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Open Access 01-12-2021 | Colorectal Cancer | Research

The circular RNA circSPARC enhances the migration and proliferation of colorectal cancer by regulating the JAK/STAT pathway

Authors: Jiaqi Wang, Yi Zhang, Hu Song, Hang Yin, Tao Jiang, Yixin Xu, Lianyu Liu, Hongyu Wang, Hong Gao, Renhao Wang, Jun Song

Published in: Molecular Cancer | Issue 1/2021

Abstract

Background

Noncoding RNAs such as circular RNAs (circRNAs) are abundant in the human body and influence the occurrence and development of various diseases. However, the biological functions of circRNAs in colorectal cancer (CRC) are largely unknown.

Methods

RT-qPCR was used to detect the expression of circRNAs and mRNA in CRC cells and tissues. Fluorescence in situ hybridization (FISH) was used to analyze the location of circSPARC. Function-based experiments were performed using circSPARC knockdown and overexpression cell lines in vitro and in vivo, including CCK8, colony formation, transwell and metastasis models. Mechanistically, luciferase reporter assay, western blots, RNA immunoprecipitation (RIP), Chromatin isolation by RNA purification (ChIRP) and immunohistochemical stainings were performed.

Results

CircSPARC was upregulated in both the tissues and plasma of CRC patients. High expression of circSPARC was associated with advanced TNM stage, lymph node metastases, and poor survival. Silencing circSPARC inhibited CRC cell migration and proliferation in vitro and vivo. Mechanistically, circSPARC sponged miR-485-3p to upregulate JAK2 expression and ultimately contribute to the accumulation of phosphorylated (p)-STAT3. Besides, circSPARC recruited FUS, which facilitated the nuclear translocation of p-STAT3.

Conclusions

These findings suggest that circSPARC might serve as a potential diagnostic and prognostic biomarker and a therapeutic target for CRC treatment by regulating JAK2/STAT3 pathway.

Available only for authorised users

Brody H. Colorectal cancer. Nature. 521(2015):S1.

Keum N, Giovannucci E. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol. 2019;16(12):713–32. https://doi.org/10.1038/s41575-019-0189-8.CrossRefPubMed

Buccafusca G, Proserpio I, Tralongo AC, Rametta Giuliano S, Tralongo P. Early colorectal cancer: diagnosis, treatment and survivorship care. Crit Rev Oncol Hematol. 2019;136:20–30. https://doi.org/10.1016/j.critrevonc.2019.01.023.CrossRefPubMed

Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360(6):563–72. https://doi.org/10.1056/NEJMoa0808268.CrossRefPubMed

Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet (London, England). 2019;394:1467–80.CrossRef

Sanger HL, Klotz G, Riesner D, Gross HJ, Kleinschmidt AK. Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. Proceed Natl Acad Sci the U S A. 1976;73:3852–6.CrossRef

Aufiero S, van den Hoogenhof MM, Reckman YJ, Beqqali A, van der Made I, Kluin J, et al. Cardiac circRNAs arise mainly from constitutive exons rather than alternatively spliced exons. RNA (New York, N.Y.). 2018;24:815–27.CrossRef

Sun H, Wu Z, Liu M, Yu L, Li J, Zhang J, et al. CircRNA may not be “circular”. Front Genet. 2021:12.

Shang Q, Yang Z, Jia R, Ge S. The novel roles of circRNAs in human cancer. Mol Cancer. 2019;18(1):6. https://doi.org/10.1186/s12943-018-0934-6.CrossRefPubMedPubMedCentral

10.

Cheng Z, Yu C, Cui S, Wang H, Jin H, Wang C, et al. circTP63 functions as a ceRNA to promote lung squamous cell carcinoma progression by upregulating FOXM1. Nat Commun. 2019;10:3200.CrossRef

11.

Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP. A ceRNA hypothesis: the Rosetta stone of a hidden RNA language? Cell. 2011;146(3):353–8. https://doi.org/10.1016/j.cell.2011.07.014.CrossRefPubMedPubMedCentral

12.

Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB, Kjems J. The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet. 2019;20(11):675–91. https://doi.org/10.1038/s41576-019-0158-7.CrossRefPubMed

13.

Leonard WJ, O'Shea JJ. Jaks and STATs: biological implications. Annu Rev Immunol. 1998;16(1):293–322. https://doi.org/10.1146/annurev.immunol.16.1.293.CrossRefPubMed

14.

Meng S, Zhou H, Feng Z, Xu Z, Tang Y, Li P, et al. CircRNA: functions and properties of a novel potential biomarker for cancer. Mol Cancer. 2017;16(1):94. https://doi.org/10.1186/s12943-017-0663-2.CrossRefPubMedPubMedCentral

15.

Li X, Yang L, Chen L-L. The biogenesis, functions, and challenges of circular RNAs. Mol Cell. 2018;71(3):428–42. https://doi.org/10.1016/j.molcel.2018.06.034.CrossRefPubMed

16.

Lai Q, Li Q, He C, Fang Y, Lin S, Cai J, et al. CTCF promotes colorectal cancer cell proliferation and chemotherapy resistance to 5-FU via the P53-hedgehog axis. Aging (Albany NY). 2020;12(16):16270–93. https://doi.org/10.18632/aging.103648.CrossRef

17.

