N6-methyladenosine-mediated SH3BP5-AS1 upregulation promotes GEM chemoresistance in pancreatic cancer by competitively sponging miR-139-5p and activating the Wnt signaling pathway

Background: Pancreatic cancer (PC) is highly malignant. Chemotherapy is the main treatment strategy, especially for patients with advanced PC. However, chemoresistance has always been a frequently encountered bottleneck. Hence, there is an urgent need to enhance the sensitivity of PC to gemcitabine (GEM). Methods A patient-derived xenograft model was used for screening the hub lncRNAs affecting GEM chemoresistance. Transwell and colony formation assays were used to assess the migration, invasion, and stemness of PC cells. qRT-PCR and western blot analyses were performed to detect the mRNA and protein levels indicated in this study, respectively. The MTT assay was performed to assess the viability of PC cells in vitro. MeRIP-qPCR was used to determine the N6-methyladenosine (m6A) modification level. RIP and pull-down were used to investigate the interaction between SH3BP5-AS1 and miR-139-5p, as well as the interactions among SH3BP5-AS1, ALKBH5, and IGF2BP1. The functional mechanism of SH3BP5-AS1 in PC was identified by gain- and loss-of-function assays and high-throughput sequencing in vitro. Results We demonstrated that SH3BP5-AS1 was significantly upregulated in GEM-resistant PC and predicted a poorer prognosis. SH3BP5-AS1 stability was regulated by ALKBH5/IGF2BP1-mediated m6A modification. Loss of SH3BP5-AS1 reduced PC cell migration and invasion and enhanced the sensitivity of PC to GEM, as confirmed by gain- and loss-of-function assays in vitro and in vivo. Bioinformatics analysis revealed that SH3BP5-AS1 acted as a ceRNA against miR-139-5p and directly targeted CTBP1, affecting the biological behavior of PC cells. The mechanistic studies revealed that the upregulation of SH3BP5-AS1 increased CTBP1 expression by directly activating the Wnt signaling pathway, promoting GEM resistance. Conclusion This study revealed that SH3BP5-AS1 activated Wnt signaling pathway by sponging miR-139-5p, upregulating CTBP1 expression, and contributing to the sensitivity of PC cells to GEM. SH3BP5-AS1 might be a potential target for PC therapy.