Abstract
Renal cell carcinoma (RCC) accounts for over 90% of primary renal tumors in adults. Although treatment approaches have steadily improved over the years, the prognosis outcome remains poor. With the aim of developing novel targets for RCC treatment, we explored the role of the circular RNA (circRNA) circ_001504 in the progression of RCC. We initially detected the expression of circ_001504 and microRNA (miRNA)-149 in RCC tissues and cells. RT-qPCR results showed that circ_001504 was highly expressed in RCC tissues, whereas miR-149 was poorly expressed. Interestingly, downregulation of circ_001504 suppressed malignant phenotypes in RCC cells, and upregulation of miR-149 exerted a similar effect. Bioinformatics analysis suggested potential binding sites between circ_001504 and miR-149, verified by a dual-luciferase reporter gene assay. Next, we identified nucleobindin 2 (NUCB2), a calcium-binding protein, as a target gene of miR-149. Furthermore, our data suggested that circ_001504 might serve as a competing endogenous RNA of miR-149, serving to elevate the expression of NUCB2. The silencing of circ_001504 resulted in decreased NUCB2 expression, which could be reversed by miR-149 inhibition. In addition, in vivo experiments demonstrated that circ_001504 depletion could suppress tumor growth in an established mouse RCC model. Collectively, reduced expression of circ_001504 lowered NUCB2 expression by sponging miR-149, thereby attenuating RCC progression, providing insight into circ_001504/miR-149/NUCB2 feedback loop into RCC treatment.
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Change history
30 December 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41417-021-00412-7
29 May 2023
This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1038/s41417-023-00630-1
References
Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet. 2009;373:1119–32.
Ljungberg B, Campbell SC, Choi HY, Jacqmin D, Lee JE, Weikert S, et al. The epidemiology of renal cell carcinoma. Eur Urol. 2011;60:615–21.
Cohen HT, McGovern FJ. Renal-cell carcinoma. N. Engl J Med. 2005;353:2477–90.
Rini BI, Rathmell WK, Godley P. Renal cell carcinoma. Curr Opin Oncol. 2008;20:300–6.
Syn NL, Teng MWL, Mok TSK, Soo RA. De-novo and acquired resistance to immune checkpoint targeting. Lancet Oncol. 2017;18:e731–41.
Ashwal-Fluss R, Meyer M, Pamudurti NR, Ivanov A, Bartok O, Hanan M, et al. circRNA biogenesis competes with pre-mRNA splicing. Mol Cell. 2014;56:55–66.
Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013;495:333–8.
Wilusz JE, Sharp PA. Molecular biology. A circuitous route to noncoding RNA. Science. 2013;340:440–1.
Qu S, Yang X, Li X, Wang J, Gao Y, Shang R, et al. Circular RNA: a new star of noncoding RNAs. Cancer Lett. 2015;365:141–8.
Shang Q, Yang Z, Jia R, Ge S. The novel roles of circRNAs in human cancer. Mol Cancer. 2019;18:6.
Dai X, Zhang N, Cheng Y, Yang T, Chen Y, Liu Z, et al. RNA-binding protein trinucleotide repeat-containing 6A regulates the formation of circular RNA circ0006916, with important functions in lung cancer cells. Carcinogenesis. 2018;39:981–92.
Xie M, Lv Y, Liu Z, Zhang J, Liang C, Liao X, et al. Identification and validation of a four-miRNA (miRNA-21-5p, miRNA-9-5p, miR-149-5p, and miRNA-30b-5p) prognosis signature in clear cell renal cell carcinoma. Cancer Manag Res. 2018;10:5759–66.
Qi C, Ma H, Zhang HT, Gao JD, Xu Y. Nucleobindin 2 expression is an independent prognostic factor for clear cell renal cell carcinoma. Histopathology. 2015;66:650–7.
Xu H, Li W, Qi K, Zhou J, Gu M, Wang Z. A novel function of NUCB2 in promoting the development and invasion of renal cell carcinoma. Oncol Lett. 2018;15:2425–30.
Gautier L, Cope L, Bolstad BM, Irizarry RA. affy–analysis of Affymetrix GeneChip data at the probe level. Bioinformatics. 2004;20:307–15.
Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2004;3:Article3.
Jin L, Li Y, Liu J, Yang S, Gui Y, Mao X, et al. Tumor suppressor miR-149-5p is associated with cellular migration, proliferation and apoptosis in renal cell carcinoma. Mol Med Rep. 2016;13:5386–92.
