FN14 expression correlates with MET in NSCLC and promotes MET-driven cell invasion.
The five-year survival rate in advanced non-small cell lung cancer (NSCLC) remains below ten percent. The invasive and metastatic nature of NSCLC tumor cells contributes to the high mortality rate, and as such the mechanisms that govern NSCLC metastasis is an active area of investigation. Two surface receptors that influence NSCLC invasion and metastasis are the hepatocyte growth factor receptor (HGFR/MET) and fibroblast growth factor-inducible 14 (FN14). MET protein is over-expressed in NSCLC tumors and associated with poor clinical outcome and metastasis. FN14 protein is also elevated in NSCLC tumors and positively correlates with tumor cell migration and invasion. In this report, we show that MET and FN14 protein expressions are significantly correlated in human primary NSCLC tumors, and the protein levels of MET and FN14 are elevated in metastatic lesions relative to patient-matched primary tumors. In vitro, HGF/MET activation significantly enhances FN14 mRNA and protein expression. Importantly, depletion of FN14 is sufficient to inhibit MET-driven NSCLC tumor cell migration and invasion in vitro. This work suggests that MET and FN14 protein expressions are associated with the invasive and metastatic potential of NSCLC. Receptor-targeted therapeutics for both MET and FN14 are in clinical development, the use of which may mitigate the metastatic potential of NSCLC.
Cancer and Cell Biology Division, The Translational Genomics Research Institute (TGen), 445 N. Fifth St., Suite 400, Phoenix, AZ, 85004, USA, twhitsett@tgen.org.
Timothy G
TG
Whitsett
Shannon P
SP
Fortin Ensign
Harshil D
HD
Dhruv
Landon J
LJ
Inge
Paul
P
Kurywchak
Kerri K
KK
Wolf
Janine
J
LoBello
Christopher B
CB
Kingsley
Jeffrey W
JW
Allen
Glen J
GJ
Weiss
Nhan L
NL
Tran
D000818:Animals; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D017931:DNA Primers; D004195:Disease Models, Animal; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009361:Neoplasm Invasiveness; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D000074050:TWEAK Receptor
D017931:DNA Primers; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met