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

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.