Abstract

In many cancers, including lung carcinomas, Fragile histidine triad (Fhit) is frequently decreased or lost. Fhit status has recently been shown to be associated with elevated in vitro and in vivo invasiveness in lung cancer. Tumor cell invasion is facilitated by epithelial-mesenchymal transition (EMT), a process by which tumor cells lose their epithelial features to acquire a mesenchymal cell-like phenotype. In this study, the mechanism underlying Fhit-regulated EMT was deciphered. Using Slug knockdown, pharmacologic inhibitors PD98059, PP1, and gefitinib as well as an anti-EGFR antibody, it was demonstrated that Fhit silencing in bronchial cells induced overexpression of two primary EMT-associated targets, MMP-9 and vimentin, to regulate cell invasion dependent on an EGFR/Src/ERK/Slug signaling pathway. Moreover, ectopic expression of Fhit in Fhit-deficient lung cancer cells downregulated this pathway. Finally, an inverse correlation was observed between Fhit and phospho-EGFR levels in a cohort of human squamous cell lung carcinoma specimens. These results demonstrate a Fhit-dependent mechanism in the control of EMT-regulated EGFR signaling. This study adds new insight into the regulatory mechanism of EMT, a process known to increase resistance to conventional and targeted therapies in lung cancer.

Highlights

  • Lung cancer is the leading cause of deaths worldwide

  • We reported that Fragile histidine triad (Fhit) inhibition is able to increase cell invasion by regulating expression of genes associated with epithelial–mesenchymal transitions (EMT), in particular vimentin and matrix metalloproteases (MMP)-9 [19]

  • We found that Slug is upregulated concomitantly with vimentin and MMP-9 after Fhit silencing in bronchial HBE4-E6/E7 cells as shown by Western blot and zymography analyses (Fig. 1A)

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Summary

Introduction

Lung cancer is the leading cause of deaths worldwide. The poor survival of patients with lung cancer is mostly attributed to early metastasis and resistance to both conventional and targeted therapies. The metastatic progression of epithelial tumors is a complex process requiring tumor cell plasticity. The step of tumor cell invasion into surrounding stromal tissue is characterized by a dedifferentiation of tumor cells, largely known to involve epithelial–mesenchymal transitions (EMT). Tumor cells undergoing EMTs lose epithelial features and engage in mesenchymal cell mimicry as observed during embryonic development [1,2,3]. During tumor invasion, cell–cell adhesion complexes, especially adherens and tight junctions, are frequently reorganized

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