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PLoS Genet. 2014 Oct 23;10(10):e1004652. doi: 10.1371/journal.pgen.1004652. eCollection 2014 Oct.

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

Author information

1
Department of Molecular Virology, Immunology and Medical Genetics, and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America; South Sea Environmental Research Division, Korea Institute of Ocean Science and Technology, Geoje, South Korea.
2
Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, Comprehensive Cancer Center and The Ohio State University Medical Center, Columbus, Ohio, United States of America.
3
Department of Molecular Virology, Immunology and Medical Genetics, and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America.
4
South Sea Environmental Research Division, Korea Institute of Ocean Science and Technology, Geoje, South Korea.
5
Department of Molecular Virology, Immunology and Medical Genetics, and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America; The Lautenberg Center for General and Tumor Immunology, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel.

Abstract

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.

PMID:
25340791
PMCID:
PMC4207614
DOI:
10.1371/journal.pgen.1004652
[Indexed for MEDLINE]
Free PMC Article

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