Mechanistic Role of circRNAs in Malignant Characterizations of Cancer Stem Cells
DOI:
https://doi.org/10.62382/jcbt.v2i3.67Keywords:
Cancer stem cells (CSCs), Circular RNAs (CircRNAs), miRNAs, Self-renewal, Metastasis, Drug/radiotherapy resistanceAbstract
Cancer stem cells (CSCs) are a type of cancer cells in tumor tissues with highly malignant characterizations, including self-renewal, migration, invasion, metastasis and drug/radio therapy resistance. Numerous regulatory RNAs such as circular RNAs (circRNAs) are deregulated in CSCs and involved in stemness properties of these types of cancer cells. Due to the high stability and the half-life, circRNAs provide a significant clinical benefit for their use as diagnostic and therapeutic biomarkers. CircRNAs interact with specific miRNAs, proteins, and DNA regions, and thus can regulate various cellular functions and signaling pathways involved in the diverse biological, physiological, cellular, and pathophysiological processes. This review introduces CSCs and their associated markers. Also, it provides an overview of the biogenesis of circRNAs and emphasizes on the oncogenic and suppressive roles of circRNAs in different types of CSCs. Also, it highlights the mechanistic roles of circRNAs as miRNA sponger or/and protein decoy in this type of cancer cells. Understanding how circRNAs affect cellular processes at a molecular level holds significant potential for both diagnostic and therapeutic approaches in cancer treatment.
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References
Ganesh K, Massagué J. Targeting metastatic cancer. Nature Medicine. 2021, 27(1), 34-44. DOI: 10.1038/s41591-020-01195-4
Yousefnia S. A comprehensive review on lncRNA LOXL1-AS1: molecular mechanistic pathways of lncRNA LOXL1-AS1 in tumorigenicity of cancer cells. Frontiers in Oncology. 2024, 14, 1384342. DOI: 10.3389/fonc.2024.1384342
Yousefnia S, Negahdary M. Role of miRNAs in Cancer: Oncogenic and Tumor Suppressor miRNAs, Their Regulation and Therapeutic Applications. Springer International Publishing: Cham. 2024, 1-27. DOI: 10.1007/16833_2024_37
Yousefnia S. Breast Cancer, Subtypes, Risk Factors, and Treatment. The Palgrave Encyclopedia of Disability. 2024, 1-14. DOI: 10.1007/978-3-031-40858-8_324-1
Blackadar CB. Historical review of the causes of cancer. World Journal of Clinical Oncology. 2016, 7(1), 54. DOI: 10.5306/wjco.v7.i1.54.
Gu A, Li JT, Li MY, Liu YB. Patient-derived xenograft model in cancer: establishment and applications. MedComm. 2025, 6(2), e70059. DOI: 10.1002/mco2.70059
Yousefnia S, Forootan FS, Forootan SS, Esfahani MHN, Gure AO, et al. Mechanistic pathways of malignancy in breast cancer stem cells. Frontiers in Oncology. 2020, 10, 452. DOI: 10.3389/fonc.2020.00452
Wang YY, Li WD, Patel SS, Cong J, Zhang N, et al. Blocking the formation of radiation–induced breast cancer stem cells. Oncotarget. 2014, 5(11), 3743. DOI: 10.18632/oncotarget.1992
Kyriazi AA, Papiris E, Kalyvianakis KK, Sakellaris G, Baritaki S. Dual effects of non-coding RNAs (ncRNAs) in cancer stem cell biology. International Journal of Mole Cular Sciences. 2020, 21(18), 6658. DOI: 10.3390/ijms21186658
Nasri N, Saharkhiz S, Dini G, Yousefnia S. Thermo-and pH-responsive targeted lipid-coated mesoporous nano silica platform for dual delivery of paclitaxel and gemcitabine to overcome HER2-positive breast cancer. International Journal of Pharmaceutics. 2023, 648, 123606. DOI: 10.1016/j.ijpharm.2023.123606
