YAP1-mediated pancreatic stellate cell activation inhibits pancreatic cancer cell proliferation
YAP1-mediated pancreatic stellate cell activation inhibits pancreatic cancer cell proliferation
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YAP1介导的胰腺星状细胞激活抑制胰腺癌细胞增殖
DOI：
10.1016/j.canlet.2019.07.015
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Liang, Zhiyong
中科院分区：
文献类型：
--
作者：
Xiao, Ying;Zhang, Hui;Liang, Zhiyong
胰腺星状细胞（PSC）在胰腺导管腺癌（PDAC）中被激活，并负责致密的促纤维增生基质。YAP 1可以诱导肝脏和乳腺肿瘤中的癌症相关成纤维细胞活化，但其对PSC的影响尚不清楚。在本研究中，我们确定了YAP 1在PDAC衍生的活化PSC的细胞核中高度表达。RNAi介导的或药理学抑制YAP 1导致PSC失活。此外，YAP 1刺激PSC中分泌的酸性和富含半胱氨酸的蛋白（Cys）的表达，RUNX 1抑制了这种表达。PSCs分泌的β-淀粉样蛋白抑制胰腺癌细胞（PCC）增殖。细胞核YAP 1在PDAC间质中的高表达与PDAC组织中TGF β 1的表达和纤维化程度显著相关。我们的研究揭示了YAP 1在PSC激活和旁分泌信号调节中的关键作用。我们的研究结果为靶向YAP 1重新编程PDAC微环境提供了新的理论基础。
Pancreatic stellate cells (PSCs) are activated in pancreatic ductal adenocarcinoma (PDAC) and are responsible for dense desmoplastic stroma. Yes-associated protein 1 (YAP1) can induce cancer-associated fibroblast activation in liver and breast tumors, but its effect on PSCs is unknown. In the present study, we determined that YAP1 was highly expressed in the nuclei of PDAC-derived activated PSCs. RNAi-mediated or pharmacological inhibition of YAP1 led to PSC deactivation. In addition, YAP1 stimulated the expression of secreted protein acidic and cysteine rich (SPARC) in PSCs, which was inhibited by RUNX1. SPARC secreted from PSCs inhibited pancreatic cancer cell (PCC) proliferation. High expression of nuclear YAP1 in tumor stroma was significantly correlated with SPARC expression and fibrosis degree in human PDAC tissues. Our study revealed a critical role for YAP1 in the regulation of PSC activation and paracrine signaling. Our findings provide insights into a novel rationale for targeting YAP1 to reprogram the PDAC microenvironment.