Emerging evidence has demonstrated that circular RNAs (circRNAs) take part in the initiation and development of pancreatic ductal adenocarcinoma (PDA), a deadly neoplasm with an extremely low 5-year survival rate. Reprogrammed glucose metabolism is a key feature of tumour development, including PDA. In this research, we evaluated the role of circRNAs in reprogrammed glucose metabolism in PDA. RNA sequencing under various glucose incubation circumstances was performed. A new circMYOF was identified. Sanger sequencing and RNase R treatment confirmed its circular RNA characteristics. Real-time PCR indicated that it was highly expressed in PDA clinical specimens and cell lines. Gain-of- and loss-of-function assays showed that circMYOF induced progression in PDA. Mechanistically, RNA pull-down and luciferase reporter experiments elucidated that circMYOF, as a competing endogenous RNA for miR-4739, facilitated glycolysis via the VEGFA/PI3K/AKT pathway. Taken together, our findings indicate that circMYOF may work as a desirable biomarker and therapeutic target for PDA patients.

Background: Somatic mutations of the TP53 gene occur frequently in pancreatic ductal adenocarcinoma (PDA). Solute carrier family 45 member A4 (SLC45A4) is a H + -dependent sugar cotransporter. The role of SLC45A4 in PDA, especially in TP53 mutant PDA, remains poorly understood. Methods:We explored the TCGA datasets to identify oncogenes in TP53 mutant PDA., colony formation and 5-ethynyl-2 0 -deoxyuridine (Edu) assays were performed to investigate the function of SLC45A4 in vitro. Glucose consumption, lactate production and ATP production were detected to evaluate glucose utilization.Extracellular acidification rate and oxygen consumption rate assays were used to evaluate glycolysis and oxidative phosphorylation. The subcutaneous xenotransplantation models were conducted to explore the function of SLC45A4 in vivo. RNAsequencing and gene set enrichment analysis were employed to explore the biological alteration caused by SLC45A4 knockdown. Western blotting was performed to evaluate the activation of glycolysis, as well as the AMPK pathway and autophagy.Results: SLC45A4 was overexpressed in PDA for which the expression was significantly higher in TP53 mutant PDA than that in wild-type PDA tissues.Moreover, high level of SLC45A4 expression was tightly associated with poor clinical outcomes in PDA patients. Silencing SLC45A4 inhibited proliferation in TP53 mutant PDA cells. Knockdown of SLC45A4 reduced glucose uptake and ATP production, which led to activation of autophagy via AMPK/ULK1 pathway. Deleting SLC45A4 in TP53 mutant HPAF-II cells inhibited the growth of xenografts in nude mice. Conclusions:The present study found that SLC45A4 prevents autophagy via AMPK/ ULK1 axis in TP53 mutant PDA, which may be a promising biomarker and therapeutic target in TP53 mutant PDA.Wenying Chen and Fengting Huang contributed equally to this work

Emerging evidences has revealed that circular RNAs (circRNAs) participate in the initiation and development of pancreatic ductal adenocarcinoma (PDAC), a deadly malignancy with extremely low 5-year survival rate. Reprogrammed glucose metabolism is a key feature of tumor development, including PDAC. In this study, we aimed to investigate the role of circRNAs in reprogrammed glucose metabolism in PDAC. RNA sequencing under various glucose incubation circumstance was performed. A new circMYOF was identified. Sanger sequencing and RNase R treatment confirmed its circular RNA characteristics. Real time PCR indicated that it was overexpressed in PDAC tissues and cell lines. Gain-of and loss-of function assay implied that circMYOF promoted progression in PDAC. Mechanically, RNA pull down and luciferase reporter assay suggested that circMYOF, exhibiting as a competing endogenous RNA (ceRNA) for miR-4739, facilitated glycolysis via VEGFA/PI3K/AKT pathway. Taken together, our finding indicates that circMYOF may be a potential biomarker and therapeutic target for PDAC patients. Citation Format: Dandan Zheng, Xianxian Huang, Juanfei Peng, Yanyan Zhuang, Yuanhua Li, Junchi Qu, Shineng Zhang, Fengting Huang. CircMYOF acts as a miR-4739 sponge to promote progression and facilitate glycolysis via VEGFA/PI3K/AKT pathway in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-026.