Progress of CircRNAs as A Promising Biomarker and Therapeutic Target for Cervical Cancer

doi:10.12280/gjfckx.20200836

Abstract

Abstract:

Circular RNAs (circRNAs) are single-stranded, covalently closed noncoding RNAs without 3′ and 5′ ends. Evidence demonstrated that circRNAs are abundant, stable and able to show cell/tissue-specific expression, which structure features show potential for noninvasive molecular biomarkers of tumors. CircRNAs express differentially and play an important role in many kinds of neoplasms by miRNA sponges, interaction with RNA binding proteins, modulating the stability of mRNAs, regulating gene transcription and translation proteins. There are no specific biomarkers for early warning and potential therapeutic targets currently. Many studies have demonstrated differential expression of circRNAs function vitally on singnal pathway and gene expression in the initiation and development of cervical cancer. CircRNAs involve in circRNA-miRNA-target gene axis mainly through miRNA sponges to promote cervical cancer cell proliferation, invasion and metastasis, and associate with tumor size, clinical stage, metastatic lymph nodes and poor prognosis.

Key words: Circular RNA, Uterine cervical neoplasms, Biomarkers,tumor, Cell proliferation, Therapy

LI He-tong, WANG Wei, HAO Min. Progress of CircRNAs as A Promising Biomarker and Therapeutic Target for Cervical Cancer[J]. Journal of International Obstetrics and Gynecology, 2021, 48(3): 322-327.

