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成纤维细胞生长因子4通过诱导肺腺癌中钙库操纵性钙内流来诱导上皮-间质转化。

FGF4 induces epithelial-mesenchymal transition by inducing store-operated calcium entry in lung adenocarcinoma.

作者信息

Qi Lisha, Song Wangzhao, Li Lingmei, Cao Lu, Yu Yue, Song Chunmin, Wang Yalei, Zhang Fei, Li Yang, Zhang Bin, Cao Wenfeng

机构信息

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.

出版信息

Oncotarget. 2016 Nov 8;7(45):74015-74030. doi: 10.18632/oncotarget.12187.

DOI:10.18632/oncotarget.12187
PMID:27677589
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5342032/
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.

摘要

几种成纤维细胞生长因子（FGF）亚型在癌症进展过程中可刺激上皮-间质转化（EMT）。FGF4和FGF7是FGF受体2（FGFR2）的两种配体。我们使用两种肺腺癌（ADC）细胞系A549和H1299发现，FGF4而非FGF7改变了细胞形态，促进了EMT相关蛋白表达，并增强了细胞增殖、迁移/侵袭及集落形成能力。此外，FGF4增加了钙库操纵性钙内流（SOCE）以及钙信号相关蛋白Orai1的表达。SOCE抑制剂2,5-二叔丁基对苯二酚（BHQ）或Orai1基因敲低可逆转FGF4所有促进EMT的作用。BHQ在小鼠异种移植模型中也抑制了FGF4诱导的EMT。最后，使用60例人肺ADC样本和21组配对标本（来自一名患者的原发性和淋巴结转移灶）来证实FGF4的临床病理意义及其与E-钙黏蛋白、波形蛋白和Orai1表达之间的相关性。因此，我们的研究表明FGF4通过提高肺ADC中的SOCE来诱导EMT。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4870/5342032/337414bbb149/oncotarget-07-74015-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4870/5342032/673808d58aa2/oncotarget-07-74015-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4870/5342032/65485906d056/oncotarget-07-74015-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4870/5342032/f2ac870ec6c1/oncotarget-07-74015-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4870/5342032/278c9c0a3bd3/oncotarget-07-74015-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4870/5342032/c4f8949442fd/oncotarget-07-74015-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4870/5342032/c1bb244a1f31/oncotarget-07-74015-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4870/5342032/337414bbb149/oncotarget-07-74015-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4870/5342032/673808d58aa2/oncotarget-07-74015-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4870/5342032/65485906d056/oncotarget-07-74015-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4870/5342032/f2ac870ec6c1/oncotarget-07-74015-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4870/5342032/278c9c0a3bd3/oncotarget-07-74015-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4870/5342032/c4f8949442fd/oncotarget-07-74015-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4870/5342032/c1bb244a1f31/oncotarget-07-74015-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4870/5342032/337414bbb149/oncotarget-07-74015-g007.jpg

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