Rahimi G, Yousefnia S, Angnes L, Negahdary M. Design a PEGylated nanocarrier containing lemongrass essential oil (LEO), a drug delivery system: Application as a cytotoxic agent against breast cancer cells. Journal of Drug Delivery Science and Technology. 2023, 80, 104183. DOI: 10.1016/j.jddst.2023.104183
Saharkhiz S, Nasri N, Dini G, Yousefnia S. Development of a new smart theranostic anti-PSMA-aptamer conjugated cationic-lipid coated mesoporous silica platform for targeted delivery of paclitaxel and CdSe/ZnS quantum dots to LNCaP cell line. Journal of Drug Delivery Science and Technology. 2023, 88, 104964. DOI: 10.1016/j.jddst.2023.104964
Yousefnia S, Negahdary M. Diagnostic application of aptamers against leukemia, multiple myeloma and lymphoma: a review. Journal of Drug Delivery Science and Technology. 2024, 100, 106103. DOI: 10.1016/j.jddst.2024.106103
Wang J, Liao ZX. Research progress of microrobots in tumor drug delivery. Food & Medicine Homology. 2024, 1(2), 9420025. DOI: 10.26599/FMH.2024.9420025
Li JT, Gu Ao, Nong XM, Zhai SY, Yue ZY, et al. Six-Membered Aromatic Nitrogen Heterocyclic Anti-Tumor Agents: Synthesis and Applications. The Chemical Record. 2023, 23(12), e202300293. DOI: 10.1002/tcr.202300293
Michor F, Polyak K. The origins and implications of intratumor heterogeneity. Cancer Prevention Research. 2010, 3(11), 1361-1364. DOI: 10.1158/1940-6207.CAPR-10-0234
Louie E, Nik S, Chen JS, Schmidt M, Song B, et al. Identification of a stem-like cell population by exposing metastatic breast cancer cell lines to repetitive cycles of hypoxia and reoxygenation. Breast Cancer Research. 2010, 12, 1-14. DOI: 10.1186/bcr2773
Naujokat C. Monoclonal antibodies against human cancer stem cells. Immunotherapy. 2014, 6(3), 290-308. DOI: 10.2217/imt.14.4
Storms RW, Trujillo AP, Springer JB, Shah L, Colvin OM, et al. Isolation of primitive human hematopoietic progenitors on the basis of aldehyde dehydrogenase activity. Proceedings of the National Academy of Sciences. 1999, 96(16), 9118-9123. DOI: 10.1073/pnas.96.16.9118
Zhao Y, Peng J, Zhang EL, Jiang N, Li J, et al. CD133 expression may be useful as a prognostic indicator in colorectal cancer, a tool for optimizing therapy and supportive evidence for the cancer stem cell hypothesis: a meta-analysis. Oncotarget. 2016, 7(9), 10023. DOI: 10.18632/oncotarget.7054
Makena MR, Ranjan A, Thirumala V, Reddy AP. Cancer stem cells: Road to therapeutic resistance and strategies to overcome resistance. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2020, 1866(4), 165339. DOI: 10.1016/j.bbadis.2018.11.015
Li MS, Xie XY, Zhou J, Sheng MY, Yin XF, et al. Quantifying circular RNA expression from RNA-seq data using model-based framework. Bioinformatics. 2017, 33(14), 2131-2139. DOI: 10.1093/bioinformatics/btx129
Doherty MR, Smigiel JM, Junk DJ, Jackson MW. Cancer Stem Cell Plasticity Drives Therapeutic Resistance. Cancers. 2016, 8(1), 8. DOI: 10.3390/cancers8010008
Schwerdtfegera M, Desiderioa V, Koboldb S, Regadd T, Zappavignad S, et al. Long non-coding RNAs in cancer stem cells. Translational Oncology. 2021, 14(8), 101134. DOI: 10.1016/j.tranon.2021.101134
Yousefnia S. A comprehensive review on miR-153: Mechanistic and controversial roles of miR-153 in tumorigenicity of cancer cells. Frontiers in Oncology. 2022, 12, 985897. DOI: 10.3389/fonc.2022.985897.
