Journal
ONCOGENE
Volume 40, Issue 15, Pages 2756-2771Publisher
SPRINGERNATURE
DOI: 10.1038/s41388-021-01739-z
Keywords
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Funding
- National Key Research and Development Program [2020YFA0712400, 2018YFC0114705]
- Special Foundation for Taishan Scholars [ts20190971]
- National Natural Science Foundation of China [81672613, 81874119, 82072912, 82004122]
- Shandong Provincial Natural Science Foundation, China [ZR2019LZL003, ZR201911010260, ZR201911050391]
- Special Support Plan for National High Level Talents (Ten Thousand Talents Program) [W01020103]
- Foundation from Clinical Research Center of Shandong University [2020SDUCRCA015]
- Qilu Hospital Clinical New Technology Developing Foundation [2018-7, 2019-3]
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The study found that the novel circRNA circHIF1A was significantly overexpressed in TNBC, associated with metastasis, poor prognosis, and the TNBC subtype. CircHIF1A modulated the expression of NFIB and FUS via a positive feedback loop, leading to activation of the AKT/STAT3 signaling pathway. CircHIF1A may serve as a potential biomarker for breast cancer diagnosis and a therapeutic target for TNBC treatment.
Emerging evidence has demonstrated that circular RNAs (circRNAs) play critical roles in the development and progression of human cancer. However, the biological functions and underlying mechanisms of circRNAs in triple-negative breast cancer (TNBC) remain to be investigated. In our present study, we found that the novel circRNA circHIF1A was significantly overexpressed in breast cancer tissues and that it was associated with metastasis, poor prognosis, and the TNBC subtype. Gain- and loss-of-function experiments were conducted to investigate the biological roles of circHIF1A in TNBC. Overexpression of circHIF1A significantly promoted TNBC growth and metastasis in vitro and in vivo, while knockdown of circHIF1A exerted the opposite effects. Mechanistically, circHIF1A modulated the expression and translocation of NFIB through posttranscriptional and posttranslational modifications, resulting in the activation of the AKT/STAT3 signaling pathway and inhibition of P21. The RNA binding protein FUS could regulate the biogenesis of circHIF1A by interacting with the flanking intron, and FUS was transcriptionally regulated by NFIB, thus forming the circHIF1A/NFIB/FUS positive feedback loop. Moreover, circHIF1A could be packaged into exosomes and was upregulated in the plasma of breast cancer patients. Our findings indicated that circHIF1A played a critical role in the growth and metastasis of TNBC via a positive feedback loop and that circHIF1A could be a promising biomarker for breast cancer diagnosis and a potential therapeutic target for TNBC treatment.
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