph node metastasis which expresses high levels of Hmga2 (482N1) (6). Using two antibodies that recognize...

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Gale Document Number: GALE|A358700557