FGFR2 maintains cancer cell differentiation via AKT signaling in esophageal squamous cell carcinoma
FGFR2 maintains cancer cell differentiation via AKT signaling in esophageal squamous cell carcinoma
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DOI：
10.1080/15384047.2021.1939638
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发表时间：
2021-06
影响因子：
3.6
通讯作者：
Osamu Maehara;G. Suda;Mitsuteru Natsuizaka;T. Shigesawa;Gouki Kanbe;M. Kimura;M. Sugiyama;M. Mizokami;Masato Nakai;T. Sho;Kenichi Morikawa;Koji Ogawa;S. Ohashi;S. Kagawa;H. Kinugasa;S. Naganuma;N. Okubo;S. Ohnishi;Hiroshi Takeda;N. Sakamoto
中科院分区：
文献类型：
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作者：
Osamu Maehara;G. Suda;Mitsuteru Natsuizaka;T. Shigesawa;Gouki Kanbe;M. Kimura;M. Sugiyama;M. Mizokami;Masato Nakai;T. Sho;Kenichi Morikawa;Koji Ogawa;S. Ohashi;S. Kagawa;H. Kinugasa;S. Naganuma;N. Okubo;S. Ohnishi;Hiroshi Takeda;N. Sakamoto
摘要成纤维细胞生长因子（FGF）及其受体（FGFR）是维持食管鳞状细胞癌（ESCC）中癌干细胞样细胞（CSC）的重要信号。然而，究竟哪种FGF受体（1、2、3、4和L1）是必需的，或者FGFRs在ESCC-CSC中是否具有明显不同的作用，仍然存在疑问。这项研究表明，FGFR 2，特别是IIIb亚型，在非CSC中高度表达。非CSC具有上皮表型，并且此类细胞在ESCC中分化更大。此外，FGFR 2通过AKT而不是MAPK信号传导诱导角质形成细胞分化并减少CSC群体。相反，FGFR 2的敲低诱导上皮-间质转化（EMT）并富集ESCC中的CSC群体。最后，使用癌症基因组图谱（TCGA）数据集的数据分析显示，FGFR 2的表达与临床ESCC样品中的癌细胞分化显著相关。目前的研究表明，每种FGFR具有不同的作用，并且FGFR 2-AKT信号传导是ESCC中角质形成细胞分化的关键驱动因素。激活FGFR 2-AKT信号可能是ESCC中靶向CSC的未来治疗选择。
ABSTRACT Fibroblast growth factors (FGFs) and their receptors (FGFRs) are important for signaling to maintain cancer stem-like cells (CSCs) in esophageal squamous cell carcinoma (ESCC). However, which FGF receptor, 1, 2, 3, 4, and L1, is essential or whether FGFRs have distinct different roles in ESCC-CSCs is still in question. This study shows that FGFR2, particularly the IIIb isoform, is highly expressed in non-CSCs. Non-CSCs have an epithelial phenotype, and such cells are more differentiated in ESCC. Further, FGFR2 induces keratinocyte differentiation through AKT but not MAPK signaling and diminishes CSC populations. Conversely, knockdown of FGFR2 induces epithelial–mesenchymal transition (EMT) and enriches CSC populations in ESCC. Finally, data analysis using The Cancer Genome Atlas (TCGA) dataset shows that expression of FGFR2 significantly correlated with cancer cell differentiation in clinical ESCC samples. The present study shows that each FGFR has a distinct role and FGFR2-AKT signaling is a key driver of keratinocyte differentiation in ESCC. Activation of FGFR2-AKT signaling could be a future therapeutic option targeting CSC in ESCC.