Figures/Tables 1

References 41

[1]	王伟, 郝敏, 陈春林, 等. 年轻Ⅰa2~Ⅱa2期子宫颈癌患者的构成比变化趋势及临床病理特征分析[J]. 中华妇产科杂志, 2019,54(10):666-672. doi: 10.3760/cma.j.issn.0529?567x.2019.10.004. doi: 10.3760/cma.j.issn.0529?567x.2019.10.004
[2]	Sanger HL, Klotz G, Riesner D, et al. Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures[J]. Proc Natl Acad Sci U S A, 1976,73(11):3852-3856. doi: 10.1073/pnas.73.11.3852. doi: 10.1073/pnas.73.11.3852 pmid: 1069269
[3]	Salzman J, Gawad C, Wang PL, et al. Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types[J]. PLoS One, 2012,7(2):e30733. doi: 10.1371/journal.pone.0030733. doi: 10.1371/journal.pone.0030733
[4]	Jeck WR, Sorrentino JA, Wang K, et al. Circular RNAs are abundant, conserved, and associated with ALU repeats[J]. RNA, 2013,19(2):141-157. doi: 10.1261/rna.035667.112. doi: 10.1261/rna.035667.112
[5]	Jeck WR, Sharpless NE. Detecting and characterizing circular RNAs[J]. Nat Biotechnol, 2014,32(5):453-461. doi: 10.1038/nbt.2890. doi: 10.1038/nbt.2890
[6]	Han YN, Xia SQ, Zhang YY, et al. Circular RNAs: A novel type of biomarker and genetic tools in cancer[J]. Oncotarget, 2017,8(38):64551-64563. doi: 10.18632/oncotarget.18350. doi: 10.18632/oncotarget.18350
[7]	Hansen TB, Jensen TI, Clausen BH, et al. Natural RNA circles function as efficient microRNA sponges[J]. Nature, 2013,495(7441):384-388. doi: 10.1038/nature11993. doi: 10.1038/nature11993
[8]	Han D, Li J, Wang H, et al. Circular RNA circMTO1 acts as the sponge of microRNA-9 to suppress hepatocellular carcinoma progression[J]. Hepatology, 2017,66(4):1151-1164. doi: 10.1002/hep.29270. doi: 10.1002/hep.29270
[9]	Weng W, Wei Q, Toden S, et al. Circular RNA ciRS-7-A Promising Prognostic Biomarker and a Potential Therapeutic Target in Colorectal Cancer[J]. Clin Cancer Res, 2017,23(14):3918-3928. doi: 10.1158/1078-0432.CCR-16-2541. doi: 10.1158/1078-0432.CCR-16-2541
[10]	Zhou Y, Shen L, Wang YZ, et al. The potential of ciRS-7 for predicting onset and prognosis of cervical cancer[J]. Neoplasma, 2020,67(2):312-322. doi: 10.4149/neo_2019_190415N334. doi: 10.4149/neo_2019_190415N334 pmid: 31884800
[11]	Du WW, Fang L, Yang W, et al. Induction of tumor apoptosis through a circular RNA enhancing Foxo3 activity[J]. Cell Death Differ, 2017,24(2):357-370. doi: 10.1038/cdd.2016.133. doi: 10.1038/cdd.2016.133
[12]	Abdelmohsen K, Panda AC, Munk R, et al. Identification of HuR target circular RNAs uncovers suppression of PABPN1 translation by CircPABPN1[J]. RNA Biol, 2017,14(3):361-369. doi: 10.1080/15476286.2017.1279788. doi: 10.1080/15476286.2017.1279788 pmid: 28080204
[13]	Liang WC, Wong CW, Liang PP, et al. Translation of the circular RNA circβ-catenin promotes liver cancer cell growth through activation of the Wnt pathway[J]. Genome Biol, 2019,20(1):84. doi: 10.1186/s13059-019-1685-4. doi: 10.1186/s13059-019-1685-4
[14]	Zheng X, Chen L, Zhou Y, et al. A novel protein encoded by a circular RNA circPPP1R12A promotes tumor pathogenesis and metastasis of colon cancer via Hippo-YAP signaling[J]. Mol Cancer, 2019,18(1):47. doi: 10.1186/s12943-019-1010-6. doi: 10.1186/s12943-019-1010-6 pmid: 30925892
[15]	Wu F, Zhou J. CircAGFG1 promotes cervical cancer progression via miR-370-3p/RAF1 signaling[J]. BMC Cancer, 2019,19(1):1067. doi: 10.1186/s12885-019-6269-x. doi: 10.1186/s12885-019-6269-x
[16]	Li X, Ma N, Zhang Y, et al. Circular RNA circNRIP1 promotes migration and invasion in cervical cancer by sponging miR-629-3p and regulating the PTP4A1/ERK1/2 pathway[J]. Cell Death Dis, 2020,11(5):399. doi: 10.1038/s41419-020-2607-9. doi: 10.1038/s41419-020-2607-9
[17]	Wang Y, Wang L, Wang W, et al. Overexpression of circular RNA hsa_circ_0001038 promotes cervical cancer cell progression by acting as a ceRNA for miR-337-3p to regulate cyclin-M3 and metastasis-associated in colon cancer 1 expression[J]. Gene, 2020,733:144273. doi: 10.1016/j.gene.2019.144273. doi: 10.1016/j.gene.2019.144273
[18]	Gao YL, Zhang MY, Xu B, et al. Circular RNA expression profiles reveal that hsa_circ_0018289 is up-regulated in cervical cancer and promotes the tumorigenesis[J]. Oncotarget, 2017,8(49):86625-86633. doi: 10.18632/oncotarget.21257. doi: 10.18632/oncotarget.21257
[19]	He J, Lv X, Zeng Z. A potential disease monitoring and prognostic biomarker in cervical cancer patients: The clinical application of circular RNA_0018289[J]. J Clin Lab Anal, 2020,34(8):e23340. doi: 10.1002/jcla.23340. doi: 10.1002/jcla.23340
[20]	Liu J, Wang D, Long Z, et al. CircRNA8924 Promotes Cervical Cancer Cell Proliferation, Migration and Invasion by Competitively Binding to MiR-518d-5p /519-5p Family and Modulating the Expression of CBX8[J]. Cell Physiol Biochem, 2018,48(1):173-184. doi: 10.1159/000491716. doi: 10.1159/000491716
