Abstract
Several fibroblast growth factor (FGF) isoforms act to stimulate epithelial-mesenchymal transition (EMT) during cancer progression. FGF4 and FGF7 are two ligands of FGF receptor 2 (FGFR2). Using two lung adenocarcinoma (ADC) cell lines, A549 and H1299, we showed that FGF4, but not FGF7, altered cell morphology, promoted EMT-associated protein expression, and enhanced cell proliferation, migration/invasion and colony initiation. In addition, FGF4 increased store-operated calcium entry (SOCE) and expression of the calcium signal-associated protein Orai1. The SOCE inhibitor 2,5-di-tert-butylhydroquinone (BHQ) or Orai1 knockdown reversed all of the EMT-promoting effects of FGF4. BHQ also inhibited FGF4-induced EMT in a mouse xenograft model. Finally, 60 human lung ADC samples and 21 sets of matched specimens (primary and metastatic foci in lymph nodes from one patient) were used to confirm the clinicopathologic significance of FGF4 and its correlation with E-cadherin, Vimentin and Orai1 expression. Our study thus shows that FGF4 induces EMT by elevating SOCE in lung ADC.
Highlights
The fibroblast growth factor (FGF) family consists of at least 23 members
Using two lung adenocarcinoma (ADC) cell lines, A549 and H1299, we showed that FGF4, but not FGF7, altered cell morphology, promoted epithelialmesenchymal transition (EMT)-associated protein expression, and enhanced cell proliferation, migration/invasion and colony initiation
Out of the 23 reported FGFs, we focused on FGF4 and FGF7, the representative FGF ligands for FGF receptor 2 (FGFR2) splice variants, and studied their functions in the EMT program of lung ADC
Summary
The fibroblast growth factor (FGF) family consists of at least 23 members. FGFs are involved in numerous physiological processes, ranging from vertebrate segmentation and elongation of the embryonic axis to skeletal development [1, 2]. The EMT program is promoted by many soluble growth factors, including FGFs [2, 7]. The activation of the FGFR/MEK/ERK pathway by FGF2 promotes cell growth and EMT in the chordoma [8] and FGF10 can induce EMT of breast cancer cells [9]. FGF8 can induce a more aggressive phenotype displaying EMT and enhanced invasion and growth in colorectal cancer cells [10]. Donnem and colleagues showed that high FGF2 expression in non-small-cell lung cancer (NSCLC) is associated with poor five-year survival [4]. Li demonstrated that immunoreactive scores of FGF1 were higher in NSCLC specimens than in peritumoral normal tissues and patients with high FGF1 expression had a lower overall survival rate [12]. NSCLC patients with www.impactjournals.com/oncotarget high FGF9 expression were reported to have a worse prognosis than those with low FGF9 expression [13]
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