Calreticulin promotes EGF-induced EMT in pancreatic cancer cells via Integrin/EGFR-ERK/MAPK signaling pathway.
Calreticulin promotes EGF-induced EMT in pancreatic cancer cells via Integrin/EGFR-ERK/MAPK signaling pathway.
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钙网蛋白通过 Integrin/EGFR-ERK/MAPK 信号通路促进 EGF 诱导的胰腺癌细胞 EMT
DOI：
10.1038/cddis.2017.547
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发表时间：
2017-10-26
影响因子：
9
通讯作者：
Ding S
中科院分区：
文献类型：
--
作者：
Sheng W;Chen C;Dong M;Wang G;Zhou J;Song H;Li Y;Zhang J;Ding S
我们前期的研究表明钙网蛋白（Calreticulin，CRT）通过ERK/MAPK通路促进胰腺癌的发生发展。我们接下来研究CRT是否通过整合素/EGFR-ERK/MAPK信号通路促进PC中EGF诱导的上皮-间充质转化（EMT），据我们所知，这还没有报道。EGF可诱导3株PC细胞发生EMT，并激活Integrin/EGFR-ERK/MAPK信号通路。CRT沉默可显著抑制EGF的功能，包括抑制EGF诱导的EMT样细胞形态，抑制EGF促进的细胞侵袭和迁移，EGF诱导E-cadherin、ZO-1和β-catenin表达减少，Integrin/EGFR-ERK/MAPK信号通路中的关键蛋白（pEGFR-tyr 1173、Fibronectin、Integrinβ1、c-Myc和pERK）表达增加。相反，CRT过表达挽救了EGF诱导的CRT沉默PC细胞中EMT相关蛋白的变化。共聚焦显微镜下，CRT与pEGFR 1173（含EGF）、Fibronectin和Integrinβ1共染色，CRT与PC细胞中的Fibronectin、Integrinβ1和c-Myc共沉淀，表明CRT与PC中的Integrin/EGFR-ERK/MAPK信号通路有密切的相互作用。在体内，CRT沉默抑制胰腺癌皮下肿瘤生长和肝转移。CRT与纤维连接蛋白、整合素β1、c-Myc和pERK呈正相关，与E-cad呈负相关。同时，上述蛋白的过度表达与PC患者的多种侵袭性临床病理特征和不良预后密切相关。CRT通过Integrin/EGFR-ERK/MAPK信号通路促进EGF诱导的PC细胞EMT，有望成为PC的治疗靶点。
Our previous study showed that Calreticulin (CRT) promoted the development of pancreatic cancer (PC) through ERK/MAPK pathway. We next investigate whether CRT promotes EGF-induced epithelial–mesenchymal transition (EMT) in PC via Integrin/EGFR-ERK/MAPK signaling, which has not been reported yet to our knowledge. EGF simultaneously induced EMT and activated Integrin/EGFR–ERK/MAPK signaling pathway in 3 PC cells. However, CRT silencing significantly inhibited EGF function, including inhibiting EGF-induced EMT-like cell morphology, EGF-enhanced cell invasion and migration, and EGF induced the decrease of E-cadherin, ZO-1, and β-catenin and the increase of the key proteins in Integrin/EGFR-ERK/MAPK signaling (pEGFR-tyr1173, Fibronectin, Integrinβ1, c-Myc and pERK). Conversely, CRT overexpression rescued the change of EMT-related proteins induced by EGF in CRT silencing PC cells. Additionally, CRT was co-stained with pEGFR1173 (with EGF), Fibronectin and Integrinβ1 by IF under confocal microscopy and was co-immunoprecipitated with Fibronectin, Integrinβ1 and c-Myc in both PC cells, all of which indicating a close interaction of CRT with Integrin/EGFR–ERK/MAPK signaling pathway in PC. In vivo, CRT silencing inhibited subcutaneous tumor growth and liver metastasis of pancreatic tumor. A positive relationship of CRT with Fibronectin, Integrinβ1, c-Myc and pERK and a negative association of CRT with E-cad was also observed in vivo and clinical samples. Meanwhile, overexpression of the above proteins was closely associated with multiple aggressive clinicopathological characteristics and the poor prognosis of PC patients. CRT promotes EGF-induced EMT in PC cells via Integrin/EGFR-ERK/MAPK signaling pathway, which would be a promising therapy target for PC.
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