MicroRNA-33a mediates the regulation of high mobility group AT-hook 2 gene (HMGA2) by thyroid transcription factor 1 (TTF-1/NKX2-1)

J Biol Chem. 2013 Jun 7;288(23):16348-16360. doi: 10.1074/jbc.M113.474643. Epub 2013 Apr 26.


In lung cancers, TTF-1 displays seemingly paradoxical activities. Although TTF-1 is amplified in primary human lung cancers, it inhibits primary lung tumors from metastasizing in a mouse model system. It was reported that the oncogenic proepithelial mesenchymal transition (EMT) high mobility group AT-hook 2 gene (HMGA2) mediates the antimetastatic function of TTF-1. To gain mechanistic insight into the metastasis-critical signaling axis of TTF-1 to HMGA2, we used both reverse and forward strategies and discovered that microRNA-33a (miR-33a) is under direct positive regulation of TTF-1. By chromatin immunoprecipitation, we determined that TTF-1 binds to the promoter of SREBF2, the host gene of miR-33a. The 3'-untranslated region (UTR) of HMGA2 contains three predicted binding sites of miR-33a. We showed that the first two highly conserved sites are conducive to HMGA2 repression by miR-33a, establishing HMGA2 as a genuine target of miR-33a. Functional studies revealed that enforced expression of miR-33a inhibits the motility of lung cancer cells, and this inhibition can be rescued by overexpression of the form of HMGA2 without the 3'-UTR, suggesting that TTF-1 keeps the prometastasis gene HMGA2 in check via up-regulating miR-33a. This study reports the first miRNAs directly regulated by TTF-1 and clarifies how TTF-1 controls HMGA2 expression. Moreover, the documented importance of SREBF2 and miR-33a in regulating cholesterol metabolism suggests that TTF-1 may be a modulator of cholesterol homeostasis in the lung. Future studies will be dedicated to understanding how miRNAs influence the oncogenic activity of TTF-1 and the role of TTF-1 in cholesterol metabolism.

Keywords: Cholesterol Regulation; Gene Regulation; HMGA2; Lung Cancer; Metastasis; MicroRNA; SREBP2; TTF-1; miR-32; miR-33a.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3' Untranslated Regions / physiology*
  • Animals
  • Cell Line
  • Cholesterol / genetics
  • Cholesterol / metabolism
  • HMGA2 Protein / biosynthesis*
  • HMGA2 Protein / genetics
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • Response Elements / physiology*
  • Sterol Regulatory Element Binding Protein 2 / biosynthesis
  • Sterol Regulatory Element Binding Protein 2 / genetics
  • Thyroid Nuclear Factor 1
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • 3' Untranslated Regions
  • HMGA2 Protein
  • MIRN33a microRNA, human
  • MicroRNAs
  • Mirn33 microRNA, mouse
  • NKX2-1 protein, human
  • Neoplasm Proteins
  • Nkx2-1 protein, mouse
  • Nuclear Proteins
  • RNA, Neoplasm
  • SREBF2 protein, human
  • Srebf2 protein, mouse
  • Sterol Regulatory Element Binding Protein 2
  • Thyroid Nuclear Factor 1
  • Transcription Factors
  • Cholesterol