期刊
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
卷 40, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13046-021-02063-w
关键词
CircRNAs; PDAC; miR-600; NACC1; Autophagy
类别
资金
- National Natural Science Foundation of China [82072706, 81871980]
- Clinical Advanced Technology Program, Jiangsu Science and Technology Agency [BE2016788]
- Project '333' of Jiangsu Province [BRA2019096]
- Project 'Talents in Medicine' of Jiangsu Province [ZDRCB2016004]
- Project 'Six Talent Peaks' of Jiangsu Province [WSW-006]
- Postgraduate Research & Practice Innovation Program of Jiangsu Province [SJCX20_0502]
- Jiangsu Key Medical Discipline [ZDXKA2016005]
The study found that circRHOBTB3 is highly expressed in PDAC, promoting autophagy and proliferation of PDAC cells through regulation of the miR-600/NACC1/Akt/mTOR axis. Clinically, the expression levels of circRHOBTB3, miR-600, and NACC1 are correlated with the prognosis of PDAC patients.
Background 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. Methods 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. Results 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. Conclusions FUS-mediated circRHOBTB3 functions as a tumor activator to promote PDAC cell proliferation by modulating miR-600/NACC1/Akt/mTOR axis regulated autophagy.
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