Paracrine Fibroblast Growth Factor Initiates Oncogenic Synergy with Epithelial FGFR/Src Transformation in Prostate Tumor Progression.
Paracrine Fibroblast Growth Factor Initiates Oncogenic Synergy with Epithelial FGFR/Src Transformation in Prostate Tumor Progression.
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DOI：
10.1016/j.neo.2018.01.006
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Cai H
中科院分区：
文献类型：
--
作者：
Li Q;Ingram L;Kim S;Beharry Z;Cooper JA;Cai H
基质上皮细胞的串扰在正常发育和肿瘤的发生发展中都起着重要作用。成纤维细胞生长因子(FGF)-FGF受体(FGFR)-Src激酶轴是介导这种串扰的主要信号转导途径之一。许多基因组研究表明，FGFR/Src的表达水平在包括前列腺癌在内的多种癌症中不受调节；然而，分泌旁腺FGF（来自基质细胞）在上皮细胞FGFRs/Src表达失调和体内肿瘤进展中的作用尚未得到很好的评估。在本研究中，我们证明了在体内正常基质微环境下，上皮细胞中野生型FGFR1/2或Src激酶的异位表达并不足以引发前列腺肿瘤的发生。然而，旁分泌FGF10与上皮FGFR1或FGFR2的异位表达协同诱导上皮-间质转化。此外，旁分泌的FGF10使fgfr2转化的上皮细胞增敏，从而启动前列腺肿瘤的发生。其次，旁分泌FGF10也与上皮Src激酶的过表达协同作用于高级别肿瘤。但是Src激酶肉豆肉酰化位点的缺失抑制了旁分泌fgf10诱导的前列腺肿瘤发生。肉豆蔻酰化的缺失会改变细胞膜中的Src水平，并抑制fgf介导的信号传导，包括抑制磷酸酪氨酸模式和FAK磷酸化。我们的研究证明了FGF/FGFRs/Src信号轴蛋白的同时解除调控可导致潜在的肿瘤进展，并提供了一种靶向Src激酶肉豆醇化以干扰致瘤过程的治疗策略。
Cross talk of stromal-epithelial cells plays an essential role in both normal development and tumor initiation and progression. Fibroblast growth factor (FGF)-FGF receptor (FGFR)-Src kinase axis is one of the major signal transduction pathways to mediate this cross talk. Numerous genomic studies have demonstrated that expression levels of FGFR/Src are deregulated in a variety of cancers including prostate cancer; however, the role that paracrine FGF (from stromal cells) plays in dysregulated expression of epithelial FGFRs/Src and tumor progression in vivo is not well evaluated. In this study, we demonstrate that ectopic expression of wild-type FGFR1/2 or Src kinase in epithelial cells was not sufficient to initiate prostate tumorigenesis under a normal stromal microenvironment in vivo. However, paracrine FGF10 synergized with ectopic expression of epithelial FGFR1 or FGFR2 to induce epithelial-mesenchymal transition. Additionally, paracrine FGF10 sensitized FGFR2-transformed epithelial cells to initiate prostate tumorigenesis. Next, paracrine FGF10 also synergized with overexpression of epithelial Src kinase to high-grade tumors. But loss of the myristoylation site in Src kinase inhibited paracrine FGF10-induced prostate tumorigenesis. Loss of myristoylation alters Src levels in the cell membrane and inhibited FGF-mediated signaling including inhibition of the phosphotyrosine pattern and FAK phosphorylation. Our study demonstrates the potential tumor progression by simultaneous deregulation of proteins in the FGF/FGFRs/Src signal axis and provides a therapeutic strategy of targeting myristoylation of Src kinase to interfere with the tumorigenic process.
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影响因子：
11.2
作者：
Cai H;Memarzadeh S;Stoyanova T;Beharry Z;Kraft AS;Witte ON
通讯作者：
Witte ON
影响因子：
11.5
作者：
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50.3
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50.3
作者：
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影响因子：
5.2
作者：
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通讯作者：
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