Inhibition of TUG1/miRNA-299-3p Axis Represses Pancreatic Cancer Malignant Progression via Suppression of the Notch1 Pathway.

Abstract

Taurine-upregulated gene 1 (TUG1) is reported to be upregulated and contributes to the progression of Pancreatic cancer(PC) by serving as an oncogene. Our aims were to explore the precise mechanism of TUG1 involved in PC pathogenesis. TUG1 and miR-299-3p expression profiles were measured by qRT-PCR. The direct interactionbetween TUG1 and miR-299-3p was explored by luciferase reporter assay. MTTassay, flow cytometry analysis, caspase-3 activity assay, Transwell invasion assay and wound healing assay were performed to evaluate cell proliferative ability, apoptosis, caspase-3 activity, invasion and migration, respectively. Western blot was conducted to examine the expressions of Ki67, Bax, Bcl-2, matrix metalloproteinase-2 (MMP-2), MMP-9, E-cadherin, N-cadherin, Snail, Notch1, Survivin, and CyclinD1. In addition, animal experiments were also implemented. TUG1 was highly expressed, while miR-299-3p was underexpressed in PC tissues and PC cells. Furthermore, the significant increase of TUG1in PC tissues of advanced patients (stage 3/4) was observed compared to patients (stage 1/2). TUG1 was negatively correlated with miR-299-3p expression in PC tissues. Moreover, TUG1 functioned as a molecular sponge of miR-299-3p to repress its expression. TUG1 knockdown suppressed cell proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT), and induced apoptosis in PC cells, and repressed tumor growth and EMT in PC xenograft models, which were reversed following reintroduction with anti-miR-299-3p. Furthermore, we found that TUG1 silencing inactivated the Notch1 pathway in PC by upregulating miR-299-3p. The results reported that inhibition of TUG1/miR-299-3p axis suppressed PC malignant progression via suppression of the Notch1 pathway.