Lnc-FSD2-31:1 in Pancreatic ductal adenocarcinoma promotes ATG7-mediated proliferation and fibrosis of cancer associated fibroblasts via exosome miR-4736

Abstract Background Long non-coding RNA (lncRNA) is closely related to the occurrence of Pancreatic ductal adenocarcinoma (PDAC). Intercellular interactions between cancer associated fibroblasts (CAFs) and cancer cells influence malignant proliferation and chemotherapy resistance of PDAC in a variety of ways. We performed the global expression profiles of lncRNA between longevity and short survival PDAC patients’ pancreatic tissues, to identify molecular mechanism of PDAC. Method Tissue microarray (TMA) was used to explore survival related lncRNA in PDAC. The localization of lncRNA was conform by RNA fluorescence in-situ hybridization (FISH) analysis. Functional assays were introduced to demonstrate the anti-tumor effects of lncRNA in vitro and in vivo. Exosomes and primary CAFs were isolated from PDAC cell lines and patient tissues. Bioinformatics and 3D co-culture model were used to find the downstream targets. KPC transgenic mouse model and human cytokine array were also applied to detect the mechanism of PDAC. Results We found that lnc-FSD2-31:1 was elevated significantly in longevity survival patients. Lnc-FSD2-31:1 suppressed PDAC proliferation, invasion, and metastasis in vitro and in vivo. Lnc-FSD2-31:1 also act as a competing endogenous RNA (ceRNA) to inhibit miR-4736 expression in PDAC cells. Exosome miR-4736 secreted by PDAC was transported to CAFs. We found miR-4736 inhibited the proliferation, autophagy and promoted the fibrosis of CAFs by binding to the 3’-untranslated region(3’-UTR) of ATG7. Under the stimulatory of miR-4736, CAFs particularly secreted IL-32α, IL-1β, IL-1ra, G-CSF, IL-2, IL-4. Furthermore, miR-4736 antagomir intraperitoneally injected can suppressed tumor growth in KPC mice. Exosome miR-4736 of plasma might be a biomarker of PDAC. Conclusions Lnc-FSD2-31:1 suppress PDAC progression and act as a competing endogenous RNA (ceRNA) to inhibit miR-4736 expression in PDAC cells. Exosome miR-4736 released by PDAC inhibit autophagy and promote fibrosis of CAFs via targeting ATG7. miR-4736 might be a promising biomarker and treatment target of PDAC.