DGCR5 is Activated by PAX5 and Promotes Pancreatic Cancer via Targeting miR-3163/TOP2A and Activating Wnt/β-Catenin Pathway

Abstract

Background: DiGeorge syndrome critical region gene 5 (DGCR5) has been shown to be associated with cancer development. However, the biological role and molecular mechanism of DGCR5 in pancreatic cancer (PC) remains largely unknown. Methods: qRT-PCR and fluorescence in situ hybridization was performed to investigate the correlation between DGCR5 expression and prognosis and clinicopathologic characteristics of PC patients. The effects of DGCR5 on PC were studied by gain & loss-of-function experiments in vitro and in vivo. RNA sequencing, bioinformatics analyses, dual-luciferase assays, chromatin immunoprecipitation assay and rescue experiments provided insights into the underlying competing endogenous RNA (ceRNA) mechanism network of DGCR5 in promoting PC progression. Results: DGCR5 was highly expressed in PC tissues compared with adjacent normal tissues and its high expression was associated with poor prognosis in PC patients. Furthermore, DGCR5 depletion inhibited the proliferation, migration and invasion by increasing apoptosis and inducing G0/G1 cell cycle arrest in vitro. Moreover, xenograft assay validated that DGCR5 promotes PC tumor growth in vivo. Mechanistically, DGCR5 was found to act as a ceRNA by sponging miR-3163 to regulate TOP2A and inhibit Wnt/β-catenin pathway. In addition, we found that DGCR5 downregulation could enhance the sensitivity of PC cells to gemcitabine, and ChIP assay showed that the transcription factor PAX5 could bind to the DGCR5 promoter and increase its transcription. Conclusions: Our study demonstrates that DGCR5 is activated by PAX5 and promotes PC progression by sponging miR-3163 to regulate TOP2A and activating wnt/β-catenin pathway, suggesting that DGCR5 may be a potential diagnostic and therapeutic target for PC.