HMGA2 enhances NSCLC progression via its function as a competing endogenous RNA (ceRNA).

  • Major finding: HMGA2 enhances NSCLC progression via its function as a competing endogenous RNA (ceRNA).

  • Mechanism:HMGA2 competes for let-7 binding, resulting in TGFBR3 derepression and increased TGF-β signaling.

  • Impact: Oncogenes such as HMGA2 may promote metastasis independently of their protein-coding functions.

The non-histone chromatin-binding protein high mobility group AT-hook 2 (HMGA2) is overexpressed in non–small cell lung cancer (NSCLC) and has been shown to promote NSCLC progression and metastasis. HMGA2 expression is negatively regulated by binding of the let-7 microRNA (miRNA) family to its 3′ untranslated region (UTR), prompting Kumar and colleagues to investigate whether the HMGA2 transcript stimulates NSCLC progression by acting as a competing endogenous RNA (ceRNA) to titrate away let-7 and derepress let-7–regulated transcripts. Consistent with this idea, the ability of HMGA2 to induce transformation of lung cancer cells was largely independent of HMGA2 protein expression and occurred without changes in let-7 miRNA levels, but was dependent on the presence of intact let-7 binding sites in the Hmga2 3′UTR. In addition, expression of wild-type but not let-7 site–mutated Hmga2 enhanced lung tumor formation and metastasis and diminished the survival of tumor-bearing mice. This metastasis-promoting effect was mediated by upregulation of a subset of let-7–regulated, putative Hmga2 ceRNA targets, in particular transforming growth factor β receptor III (Tgfbr3); Hmga2 ceRNA inhibited Tgfbr3 recruitment to Argonaute 2, thereby preventing miRNA-induced repression of Tgfbr3 and potentiating downstream TGF-β pathway activation. Depletion of TGFBR3 or inhibition of TGF-β signaling suppressed anchorage-independent growth of lung cancer cell lines, suggesting that regulation of this pathway by Hmga2 ceRNA function is required for lung cancer progression. Moreover, HMGA2 and TGFBR3 transcript levels were coordinately overexpressed in two large datasets of patients with NSCLC, further supporting TGFBR3 as a critical target of HMGA2 ceRNA. These results identify HMGA2 as a ceRNA that promotes NSCLC progression and metastasis through competition for let-7 binding and suggest that other oncogenes may similarly contribute to tumorigenesis independently of their protein-coding functions.

Kumar MS, Armenteros-Monterroso E, East P, Chakravorty P, Matthews N, Winslow MM, et al. HMGA2 functions as a competing endogenous RNA to promote lung cancer progression. Nature 2014;505:212–7.

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