FGF4 induces epithelial-mesenchymal transition by inducing store-operated calcium entry in lung adenocarcinoma.
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.
Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.|The Key Laboratory of Tianjin Cancer Prevention and Treatment, Tianjin 300060, China.|National Clinical Research Center for Cancer, Tianjin 300060, China.
Lisha
L
Qi
Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.|Tianjin Medical University, Tianjin 300070, China.|The Key Laboratory of Tianjin Cancer Prevention and Treatment, Tianjin 300060, China.|National Clinical Research Center for Cancer, Tianjin 300060, China.
Wangzhao
W
Song
Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.|The Key Laboratory of Tianjin Cancer Prevention and Treatment, Tianjin 300060, China.|National Clinical Research Center for Cancer, Tianjin 300060, China.
Lingmei
L
Li
Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.|Tianjin Medical University, Tianjin 300070, China.|The Key Laboratory of Tianjin Cancer Prevention and Treatment, Tianjin 300060, China.|National Clinical Research Center for Cancer, Tianjin 300060, China.
Lu
L
Cao
Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.|The Key Laboratory of Tianjin Cancer Prevention and Treatment, Tianjin 300060, China.|National Clinical Research Center for Cancer, Tianjin 300060, China.
Yue
Y
Yu
Department of Family Planning, Maternity & Child Care Center of Luoyang, Luoyang 471000, China.
Chunmin
C
Song
Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.|The Key Laboratory of Tianjin Cancer Prevention and Treatment, Tianjin 300060, China.|National Clinical Research Center for Cancer, Tianjin 300060, China.
Yalei
Y
Wang
The Key Laboratory of Tianjin Cancer Prevention and Treatment, Tianjin 300060, China.|National Clinical Research Center for Cancer, Tianjin 300060, China.|Research Center of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
Fei
F
Zhang
Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.|Tianjin Medical University, Tianjin 300070, China.|The Key Laboratory of Tianjin Cancer Prevention and Treatment, Tianjin 300060, China.|National Clinical Research Center for Cancer, Tianjin 300060, China.
Yang
Y
Li
Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.|The Key Laboratory of Tianjin Cancer Prevention and Treatment, Tianjin 300060, China.|National Clinical Research Center for Cancer, Tianjin 300060, China.
Bin
B
Zhang
Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.|The Key Laboratory of Tianjin Cancer Prevention and Treatment, Tianjin 300060, China.|National Clinical Research Center for Cancer, Tianjin 300060, China.
Wenfeng
W
Cao
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D051519:Fibroblast Growth Factor 4 / Q000378:metabolism* / Q000494:pharmacology; D051523:Fibroblast Growth Factor 7 / Q000378:metabolism / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D000071740:ORAI1 Protein / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D015820:Cadherins; C496445:FGF4 protein, human; C496453:FGF7 protein, human; D051519:Fibroblast Growth Factor 4; D000071740:ORAI1 Protein; D014746:Vimentin; D051523:Fibroblast Growth Factor 7; D051497:Receptor, Fibroblast Growth Factor, Type 2; D002118:Calcium
FGF4; FGF7; Orai1; epithelial-mesenchymal transition; store-operated calcium entry
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