Fragile Histidine Triad (FHIT) gene Suppresses Metastasis and Epithelial-Mesenchymal Transition (EMT) through Modulation of microRNAs in Lung Cancer

Abstract

Metastasis is the principal cause of cancer death and occurs in complex multiple processes which require the concerted action of many genes. Recent studies indicate that the Fragile Histidine Triad (FHIT) gene functions as a potential tumor suppressor in a variety of common human cancers. However, its role in metastasis progression remains unknown. Here, via in vivo and in vitro assays, we reveal that the enforced expression of Fhit significantly suppresses metastasis, leading to inhibition of the epithelial-mesenchymal transition (EMT) known as a crucial process in cancer metastasis through coordinate modulation of EMT-related genes. In particular, we show that miR-30c, profiled as a Fhit-upregulated microRNA, contributes to this function of Fhit to suppress metastasis and EMT by directly targeting metastasis gene Metadherin (MTDH), High-mobility group AT&#8212 hook 2 (HMGA2), and the mesenchymal markers, Vimentin and Fibronectin, 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, non-metastatic and metastatic tumors, serving as a potential biomarker for metastasis in lung cancer. suppressor in a variety of common human cancers. However, its role in metastasis progression remains unknown. Here, via in vivo and in vitro assays, we reveal that the enforced expression of Fhit significantly suppresses metastasis, leading to inhibition of the epithelial-mesenchymal transition (EMT) known as a crucial process in cancer metastasis through coordinate modulation of EMT-related genes. In particular, we show that miR-30c, profiled as a Fhit-upregulated microRNA, contributes to this function of Fhit to suppress metastasis and EMT by directly targeting metastasis gene Metadherin (MTDH), High-mobility group AT&#8212 hook 2 (HMGA2), and the mesenchymal markers, Vimentin and Fibronectin, 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, non-metastatic and metastatic tumors, serving as a potential biomarker for metastasis in lung cancer.