Circulating RNAs, circ_4911 and circ_4302, are novel regulators of endothelial cell function under a hepatocellular carcinoma microenvironment

Yan,Kun; Cheng,Wei; Xu,Xin; Cao,Gang; Ji,Zongzheng; Li,Yiming

doi:10.3892/or.2020.7702

Circulating RNAs, circ_4911 and circ_4302, are novel regulators of endothelial cell function under a hepatocellular carcinoma microenvironment

Authors:
- Kun Yan
- Wei Cheng
- Xin Xu
- Gang Cao
- Zongzheng Ji
- Yiming Li
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Affiliations: Department of General Surgery, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China, Department of Respiration, Xi'an Children Hospital, Xi'an, Shaanxi 710003, P.R. China
Published online on: July 23, 2020 https://doi.org/10.3892/or.2020.7702
Pages: 1727-1735

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Abstract

Hepatocellular carcinoma (HCC) is a common hypervascular tumor disease. Endothelial cells, as a crucial component of the tumor microenvironment, have been reported to participate in angiogenesis and influence the development of tumors, including HCC. Recent studies have demonstrated that circulating RNAs (circRNAs) participate in the functional regulation of endothelial cells. However, the expression and function of circRNAs in endothelial cells under the HCC microenvironment is still unclear. In the present study, we analyzed the expression profiles and investigated the role of circRNAs in human umbilical vein endothelial cells (HUVECs) co‑cultured with human primary hepatoma cells. Based on an RNA‑sequencing assay, we screened 19 significantly downregulated circRNAs in HUVECs under an HCC microenvironment. Subsequently, we validated the expression of the candidate circRNAs using RT‑qPCR, and selected two of the most downregulated circRNAs among them, circ_4911 and circ_4302. Next, through circRNA overexpression experiments, we demonstrated that overexpression of circ_4911 and circ_4302 both inhibited the proliferation and migration of HUVECs, and arrested cells at the GO/G1 stage, while promoting adhesion. Overall, in the present study, we identified the roles of circ_4911 and circ_4302 in regulating functions of HUVECs under an HCC microenvironment.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2018. CA Cancer J Clin. 68:7–30. 2018. View Article : Google Scholar : PubMed/NCBI
2	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
3	Sun HZ, Song YL and Wang XY: Effects of different anesthetic methods on cellular immune and neuroendocrine functions in patients with hepatocellular carcinoma before and after surgery. J Clin Lab Anal. 30:1175–1182. 2016. View Article : Google Scholar : PubMed/NCBI
4	Feng T, Yu H, Xia Q, Ma Y, Yin H, Shen Y and Liu X: Cross-Talk mechanism between endothelial cells and hepatocellular carcinoma cells via growth factors and integrin pathway promotes tumor angiogenesis and cell migration. Oncotarget. 8:69577–69593. 2017. View Article : Google Scholar : PubMed/NCBI
5	Tomizawa M, Kondo F and Kondo Y: Growth patterns and interstitial invasion of small hepatocellular carcinoma. Pathol Int. 45:352–358. 1995. View Article : Google Scholar : PubMed/NCBI
6	Yukawa H, Suzuki K, Aoki K, Arimoto T, Yasui T, Kaji N, Ishikawa T, Ochiya T and Baba Y: Imaging of angiogenesis of human umbilical vein endothelial cells by uptake of exosomes secreted from hepatocellular carcinoma cells. Sci Rep. 8:67652018. View Article : Google Scholar : PubMed/NCBI
7	Park JH, Kim SH, Choi MC, Lee J, Oh DY, Im SA, Bang YJ and Kim TY: Class II histone deacetylases play pivotal roles in heat shock protein 90-mediated proteasomal degradation of vascular endothelial growth factor receptors. Biochem Biophy Res Commun. 368:318–322. 2008. View Article : Google Scholar
8	Zhao Y and Adjei AA: Targeting angiogenesis in cancer therapy: Moving beyond vascular endothelial growth factor. Oncologist. 20:660–673. 2015. View Article : Google Scholar : PubMed/NCBI
9	Sun J and Liao JK: Induction of angiogenesis by heat shock protein 90 mediated by protein kinase akt and endothelial nitric oxide synthase. Arterioscler Thromb Vasc Biol. 24:2238–2244. 2004. View Article : Google Scholar : PubMed/NCBI
10	Weis SM and Cheresh DA: Tumor angiogenesis: Molecular pathways and therapeutic targets. Nat Med. 17:1359–1370. 2011. View Article : Google Scholar : PubMed/NCBI
