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Fyn/异质核核糖核蛋白 E1 信号通过影响整合素 β1 的可变剪接调节胰腺癌转移。

Fyn/heterogeneous nuclear ribonucleoprotein E1 signaling regulates pancreatic cancer metastasis by affecting the alternative splicing of integrin β1.

机构信息

Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China.

Department of Cell Biology, Third Military Medical University, Chongqing 400038, P.R. China.

出版信息

Int J Oncol. 2017 Jul;51(1):169-183. doi: 10.3892/ijo.2017.4018. Epub 2017 May 24.

DOI:10.3892/ijo.2017.4018
PMID:28560430
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5467783/
Abstract

Pancreatic cancer is characterized by a dense desmoplastic reaction in which extracellular matrix proteins accumulate and surround tumor cells. Integrins and their related signaling molecules are associated with progression of pancreatic cancer. In the present study, the association between the metastasis of pancreatic cancer and the expression of hnRNP E1 and integrin β1 was evaluated. In vitro and in vivo experiments were designed to study the mechanism underlying the regulation of integrin β1 splicing by the Fyn/hnRNP E1 spliceosome. Expression of hnRNP E1 and integrin β1A were associated with metastasis of pancreatic cancer. Inhibition of Fyn activity upregulated the expression of P21-activated kinase 1 and promoted the phosphorylation and nuclear localization of hnRNP E1, leading to the construction of a spliceosome complex that affected the alterative splicing of integrin β1. In the hnRNP E1 spliceosome complex, hnRNP A1 and serine/arginine-rich splicing factor 1 were responsible for binding to the pre-mRNA of integrin β1. Suppression of Fyn activity and/or overexpression of hnRNP E1 decreased the metastasis of pancreatic cancer cells. In pancreatic cancer, the present study demonstrated a novel mechanism by which Fyn/hnRNP E1 signaling regulates pancreatic cancer metastasis by affecting the alternative splicing of integrin β1. hnRNP E1 and integrin β1A are associated with the metastasis of pancreatic cancer and may be novel molecular targets for pancreatic cancer treatment.

摘要

胰腺癌的特征是致密的纤维母细胞反应，其中细胞外基质蛋白积累并包围肿瘤细胞。整合素及其相关信号分子与胰腺癌的进展有关。本研究评估了胰腺癌转移与 hnRNP E1 和整合素β1 表达之间的关系。设计了体外和体内实验来研究 Fyn/hnRNP E1 剪接体调节整合素β1 剪接的机制。hnRNP E1 和整合素β1A 的表达与胰腺癌的转移有关。抑制 Fyn 活性上调了 P21 激活激酶 1 的表达，并促进了 hnRNP E1 的磷酸化和核定位，从而构建了一个影响整合素β1 可变剪接的剪接体复合物。在 hnRNP E1 剪接体复合物中，hnRNP A1 和富含丝氨酸/精氨酸的剪接因子 1 负责与整合素β1 的前体 mRNA 结合。抑制 Fyn 活性和/或过表达 hnRNP E1 可降低胰腺癌细胞的转移。在胰腺癌中，本研究证明了 Fyn/hnRNP E1 信号通过影响整合素β1 的可变剪接来调节胰腺癌转移的新机制。hnRNP E1 和整合素β1A 与胰腺癌的转移有关，可能是胰腺癌治疗的新的分子靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd8b/5467783/af6828fab83c/IJO-51-01-0169-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd8b/5467783/876a09df1d2e/IJO-51-01-0169-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd8b/5467783/bdc4caa3ef2b/IJO-51-01-0169-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd8b/5467783/5acb7ba89db0/IJO-51-01-0169-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd8b/5467783/928a1a10d035/IJO-51-01-0169-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd8b/5467783/af6828fab83c/IJO-51-01-0169-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd8b/5467783/876a09df1d2e/IJO-51-01-0169-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd8b/5467783/bdc4caa3ef2b/IJO-51-01-0169-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd8b/5467783/5acb7ba89db0/IJO-51-01-0169-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd8b/5467783/928a1a10d035/IJO-51-01-0169-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd8b/5467783/af6828fab83c/IJO-51-01-0169-g04.jpg

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