[21]	Hu C, Wang Y, Li A, et al. Overexpressed circ_0067934 acts as an oncogene to facilitate cervical cancer progression via the miR-545/EIF3C axis[J]. J Cell Physiol, 2019,234(6):9225-9232. doi: 10.1002/jcp.27601. doi: 10.1002/jcp.27601
[22]	Wang J, Li H, Liang Z. circ-MYBL2 Serves As A Sponge For miR-361-3p Promoting Cervical Cancer Cells Proliferation And Invasion[J]. Onco Targets Ther, 2019,12:9957-9964. doi: 10.2147/OTT.S218976. doi: 10.2147/OTT.S218976
[23]	Ma H, Tian T, Liu X, et al. Upregulated circ_0005576 facilitates cervical cancer progression via the miR-153/KIF20A axis[J]. Biomed Pharmacother, 2019,118:109311. doi: 10.1016/j.biopha.2019.109311. doi: 10.1016/j.biopha.2019.109311
[24]	Song T, Xu A, Zhang Z, et al. CircRNA hsa_circRNA_101996 increases cervical cancer proliferation and invasion through activating TPX2 expression by restraining miR-8075[J]. J Cell Physiol, 2019,234(8):14296-14305. doi: 10.1002/jcp.28128. doi: 10.1002/jcp.28128
[25]	Qian W, Huang T, Feng W. Circular RNA HIPK3 Promotes EMT of Cervical Cancer Through Sponging miR-338-3p to Up-Regulate HIF-1α[J]. Cancer Manag Res, 2020,12:177-187. doi: 10.2147/CMAR.S232235. doi: 10.2147/CMAR.S232235
[26]	Chen R, Mao L, Shi R, et al. circRNA MYLK Accelerates Cervical Cancer via Up-Regulation of RHEB and Activation of mTOR Signaling[J]. Cancer Manag Res, 2020,12:3611-3621. doi: 10.2147/CMAR.S238172. doi: 10.2147/CMAR.S238172 pmid: 32547198
[27]	Ou R, Mo L, Tang H, et al. circRNA-AKT1 Sequesters miR-942-5p to Upregulate AKT1 and Promote Cervical Cancer Progression[J]. Mol Ther Nucleic Acids, 2020,20:308-322. doi: 10.1016/j.omtn.2020.01.003. doi: 10.1016/j.omtn.2020.01.003
[28]	Tian J, Liang L. Involvement of circular RNA SMARCA5/microRNA-620 axis in the regulation of cervical cancer cell proliferation, invasion and migration[J]. Eur Rev Med Pharmacol Sci, 2018,22(24):8589-8598. doi: 10.26355/eurrev_201812_16622. doi: 16622 pmid: 30575898
[29]	Zhang J, Zhao X, Zhang J, et al. Circular RNA hsa_circ_0023404 exerts an oncogenic role in cervical cancer through regulating miR-136/TFCP2/YAP pathway[J]. Biochem Biophys Res Commun, 2018,501(2):428-433. doi: 10.1016/j.bbrc.2018.05.006. doi: 10.1016/j.bbrc.2018.05.006
[30]	Cai H, Zhang P, Xu M, et al. Circular RNA hsa_circ_0000263 participates in cervical cancer development by regulating target gene of miR-150-5p[J]. J Cell Physiol, 2019,234(7):11391-11400. doi: 10.1002/jcp.27796. doi: 10.1002/jcp.27796
[31]	Ma HB, Yao YN, Yu JJ, et al. Extensive profiling of circular RNAs and the potential regulatory role of circRNA-000284 in cell proliferation and invasion of cervical cancer via sponging miR-506[J]. Am J Transl Res, 2018,10(2):592-604.
[32]	Ding L, Zhang H. Circ-ATP8A2 promotes cell proliferation and invasion as a ceRNA to target EGFR by sponging miR-433 in cervical cancer[J]. Gene, 2019,705:103-108. doi: 10.1016/j.gene.2019.04.068. doi: S0378-1119(19)30426-3 pmid: 31029604
[33]	Mao Y, Zhang L, Li Y. circEIF4G2 modulates the malignant features of cervical cancer via the miR-218/HOXA1 pathway[J]. Mol Med Rep, 2019,19(5):3714-3722. doi: 10.3892/mmr.2019.10032. doi: 10.3892/mmr.2019.10032
[34]	Ou R, Lv J, Zhang Q, et al. circAMOTL1 Motivates AMOTL1 Expression to Facilitate Cervical Cancer Growth[J]. Mol Ther Nucleic Acids, 2020,19:50-60. doi: 10.1016/j.omtn.2019.09.022. doi: 10.1016/j.omtn.2019.09.022
[35]	Jiao J, Zhang T, Jiao X, et al. hsa_circ_0000745 promotes cervical cancer by increasing cell proliferation, migration, and invasion[J]. J Cell Physiol, 2020,235(2):1287-1295. doi: 10.1002/jcp.29045. doi: 10.1002/jcp.29045
[36]	Ji F, Du R, Chen T, et al. Circular RNA circSLC26A4 Accelerates Cervical Cancer Progression via miR-1287-5p/HOXA7 Axis[J]. Mol Ther Nucleic Acids, 2020,19:413-420. doi: 10.1016/j.omtn.2019. 11.032. doi: 10.1016/j.omtn.2019. 11.032
[37]	Wang M, Yu F, Wu W, et al. Circular RNAs: A novel type of non-coding RNA and their potential implications in antiviral immunity[J]. Int J Biol Sci, 2017,13(12):1497-1506. doi: 10.7150/ijbs.22531. doi: 10.7150/ijbs.22531 pmid: 29230098
[38]	Zheng SR, Zhang HR, Zhang ZF, et al. Human papillomavirus 16 E7 oncoprotein alters the expression profiles of circular RNAs in Caski cells[J]. J Cancer, 2018,9(20):3755-3764. doi: 10.7150/jca.24253. doi: 10.7150/jca.24253
[39]	Zhao J, Lee EE, Kim J, et al. Transforming activity of an oncoprotein-encoding circular RNA from human papillomavirus[J]. Nat Commun, 2019,10(1):2300. doi: 10.1038/s41467-019-10246-5. doi: 10.1038/s41467-019-10246-5
[40]	Li S, Teng S, Xu J, et al. Microarray is an efficient tool for circRNA profiling[J]. Brief Bioinform, 2019,20(4):1420-1433. doi: 10.1093/bib/bby006. doi: 10.1093/bib/bby006
[41]	Gong J, Jiang H, Shu C, et al. Integrated analysis of circular RNA-associated ceRNA network in cervical cancer: Observational Study[J]. Medicine(Baltimore), 2019,98(34):e16922. doi: 10.1097/MD.0000000000016922. doi: 10.1097/MD.0000000000016922

