NNT-AS1 in CAFs-derived exosomes inhibits miR-889-3p in PDAC cells and then promotes proliferation, metastasis, and metabolic reprogramming through favorably regulating HIF-1α
Zhang, Pingping, Qun Wang, Weijun Lu, Feng Zhang, Dongde Wu, and junwei sun. 2021. “NNT-AS1 in CAFs-Derived Exosomes Inhibits MiR-889-3p in PDAC Cells and Then Promotes Proliferation, Metastasis, and Metabolic Reprogramming through Favorably Regulating HIF-1α,” October. https://doi.org/10.21203/rs.3.rs-955277/v1.
Background: It is metabolic and signaling crosstalk between stromal cells and tumors in the tumor microenvironment, which influences several aspects of tumor formation and drug resistance, including metabolic reprogramming. Despite considerable findings linking lncRNAs in HIF-1-related regulatory networks to cancer cell proliferation and apoptosis, little emphasis has been given to the lncRNAs' role in communication between cancer-associated fibroblasts (CAFs) and tumor cells. Previously, we observed that NNT-AS1 was substantially expressed in CAFs cells and CAFs exosomes, and subsequently investigated the influence of CAFs exosomal NNT-AS1 on glucose metabolism, proliferation, and metastasis of PDAC cells. Methods: Transmission electron microscopy was used to examine exosomes secreted by PDAC patient-derived CAFs. qRT-PCR was used to evaluate at the expression of NNT-AS1, miR-889-3p, and HIF-1. The role of CAFs-derived exosomal NNT-AS1 in PDAC cell proliferation, metastasis, and metabolism has been identified. Dual luciferase reporter assays were used to look at the binding between NNT-AS1, miR-889-3p, and HIF-1. Results: After PDAC cells co-culture exosomes secreted by CAFs, we found that they alter glucose metabolism, proliferation, and metastasis. In PDAC cells, CAF-derived exosomal lncRNA NNT-AS1 acted as a molecular sponge for miR-889-3p. Furthermore, HIF-1 could be targeted by miR-889-3p and was controlled by NNT-AS1. Conclusion: This study explores the mechanism by which NNT-AS1 influences the interaction of CAFs on glycolytic remodeling, proliferation, and metastasis of tumor cells through regulating miR-889-3p/HIF-1α, which also helps discover new clinical treatment targets for PDAC.View full article