N6-methyladenosine-mediated SH3BP5-AS1 upregulation promotes GEM chemoresistance in pancreatic cancer by activating the Wnt signaling pathway

• Published in: Biology direct 2022-11, Vol.17 (1), p.33-33, Article 33
• Main Authors: Lin, Chengjie, Wang, Yan, Dong, Yihong, Lai, Shihui, Wang, Liang, Weng, Shangeng, Zhang, Xiang
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Bioinformatics; Cancer; Cancer therapies; Cell Line, Tumor; Cell migration; Cell Proliferation - genetics; Cellular signal transduction; Chemoresistance; Chemotherapy; Drug resistance; Drug Resistance, Neoplasm - genetics; Drug therapy; Gemcitabine; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Humans; Medical prognosis; Metastasis; MicroRNAs - metabolism; N6-methyladenosine; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Pheochromocytoma cells; Physiological aspects; Proteins; RNA; RNA, Long Noncoding - metabolism; Sensitivity enhancement; SH3BP5-AS1; Signal transduction; Signaling; Up-Regulation; Wnt protein; Wnt proteins; Wnt signaling pathway; Wnt Signaling Pathway - genetics
• ISSN: 1745-6150; 1745-6150
• DOI: 10.1186/s13062-022-00347-5

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). 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. 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.