FHIT suppresses epithelial-mesenchymal transition (EMT) and metastasis in lung cancer through modulation of microRNAs.

Metastasis is the principal cause of cancer death and occurs through multiple, complex processes that involve the concerted action of many genes. A number of studies have indicated that the Fragile Histidine Triad (FHIT) gene product, FHIT, functions as a tumor suppressor in a variety of common human cancers. Although there are suggestions of a role for FHIT loss in progression of various cancers, a role for such loss in metastasis has not been defined. Here, via in vivo and in vitro assays, we reveal that the enforced expression of FHIT significantly suppresses metastasis, accompanied by inhibition of the epithelial-mesenchymal transition (EMT), a process involved in metastasis through coordinate modulation of EMT-related genes. Specifically, miR-30c, a FHIT-upregulated microRNA, contributes to FHIT function in suppression of EMT and metastasis by directly targeting metastasis genes Metadherin (MTDH), High-mobility group AT-hook 2 (HMGA2), and the mesenchymal markers, Vimentin (VIM) and Fibronectin (FN1), in human lung cancer. Finally, we demonstrate that the expression pattern of FHIT and miR-30c is inversely correlated with that of MTDH and HMGA2 in normal tissue, non-metastatic and metastatic tumors, serving as a potential biomarker for metastasis in lung cancer.
AuthorsSung-Suk Suh, Ji Young Yoo, Ri Cui, Balveen Kaur, Kay Huebner, Taek-Kyun Lee, Rami I Aqeilan, Carlo M Croce
JournalPLoS genetics (PLoS Genet) Vol. 10 Issue 10 Pg. e1004652 (Oct 2014) ISSN: 1553-7404 [Electronic] United States
PMID25340791 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Cell Adhesion Molecules
  • Fibronectins
  • HMGA2 Protein
  • MIRN30 microRNA, human
  • MTDH protein, human
  • MicroRNAs
  • Neoplasm Proteins
  • Vimentin
  • fragile histidine triad protein
  • Acid Anhydride Hydrolases
  • Acid Anhydride Hydrolases (biosynthesis, genetics)
  • Cell Adhesion Molecules
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition (genetics)
  • Fibronectins (biosynthesis)
  • Gene Expression Regulation, Neoplastic
  • HMGA2 Protein (biosynthesis)
  • Humans
  • Lung Neoplasms (genetics, pathology)
  • MicroRNAs (biosynthesis, genetics)
  • Neoplasm Metastasis
  • Neoplasm Proteins (biosynthesis, genetics)
  • Vimentin (biosynthesis)

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