circRNA	表达水平	作用机制通路	功能	参考文献
has_circ_0004771（circNRIP1）	上调	has_circ_0004771/miR-629-3p/PTP4A1/ERK1/2	促进宫颈癌细胞的增殖、侵袭和迁移;淋巴脉管间隙浸润	[16]
has_circ_0001038	上调	has_circ_0001038/miR-337-3p/CNNM3, MACC1	分别促进宫颈癌细胞的增殖、侵袭	[17]
has_circ_0018289	上调	has_circ_0018289/miR-497	促进宫颈癌细胞的增殖、侵袭和迁移	[18-19]
circRNA8924	上调	circRNA8924/miR-518d-5p/519-5p/CBX8	促进宫颈癌细胞的增殖、侵袭和迁移	[20]
circ_0067934	上调	circ_0067934/miRNA-545/EIF3C	促进宫颈癌细胞增殖、菌落形成、迁移、侵袭和EMT	[21]
has_circ_0060467（circMYBL2）	上调	has_circ_0060467/miR-361-3p	促进宫颈癌细胞增殖、侵袭和EMT过程	[22]
circ_0005576	上调	circ_0005576/miR-153-3p/KIF20A	促进细胞增殖、集落形成、迁移和侵袭	[23]
has_circ_101996	上调	has_circRNA_101996/miRNA-8075/TPX2	促进宫颈癌细胞的增殖、侵袭和迁移	[24]
circ-HIPK3	上调	circ-HIPK3/miR-338-3p/HIF-1α	促进宫颈癌细胞的增殖、侵袭和迁移	[25]
circMYLK	上调	circMYLK/miR-1301-3p/RHEB/mTOR	促进宫颈癌细胞克隆、增殖能力	[26]
circ-0033550（circ-AKT1）	上调	circ-AKT1/miR-942-5p/AKT1	促进宫颈癌细胞增殖、侵袭及EMT	[27]
has_circ_0001445（circSMARCA5）	下调	circSMARCA5/miR-620	促进宫颈癌细胞的增殖、侵袭和迁移并诱导细胞周期停滞	[28]
has_circ_0023404	上调	has_circ_0023404/miR-136/TFCP2/YAP	促进宫颈癌细胞的增殖、侵袭和迁移并诱导细胞周期停滞	[29]
has_circ_0000263	上调	has_circ_0000263/miRNA-150-5p/MDM4/p53	促进宫颈癌细胞的增殖、侵袭,影响凋亡和细胞周期	[30]
circRNA-000284	上调	circRNA-000284/miRNA-506/Snail-2	促进细胞增殖和侵袭同时使细胞周期停滞在G0/G1期	[31]
circ-ATP8A2	上调	circ-ATP8A2/miR-433/EGFR	促进宫颈癌细胞的增殖、侵袭和迁移及促进细胞凋亡	[32]
circEIF4G2	上调	circEIF4G2/miR218/HOXA1	细胞增殖、集落形成、迁移和侵袭	[33]
circ_0004214（circAMOTL1）	上调	circAMOTL1/miR-485-5p/AMOTL1	促进宫颈癌细胞增殖	[34]
has_circ_0000745	上调	has_circ_0000745/E-cadherin	促进宫颈癌细胞的增殖、侵袭和迁移	[35]
circSLC26A4	上调	QKI/circSLC26A4/miR-1287-5p/HOXA7	促进宫颈癌细胞的增殖、侵袭	[36]

