Addiction of mesenchymal phenotypes on the FGF/FGFR axis in oral squamous cell carcinoma cells
Addiction of mesenchymal phenotypes on the FGF/FGFR axis in oral squamous cell carcinoma cells
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DOI：
10.1371/journal.pone.0217451
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发表时间：
2019-11-04
期刊：
影响因子：
3.7
通讯作者：
Saitoh, Masao
中科院分区：
文献类型：
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作者：
Osada, Asami Hotta;Endo, Kaori;Saitoh, Masao
上皮-间质转化（EMT）是上皮肿瘤进展过程中发生的重要形态学事件。ZEB 1/2是EMT转录因子，与EMT表型和乳腺癌侵袭性正相关。ZEB 1/2通过抑制上皮剪接调节蛋白ESRP 1和ESRP 2来调节成纤维细胞生长因子受体（FGFR）的选择性剪接并因此调节同种型转换。在这里，我们表明，间充质样表型的口腔鳞状细胞癌（OSCC）细胞依赖于自分泌的FGF-FGFR信号。间质样OSCC细胞表达低水平的ESRP 1/2和高水平的ZEB 1/2，导致FGFR的IIIc亚型FGFR（IIIc）的组成性表达。相比之下，上皮样OSCC细胞显示出这些蛋白质的相反表达谱和FGFR 2的IIIb-同种型FGFR 2（IIIb）的组成性表达。重要的是，ERK 1/2通过FGFR 1（IIIc）组成性磷酸化，FGFR 1（IIIc）被间充质样OSCC细胞自主分泌的因子激活，并参与ZEB 1的持续高水平表达。用抑制剂或siRNA拮抗FGFR 1显著抑制ZEB 1表达并恢复上皮样性状。因此，自分泌FGF-FGFR（IIIc）信号似乎是负责维持ZEB 1/2在高水平和EMT表型在口腔鳞癌细胞。
The epithelial-mesenchymal transition (EMT) is a crucial morphological event that occurs during epithelial tumor progression. ZEB1/2 are EMT transcription factors that are positively correlated with EMT phenotypes and breast cancer aggressiveness. ZEB1/2 regulate the alternative splicing and hence isoform switching of fibroblast growth factor receptors (FGFRs) by repressing the epithelial splicing regulatory proteins, ESRP1 and ESRP2. Here, we show that the mesenchymal-like phenotypes of oral squamous cell carcinoma (OSCC) cells are dependent on autocrine FGF-FGFR signaling. Mesenchymal-like OSCC cells express low levels of ESRP1/2 and high levels of ZEB1/2, resulting in constitutive expression of the IIIc-isoform of FGFR, FGFR(IIIc). By contrast, epithelial-like OSCC cells showed opposite expression profiles for these proteins and constitutive expression of the IIIb-isoform of FGFR2, FGFR2(IIIb). Importantly, ERK1/2 was constitutively phosphorylated through FGFR1(IIIc), which was activated by factors secreted autonomously by mesenchymal-like OSCC cells and involved in sustained high-level expression of ZEB1. Antagonizing FGFR1 with either inhibitors or siRNAs considerably repressed ZEB1 expression and restored epithelial-like traits. Therefore, autocrine FGF-FGFR(IIIc) signaling appears to be responsible for sustaining ZEB1/2 at high levels and the EMT phenotype in OSCC cells.