van Schooneveld E, Wouters MC, der Auwera IV, Peeters DJ, Wildiers H, et al. Expression profiling of cancerous and normal breast tissues identifies microRNAs that are differentially expressed in serum from patients with (metastatic) breast cancer and healthy volunteers. Breast Cancer Research. 2012, 14(1), R34. DOI: 10.1186/bcr3127
Liu C, Tang DG. MicroRNA Regulation of Cancer Stem Cells. Cancer Research. 2011, 71(18), 5950-5954. DOI: 10.1158/0008-5472.CAN-11-1035
Khan AQ, Ahmed E, Elareer NR, Junejo K, Steinhoff M, et al. Role of miRNA-Regulated Cancer Stem Cells in the Pathogenesis of Human Malignancies. Cells. 2019, 8(8), 840. DOI: 10.3390/cells8080840
Chen SS, Zhu JM, Wang F, Guan ZF, Ge YY, et al. LncRNAs and their role in cancer stem cells. Oncotarget. 2017, 8(66), 110685-110692. DOI: 10.18632/oncotarget.22161
Jahangiri L, Ishola T, Pucci P, Trigg RM, Pereira J, et al. The Role of Autophagy and lncRNAs in the Maintenance of Cancer Stem Cells. Cancers. 2021, 13(6), 1239. DOI: 10.3390/cancers13061239
Hüttenhofer A, Schattner P, Polacek N. Non-coding RNAs: hope or hype? Trends in Genetics. 2005, 21(5), 289-297. DOI: 10.1016/j.tig.2005.03.007
Xiao J, Joseph S, Xia MW, Teng F, Chen XJ, et al. Circular RNAs Acting as miRNAs’ Sponges and Their Roles in Stem Cells. Journal of Clinical Medicine. 2022, 11(10), 2909. DOI: 10.3390/jcm11102909
Wang H, Feng C, Jin Y, Tan WY, Wei FL. Identification and characterization of circular RNAs involved in mechanical force‐induced periodontal ligament stem cells. Journal of Cellular Physiology. 2019, 234(7), 10166-10177. DOI: 10.1002/jcp.27686
Hansen TB, Kjems J, Damgaard CK. Circular RNA and miR-7 in cancer. Cancer Research. 2013, 73(18), 5609-5612. DOI: 10.1158/0008-5472.CAN-13-1568
Szabo L, Morey R, Nathan JP, Wang PL, Afari N, et al. Statistically based splicing detection reveals neural enrichment and tissue-specific induction of circular RNA during human fetal development. Genome Biology. 2015, 16, 1-26. DOI: 10.1186/s13059-015-0690-5
Starke S, Jost I, Rossbach O, Schneider T, Schreiner S, et al. Exon circularization requires canonical splice signals. Cell Reports. 2015, 10(1), 103-111. DOI: 10.1016/j.celrep.2014.12.002
Santer L, Bär C, Thum T. Circular RNAs: a novel class of functional RNA molecules with a therapeutic perspective. Molecular Therapy. 2019, 27(8), 1350-1363. DOI: 10.1016/j.ymthe.2019.07.001
Ragan C, Goodall GJ, Shirokikh NE, Preiss T. Insights into the biogenesis and potential functions of exonic circular RNA. Scientific Reports. 2019, 9(1), 2048. DOI: 10.1038/s41598-018-37037-0
Li X, Yang L, Chen LL. The Biogenesis, Functions, and Challenges of Circular RNAs. Molecular Cell. 2018, 71(3), 428-442. DOI: 10.1016/j.molcel.2018.06.034
Meng SJ, Zhou HC, Feng ZY, Xu ZH, Tang Y, et al. CircRNA: functions and properties of a novel potential biomarker for cancer. Molecular Cancer. 2017, 16(1), 94. DOI: 10.1186/s12943-017-0663-2