Luo W, Wang L, Luo MH, Huang YZ, Yang H, Zhou Y, et al. hsa-mir-3199-2 and hsa-mir-1293 as novel prognostic biomarkers of papillary renal cell carcinoma by COX ratio risk regression model screening. J Cell Biochem. 2017;118:3488–94.
Jeck WR, Sharpless NE. Detecting and characterizing circular RNAs. Nat Biotechnol. 2014;32:453–61.
Chen Y, Li C, Tan C, Liu X. Circular RNAs: a new frontier in the study of human diseases. J Med Genet. 2016;53:359–65.
Xiong Y, Zhang J, Song C. CircRNA ZNF609 functions as a competitive endogenous RNA to regulate FOXP4 expression by sponging miR-138-5p in renal carcinoma. J Cell Physiol. 2019;234:10646–54.
Wang G, Xue W, Jian W, Liu P, Wang Z, Wang C, et al. The effect of Hsa_circ_0001451 in clear cell renal cell carcinoma cells and its relationship with clinicopathological features. J Cancer. 2018;9:3269–77.
Bachmayr-Heyda A, Reiner AT, Auer K, Sukhbaatar N, Aust S, Bachleitner-Hofmann T, et al. Correlation of circular RNA abundance with proliferation–exemplified with colorectal and ovarian cancer, idiopathic lung fibrosis, and normal human tissues. Sci Rep. 2015;5:8057.
Zhou B, Zheng P, Li Z, Li H, Wang X, Shi Z, et al. CircPCNXL2 sponges miR-153 to promote the proliferation and invasion of renal cancer cells through upregulating ZEB2. Cell Cycle. 2018;17:2644–54.
Peng L, Yuan XQ, Li GC. The emerging landscape of circular RNA ciRS-7 in cancer (Review). Oncol Rep. 2015;33:2669–74.
Cao X, Liu XM, Zhou LH. Recent progress in research on the distribution and function of NUCB2/nesfatin-1 in peripheral tissues. Endocr J. 2013;60:1021–7.
Zhang H, Qi C, Wang A, Li L, Xu Y. High expression of nucleobindin 2 mRNA: an independent prognostic factor for overall survival of patients with prostate cancer. Tumour Biol. 2014;35:2025–8.
Kalnina Z, Silina K, Bruvere R, Gabruseva N, Stengrevics A, Barnikol-Watanabe S, et al. Molecular characterisation and expression analysis of SEREX-defined antigen NUCB2 in gastric epithelium, gastritis and gastric cancer. Eur J Histochem. 2009;53:7–18.
Kan JY, Yen MC, Wang JY, Wu DC, Chiu YJ, Ho YW, et al. Nesfatin-1/Nucleobindin-2 enhances cell migration, invasion, and epithelial-mesenchymal transition via LKB1/AMPK/TORC1/ZEB1 pathways in colon cancer. Oncotarget. 2016;7:31336–49.
Zhao J, Yun X, Ruan X, Chi J, Yu Y, Li Y, et al. High expression of NUCB2 promotes papillary thyroid cancer cells proliferation and invasion. Onco Targets Ther. 2019;12:1309–18.
He Y, Yu D, Zhu L, Zhong S, Zhao J, Tang J. miR-149 in human cancer: a systemic review. J Cancer. 2018;9:375–88.
Fujii T, Shimada K, Tatsumi Y, Fujimoto K, Konishi N. Syndecan-1 responsive microRNA-126 and 149 regulate cell proliferation in prostate cancer. Biochem Biophys Res Commun. 2015;456:183–9.
Ghasemi A, Fallah S, Ansari M. MicroRNA-149 is epigenetically silenced tumor-suppressive microRNA, involved in cell proliferation and downregulation of AKT1 and cyclin D1 in human glioblastoma multiforme. Biochem Cell Biol. 2016;94:569–76.
Acknowledgements
We would like to show sincere appreciation to the reviewers for critical comments on this article.
Funding
The study was supported by Project of Jilin Provincial Finance Department (No. 2019SCZT084).
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RX and DQ designed the study. HX collated the data, DC carried out data analyses and produced the initial draft of the paper. RX contributed to drafting the paper. All authors have read and approved the final submitted paper.
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Xin, R., Qu, D., Xu, H. et al. RETRACTED ARTICLE: circ_001504 promotes the development of renal cell carcinoma by sponging microRNA-149 to increase NUCB2. Cancer Gene Ther 28, 667–678 (2021). https://doi.org/10.1038/s41417-020-00247-8
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DOI: https://doi.org/10.1038/s41417-020-00247-8
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