miR-214 coordinates melanoma progression by upregulating ALCAM through TFAP2 and miR-148b downmodulation

Cancer Res. 2013 Jul 1;73(13):4098-111. doi: 10.1158/0008-5472.CAN-12-3686. Epub 2013 May 10.


Malignant melanoma is one of the most aggressive human cancers, but the mechanisms governing its metastatic dissemination are not fully understood. Upregulation of miR-214 and ALCAM and the loss of TFAP2 expression have been implicated in this process, with TFAP2 a direct target of miR-214. Here, we link miR-214 and ALCAM as well as identify a core role for miR-214 in organizing melanoma metastasis. miR-214 upregulated ALCAM, acting transcriptionally through TFAP2 and also posttranscriptionally through miR-148b (itself controlled by TFAP2), both negative regulators of ALCAM. We also identified several miR-214-mediated prometastatic functions directly promoted by ALCAM. Silencing ALCAM in miR-214-overexpressing melanoma cells reduced cell migration and invasion without affecting growth or anoikis in vitro, and it also impaired extravasation and metastasis formation in vivo. Conversely, cell migration and extravasation was reduced in miR-214-overexpressing cells by upregulation of either miR-148b or TFAP2. These findings were consistent with patterns of expression of miR-214, ALCAM, and miR-148b in human melanoma specimens. Overall, our results define a pathway involving miR-214, miR-148b, TFAP2, and ALCAM that is critical for establishing distant metastases in melanoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics*
  • Antigens, CD / metabolism
  • Base Sequence
  • Cell Adhesion Molecules, Neuronal / genetics*
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Female
  • Fetal Proteins / genetics*
  • Fetal Proteins / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / secondary
  • Melanoma / metabolism*
  • Melanoma / secondary
  • Mice
  • Mice, Nude
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • MicroRNAs / physiology*
  • Neoplasm Invasiveness
  • Neoplasm Transplantation
  • RNA Interference
  • Transcription Factor AP-2 / genetics*
  • Transcription Factor AP-2 / metabolism
  • Transcription, Genetic
  • Up-Regulation


  • ALCAM protein, human
  • Antigens, CD
  • Cell Adhesion Molecules, Neuronal
  • Fetal Proteins
  • MIRN148 microRNA, human
  • MIRN214 microRNA, human
  • MicroRNAs
  • Transcription Factor AP-2