Xiong H, Zhang Z, Tian X, Sun D, Liang Q, Zhang Y, et al. Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells. Neoplasia (New York, N.Y.). 2008;10:287–97.CrossRef

18.

Yu C, Kuo H. The emerging roles and functions of circular RNAs and their generation. J Biomed Sci. 2019;26(1):29. https://doi.org/10.1186/s12929-019-0523-z.CrossRefPubMedPubMedCentral

19.

Liang C, Zhao T, Li H, He F, Zhao X, Zhang Y, et al. Long non-coding RNA ITIH4-AS1 accelerates the proliferation and metastasis of colorectal Cancer by activating JAK/STAT3 signaling. Mol Ther Nucleic acids. 2019;18:183–93. https://doi.org/10.1016/j.omtn.2019.08.009.CrossRefPubMedPubMedCentral

20.

Yin Y, Long J, He Q, Li Y, Liao Y, He P, et al. Emerging roles of circRNA in formation and progression of cancer. J Cancer. 2019;10(21):5015–21. https://doi.org/10.7150/jca.30828.CrossRefPubMedPubMedCentral

21.

Tang X, Ren H, Guo M, Qian J, Yang Y, Gu C. Review on circular RNAs and new insights into their roles in cancer. Comput Struct Biotechnol J. 2021;19:910–28. https://doi.org/10.1016/j.csbj.2021.01.018.CrossRefPubMedPubMedCentral

22.

Yang N, Xu B, Kong P, Han M, Li B-H. Hsa_circ_0002320: a novel clinical biomarker for colorectal cancer prognosis. Medicine (Baltimore). 2020;99(28):e21224. https://doi.org/10.1097/MD.0000000000021224.CrossRef

23.

Wang X, Ren Y, Ma S, Wang S. Circular RNA 0060745, a novel circRNA, promotes colorectal Cancer cell proliferation and metastasis through miR-4736 sponging. OncoTarg Ther. 2020;13:1941–51. https://doi.org/10.2147/OTT.S240642.CrossRef

24.

Chen H-Y, Li X-N, Ye C-X, Chen Z-L, Wang Z-J. Circular RNA circHUWE1 is upregulated and promotes cell proliferation, migration and invasion in colorectal Cancer by sponging miR-486. OncoTarg Ther. 2020;13:423–34. https://doi.org/10.2147/OTT.S233338.CrossRef

25.

Tan S, Gou Q, Pu W, Guo C, Yang Y, Wu K, et al. Circular RNA F-circEA produced from EML4-ALK fusion gene as a novel liquid biopsy biomarker for non-small cell lung cancer. Cell Res. 2018;28(6):693–5. https://doi.org/10.1038/s41422-018-0033-7.CrossRefPubMedPubMedCentral

26.

Wang Y, Liu J, Ma J, Sun T, Zhou Q, Wang W, et al. Exosomal circRNAs: biogenesis, effect and application in human diseases. Mol Cancer. 2019;18(1):116. https://doi.org/10.1186/s12943-019-1041-z.CrossRefPubMedPubMedCentral

27.

Debaugny RE, Skok JA. CTCF and CTCFL in cancer. Curr Opin Genet Dev. 2020;61:44–52. https://doi.org/10.1016/j.gde.2020.02.021.CrossRefPubMedPubMedCentral

28.

Argetsinger LS, Stuckey JA, Robertson SA, Koleva RI, Cline JM, Marto JA, et al. Tyrosines 868, 966, and 972 in the kinase domain of JAK2 are autophosphorylated and required for maximal JAK2 kinase activity. Mol Endocrinol (Baltimore, Md.). 2010;24:1062–76.CrossRef

29.

Hua Q, Mi B, Xu F, Wen J, Zhao L, Liu J, et al. Hypoxia-induced lncRNA-AC020978 promotes proliferation and glycolytic metabolism of non-small cell lung cancer by regulating PKM2/HIF-1α axis. Theranostics. 2020;10(11):4762–78. https://doi.org/10.7150/thno.43839.CrossRefPubMedPubMedCentral

30.

Liu C, Zhang Y, She X, Fan L, Li P, Feng J, et al. A cytoplasmic long noncoding RNA LINC00470 as a new AKT activator to mediate glioblastoma cell autophagy. J Hematol Oncol. 2018;11(1):77. https://doi.org/10.1186/s13045-018-0619-z.CrossRefPubMedPubMedCentral

Title: The circular RNA circSPARC enhances the migration and proliferation of colorectal cancer by regulating the JAK/STAT pathway
Authors: Jiaqi Wang
Yi Zhang
Hu Song
Hang Yin
Tao Jiang
Yixin Xu
Lianyu Liu
Hongyu Wang
Hong Gao
Renhao Wang
Jun Song
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Colorectal Cancer
Colorectal Cancer
Biomarkers
Published in: Molecular Cancer / Issue 1/2021
Electronic ISSN: 1476-4598
DOI: https://doi.org/10.1186/s12943-021-01375-x

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Abstract

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Conclusions

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