11	Manzi M, Bacigalupo ML, Carabias P, Elola MT, Wolfenstein-Todel C, Rabinovich GA, Espelt MV and Troncoso MF: Galectin-1 controls the proliferation and migration of liver sinusoidal endothelial cells and their interaction with hepatocarcinoma cells. J Cell Physiol. 231:1522–1533. 2016. View Article : Google Scholar : PubMed/NCBI
12	Vasudev NS and Reynolds AR: Erratum to: Anti-Angiogenic therapy for cancer: Current progress, unresolved questions and future directions. Angiogenesis. 17:495–497. 2014. View Article : Google Scholar
13	Zheng XB, Zhang M and Xu MQ: Detection and characterization of ciRS-7: A potential promoter of the development of cancer. Neoplasma. 64:321–328. 2017. View Article : Google Scholar : PubMed/NCBI
14	Szabo L and Salzman J: Detecting circular RNAs: Bioinformatic and experimental challenges. Nat Rev Genet. 17:679–692. 2016. View Article : Google Scholar : PubMed/NCBI
15	Yao T, Chen Q, Fu L and Guo J: Circular RNAs: Biogenesis, properties, roles, and their relationships with liver diseases. Hepatol Res. 47:497–504. 2017. View Article : Google Scholar : PubMed/NCBI
16	Shang FF, Luo S, Liang X and Xia Y: Alterations of circular RNAs in hyperglycemic human endothelial cells. Biochem Biophys Res Commun. 499:551–555. 2018. View Article : Google Scholar : PubMed/NCBI
17	Hou LD and Zhang J: Circular RNAs: An emerging type of RNA in cancer. Int J Immunopathol Pharmacol. 30:1–6. 2017. View Article : Google Scholar : PubMed/NCBI
18	Fu L, Yao T, Chen Q, Mo X, Hu Y and Guo J: Screening differential circular RNA expression profiles reveals hsa_circ_0004018 is associated with hepatocellular carcinoma. Oncotarget. 8:58405–58416. 2017. View Article : Google Scholar : PubMed/NCBI
19	Dang RY, Liu FL and Li Y: Circular RNA hsa_circ_0010729 regulates vascular endothelial cell proliferation and apoptosis by targeting the miR-186/HIF-1α axis. Biochem Biophys Res Commun. 490:104–110. 2017. View Article : Google Scholar : PubMed/NCBI
20	Jes-Niels B, Nicolas J, Heumüller AW, Chen W, Boon RA, Stellos K, Zeiher AM, John D, Uchida S and Dimmeler S: Identification and characterization of hypoxia-regulated endothelial circular RNA. Circ Res. 117:884–890. 2015. View Article : Google Scholar : PubMed/NCBI
21	Li CY, Ma L and Yu B: Circular RNA hsa_circ_0003575 regulates oxLDL induced vascular endothelial cells proliferation and angiogenesis. Biomed Pharmacother. 95:1514–1519. 2017. View Article : Google Scholar : PubMed/NCBI
22	Li J, Li Z, Jiang P, Peng M, Zhang X, Chen K, Liu H, Bi H, Liu X and Li X: Circular RNA IARS (circ-IARS) secreted by pancreatic cancer cells and located within exosomes regulates endothelial monolayer permeability to promote tumor metastasis. J Exp Clin Cancer Res. 37:1772018. View Article : Google Scholar : PubMed/NCBI
23	Young MD, Wakefield MJ, Smyth GK and Oshlack A: Gene ontology analysis for RNA-seq: Accounting for selection bias. Genome Biol. 11:R142010. View Article : Google Scholar : PubMed/NCBI
24	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
25	Zhao W, Cheng Y, Zhang C, You Q, Shen X, Guo W and Jiao Y: Genome-Wide identification and characterization of circular RNAs by high throughput sequencing in soybean. Sci Rep. 7:56362017. View Article : Google Scholar : PubMed/NCBI
26	Pan L, Lian W, Zhang X, Han S, Cao C, Li X and Li M: Human circular RNA-0054633 regulates high glucose-induced vascular endothelial cell dysfunction through the microRNA-218/roundabout 1 and microRNA-218/heme oxygenase-1 axes. Int J Mol Med. 42:597–606. 2018.PubMed/NCBI
27	Brenner W, Beitz S, Schneider E, Benzing F, Unger RE, Roos FC, Thüroff JW and Hampel C: Adhesion of renal carcinoma cells to endothelial cells depends on PKCmu. BMC Cancer. 10:1832010. View Article : Google Scholar : PubMed/NCBI
28	Meng J, Liu Y, Han J, Tan Q, Chen S, Qiao K, Zhou H, Sun T and Yang C: Hsp90β promoted endothelial cell-dependent tumor angiogenesis in hepatocellular carcinoma. Mol Cancer. 16:722017. View Article : Google Scholar : PubMed/NCBI
29	Choi H and Moon A: Crosstalk between cancer cells and endothelial cells: Implications for tumor progression and intervention. Arch Pharm Res. 41:711–724. 2018. View Article : Google Scholar : PubMed/NCBI