Yoshida K, Yamamoto Y, Ochiya T. miRNA signaling networks in cancer stem cells. Regenerative Therapy. 2021, 17, 1-7. DOI: 10.1016/j.reth.2021.01.004
Misir S, Hepokur C, Aliyazicioglu Y, Enguita FJ. Circular RNAs serve as miRNA sponges in breast cancer. Breast Cancer. 2020, 27(6), 1048-1057. DOI: 10.1007/s12282-020-01140-w
Lu Q, Liu TY, Feng HJ, Yang R, Zhao XZ, et al. Circular RNA circSLC8A1 acts as a sponge of miR-130b/miR-494 in suppressing bladder cancer progression via regulating PTEN. Molecular Cancer. 2019, 18(1), 111. DOI: 10.1186/s12943-019-1040-0
Liu YP, Heng JY, Zhao XY, Li EY. The inhibition of circular RNA circNOLC1 by propofol/STAT3 attenuates breast cancer stem cells function via miR-365a-3p/STAT3 signaling. Journal of Translational Medicine. 2021, 19(1), 467. DOI: 10.1186/s12967-021-03133-5
Singh S, Sinha T, Panda AC. Regulation of microRNA by circular RNA. Wiley Interdisciplinary Reviews. RNA. 2024, 15(1), e1820. DOI: 10.1002/wrna.1820
Song J, Wang HL, Song KH, Ding ZW, Wang HL, et al. CircularRNA_104670 plays a critical role in intervertebral disc degeneration by functioning as a ceRNA. Experimental & Molecular Medicine. 2018, 50(8), 1-12. DOI: 10.1038/s12276-018-0125-y
Du WW, Yang WN, Chen Y, Wu ZK, Foster FS, et al. Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses. European Heart Journal. 2017, 38(18), 1402-1412. DOI: 10.1093/eurheartj/ehw001
Du WW, Yang WN, Liu E, Yang ZG, Dhaliwal P, et al. Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic Acids Research. 2016, 44(6), 2846-2858. DOI: 10.1093/nar/gkw027
Du WW, Yang WN, Li XM, Awan FM, Yang ZG, et al. A circular RNA circ-DNMT1 enhances breast cancer progression by activating autophagy. Oncogene. 2018, 37(44), 5829-5842. DOI: 10.1038/s41388-018-0369-y
Gu Y, Wang YY, He LY, Zhang JH, Zhu XX, et al. Circular RNA circIPO11 drives self-renewal of liver cancer initiating cells via Hedgehog signaling. Molecular Cancer. 2021, 20(1), 132. DOI: 10.1186/s12943-021-01435-2
Wu HH, Pan XY, Yang Y, Shen HB. Recognizing binding sites of poorly characterized RNA-binding proteins on circular RNAs using attention Siamese network. Briefings in Bioinformatics. 2021, 22(6), bbab279. DOI: 10.1093/bib/bbab279
Shi PX, Li YT, Guo QS. Circular RNA circPIP5K1A contributes to cancer stemness of osteosarcoma by miR-515-5p/YAP axis. Journal of Translational Medicine. 2021, 19(1), 464. DOI: 10.1186/s12967-021-03124-6
Lin XT, Chen WY, Wei FQ, Xie XM. TV-circRGPD6 Nanoparticle Suppresses Breast Cancer Stem Cell-Mediated Metastasis via the miR-26b/YAF2 Axis. Molecular Therapy. 2021, 29(1), 244-262. DOI: 10.1016/j.ymthe.2020.09.005
Liu YM, Gao XX, Wang S, Yuan XM, Pang YQ, et al. Cancer Stem Cells are Regulated by STAT3 Signalling in Wilms Tumour. Journal of Cancer. 2018, 9(8), 1486-1499. DOI: 10.7150/jca.23277
Wei SX, Li JL, Tang MB, Zhang KW, Gao XL, et al. STAT3 and p63 in the Regulation of Cancer Stemness. Frontiers in Genetics. 2022, 13, 909251. DOI: 10.3389/fgene.2022.909251
