Fhit regulates EMT targets through an EGFR/Src/ERK/Slug signaling axis in human bronchial cells.
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.


CONCLUSIONS
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.
Authors' Affiliations: INSERM UMR-S 903, SFR CAP-Santé (FED 4231), University of Reims Champagne-Ardenne, Reims, France; 2CNRS UMR 7369, SFR CAP-Santé (FED 4231), University of Reims Champagne-Ardenne, Reims, France; 3Laboratory of Histology, CHU of Reims, Reims, France; and 4Laboratory of Developmental and Tumor Biology, GIGA-Cancer, University of Liège, CHU of Sart-Tilman, Liège, Belgium.
Audrey
A
Joannes
Simon
S
Grelet
Laurent
L
Duca
Christine
C
Gilles
Claire
C
Kileztky
Véronique
V
Dalstein
Philippe
P
Birembaut
Myriam
M
Polette
Béatrice
B
Nawrocki-Raby
D017766:Acid Anhydride Hydrolases / Q000378:metabolism*; D001980:Bronchi / Q000166:cytology* / Q000378:metabolism; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D009363:Neoplasm Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism*; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D066246:ErbB Receptors; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D019061:src-Family Kinases; D000099170:Bis(5'-adenosyl)triphosphatase; C000604407:SNAI1 protein, human; C512478:EGFR protein, human