circRNA	表达水平	作用机制通路	功能	参考文献
has_circ_0004771（circNRIP1）	上调	has_circ_0004771/miR-629-3p/PTP4A1/ERK1/2	促进宫颈癌细胞的增殖、侵袭和迁移;淋巴脉管间隙浸润	[16]
has_circ_0001038	上调	has_circ_0001038/miR-337-3p/CNNM3, MACC1	分别促进宫颈癌细胞的增殖、侵袭	[17]
has_circ_0018289	上调	has_circ_0018289/miR-497	促进宫颈癌细胞的增殖、侵袭和迁移	[18-19]
circRNA8924	上调	circRNA8924/miR-518d-5p/519-5p/CBX8	促进宫颈癌细胞的增殖、侵袭和迁移	[20]
circ_0067934	上调	circ_0067934/miRNA-545/EIF3C	促进宫颈癌细胞增殖、菌落形成、迁移、侵袭和EMT	[21]
has_circ_0060467（circMYBL2）	上调	has_circ_0060467/miR-361-3p	促进宫颈癌细胞增殖、侵袭和EMT过程	[22]
circ_0005576	上调	circ_0005576/miR-153-3p/KIF20A	促进细胞增殖、集落形成、迁移和侵袭	[23]
has_circ_101996	上调	has_circRNA_101996/miRNA-8075/TPX2	促进宫颈癌细胞的增殖、侵袭和迁移	[24]
circ-HIPK3	上调	circ-HIPK3/miR-338-3p/HIF-1α	促进宫颈癌细胞的增殖、侵袭和迁移	[25]
circMYLK	上调	circMYLK/miR-1301-3p/RHEB/mTOR	促进宫颈癌细胞克隆、增殖能力	[26]
circ-0033550（circ-AKT1）	上调	circ-AKT1/miR-942-5p/AKT1	促进宫颈癌细胞增殖、侵袭及EMT	[27]
has_circ_0001445（circSMARCA5）	下调	circSMARCA5/miR-620	促进宫颈癌细胞的增殖、侵袭和迁移并诱导细胞周期停滞	[28]
has_circ_0023404	上调	has_circ_0023404/miR-136/TFCP2/YAP	促进宫颈癌细胞的增殖、侵袭和迁移并诱导细胞周期停滞	[29]
has_circ_0000263	上调	has_circ_0000263/miRNA-150-5p/MDM4/p53	促进宫颈癌细胞的增殖、侵袭,影响凋亡和细胞周期	[30]
circRNA-000284	上调	circRNA-000284/miRNA-506/Snail-2	促进细胞增殖和侵袭同时使细胞周期停滞在G0/G1期	[31]
circ-ATP8A2	上调	circ-ATP8A2/miR-433/EGFR	促进宫颈癌细胞的增殖、侵袭和迁移及促进细胞凋亡	[32]
circEIF4G2	上调	circEIF4G2/miR218/HOXA1	细胞增殖、集落形成、迁移和侵袭	[33]
circ_0004214（circAMOTL1）	上调	circAMOTL1/miR-485-5p/AMOTL1	促进宫颈癌细胞增殖	[34]
has_circ_0000745	上调	has_circ_0000745/E-cadherin	促进宫颈癌细胞的增殖、侵袭和迁移	[35]
circSLC26A4	上调	QKI/circSLC26A4/miR-1287-5p/HOXA7	促进宫颈癌细胞的增殖、侵袭	[36]