THE AMERICAN JOURNAL OF PATHOLOGY

Zhang T, Choi S, Zhang T, Chen Z, Chi Y, Huang S, Xiang JZ and Nancy Du YC

Am J Pathol. 2020.

DOI: https://doi.org/10.1016/j.ajpath.2019.11.007

Abstract

The incidence of pancreatic neuroendocrine tumor (PNET) is increasing, and it presents with various clinical manifestations and an unfavorable survival rate. A better understanding of the drivers of PNET tumorigenesis is urgently needed. Distinct miRNA signatures have been identified for different stages of tumorigenesis in both human and mouse PNETs. The functions of these miRNAs are poorly understood. miR431 is the most up-regulated miRNA in the metastatic signature. However, it is unknown whether miR431 contributes to metastasis of PNETs. Herein, we show that miR431 overexpression activates Ras/extracellular signal-regulated kinase (Erk) signaling and promotes epithelial-mesenchymal transition, migration/invasion in vitro, and metastasis in both xenograft and spontaneous mouse models of PNET. Treatment of PNET cells with Erk inhibitor or locked nucleic acids sequestering miR431 inhibits invasion. Four target prediction modules and dual-luciferase reporter assays were used to identify potential mRNA targets of miR431. A Ras GTPase activating protein tumor suppressor, DAB2 interacting protein (DAB2IP), was discovered as an miR431 target. Overexpression of DAB2IP’s rat homolog DIP, but not its mutant defective in Ras GTPase activating protein activity, reverses miR431‘s effect on promoting invasion, Erk phosphorylation, and epithelial-mesenchymal transition of PNETs. Taken together, miR431 silences DAB2IP to active Ras/Erk and promote metastasis of PNETs. miR431 may be targeted to manage metastatic PNETs.