FUS-induced circRHOBTB3 facilitates cell proliferation via miR-600/NACC1 mediated autophagy response in pancreatic ductal adenocarcinoma

• Published in: Journal of experimental & clinical cancer research Vol. 40; no. 1; p. 261
• Main Authors: Yang, Taoyue, Shen, Peng, Chen, Qun, Wu, Pengfei, Yuan, Hao, Ge, Wanli, Meng, Lingdong, Huang, Xumin, Fu, Yuzhe, Zhang, Yihan, Hu, Weikang, Miao, Yi, Lu, Zipeng, Jiang, Kuirong
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 20.08.2021; BioMed Central; BMC
• Subjects: Adenocarcinoma; Adult; Aged; Alternative Splicing; Animals; Autophagy; Autophagy - genetics; Biomarkers; Biosynthesis; Cancer therapies; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell growth; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation; Chemotherapy; CircRNAs; Development and progression; Disease Models, Animal; Exons; Female; Gene expression; Gene Expression Regulation, Neoplastic; Health aspects; Humans; Male; Mice; MicroRNA; MicroRNAs - genetics; Middle Aged; miR-600; Models, Biological; NACC1; Neoplasm Proteins - genetics; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; PDAC; Plasmids; Prognosis; Protein binding; Proteins; Proto-Oncogene Proteins c-akt; Repressor Proteins - genetics; rho GTP-Binding Proteins - genetics; RNA Interference; RNA, Circular - genetics; RNA-Binding Protein FUS - metabolism; Signal Transduction; TOR Serine-Threonine Kinases - metabolism; Xenograft Model Antitumor Assays; China; United States > US; CircRNAs; PDAC; miR-600; Autophagy; NACC1
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-021-02063-w

Circular RNAs (circRNAs) are becoming a unique member of non-coding RNAs (ncRNAs) with emerging evidence of their regulatory roles in various cancers. However, with regards to pancreatic ductal adenocarcinoma (PDAC), circRNAs biological functions remain largely unknown and worth investigation for potential therapeutic innovation. In our previous study, next-generation sequencing was used to identify differentially expressed circRNAs in 3 pairs of PDAC and adjacent normal tissues. Further validation of circRHOBTB3 expression in PDAC tissues and cell lines and gain-and-loss function experiments verified the oncogenic role of circRHOBTB3. The mechanism of circRHOBTB3 regulatory role was validated by pull-down assays, RIP, luciferase reporter assays. The autophagy response of PANC-1 and MiaPaca-2 cells were detected by mCherry-GFP-LC3B labeling and confocal microscopy, transmission electron microscopy and protein levels of LC3B or p62 via Western blot. circRHOBTB3 is highly expressed in PDAC cell lines and tissues, which also promotes PDAC autophagy and then progression in vitro and in vivo. Mechanistically, circRHOBTB3 directly binds to miR-600 and subsequently acts as a miRNA-sponge to maintain the expression level of miR-600-targeted gene NACC1, which facilitates the autophagy response of PDAC cells for adaptation of proliferation via Akt/mTOR pathway. Moreover, the RNA-binding protein FUS (FUS) directly binds to pre-RHOBTB3 mRNA to mediate the biogenesis of circRHOBTB3. Clinically, circRHOBTB3, miR-600 and NACC1 expression levels are correlated with the prognosis of PDAC patients and serve as independent risk factors for PDAC patients. FUS-mediated circRHOBTB3 functions as a tumor activator to promote PDAC cell proliferation by modulating miR-600/NACC1/Akt/mTOR axis regulated autophagy.