Yan YB, Jin XY, Sun HB, Pang SN, Kong XL, et al. MiR-139-5p Targetedly Regulates YAF2 and Mediates the AKT/P38 MAPK Signaling Pathway to Alleviate the Metastasis of Non-Small Cell Lung Cancer Cells and Their Resistance Against Cisplatin. Cancer Management and Research. 2021, 13, 3639-3650. DOI: 10.2147/CMAR.S254671
Chen F, Zhang HY, Wang J. Circular RNA CircSHKBP1 accelerates the proliferation, invasion, angiogenesis, and stem cell-like properties via modulation of microR-766-5p/high mobility group AT-hook 2 axis in laryngeal squamous cell carcinoma. Bioengineered. 2022, 13(5), 11551-11563. DOI: 10.1080/21655979.2022.2068922
Mansoori B, Duijf PHG, Mohammadi A, Najafi S, Roshani E, et al. Overexpression of HMGA2 in breast cancer promotes cell proliferation, migration, invasion and stemness. Expert Opinion on Therapeutic Targets. 2020, 24(3), 255-265. DOI: 10.1080/14728222.2020.1736559
Xia YW, Lv JL, Jiang TL, Li BW, Li Y, et al. CircFAM73A promotes the cancer stem cell-like properties of gastric cancer through the miR-490-3p/HMGA2 positive feedback loop and HNRNPK-mediated β-catenin stabilization. Journal of Experimental & Clinical Cancer Research. 2021, 40(1), 103. DOI: 10.1186/s13046-021-01896-9
Chen HR, Li YS. Circular RNA hsa_circ_0000915 promotes propranolol resistance of hemangioma stem cells in infantile haemangiomas. Human Genomics. 2022, 16(1), 43. DOI: 10.1186/s40246-022-00416-w
Wan WB, Wu K, Peng K, Qiu ZQ, Duan ZB, et al. High level of RNF187 contributes to the progression and drug resistance of osteosarcoma. Journal of Cancer. 2020, 11(6), 1351-1358. DOI: 10.7150/jca.33488
Chen ZZ, Lu TK, Huang L, Wang ZW, Yan ZY, et al. Circular RNA cia-MAF drives self-renewal and metastasis of liver tumor-initiating cells via transcription factor MAFF. The Journal of Clinical Investigation. 2021, 131(19), e148020. DOI: 10.1172/JCI148020
Moon EJ, Mello SS, Li CG, Chi JT, Thakkar K, et al. The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling. Nature Communications. 2021, 12(1), 4308. DOI: 10.1038/s41467-021-24631-6
Xu YJ, Wu W, Han Q, Wang YL, Li CC, et al. New Insights into the Interplay between Non-Coding RNAs and RNA-Binding Protein HnRNPK in Regulating Cellular Functions. Cells. 2019, 8(1), 62. DOI: 10.3390/cells8010062
Tian Y, Gao P, Dai D, Chen L, Chu X, et al. Circular RNA circSETD3 hampers cell growth, migration, and stem cell properties in bladder cancer through sponging miR-641 to upregulate PTEN. Cell Cycle. 2021, 20(16), 1589-1602. DOI: 10.1080/15384101.2021.1954758
Chen L, Shan G. CircRNA in cancer: fundamental mechanism and clinical potential. Cancer Letters. 2021, 505, 49-57. DOI: 10.1016/j.canlet.2021.02.004
Feng ZY, Meng SJ, Zhou HC, Xu ZH, Tang Y, et al. Functions and Potential Applications of Circular RNAs in Cancer Stem Cells. Frontiers in Oncology. 2019, 9, 500. DOI: 10.3389/fonc.2019.00500
Han T, Chen LJ, Li KR, Hu QL, Zhang Y, et al. Significant CircRNAs in liver cancer stem cell exosomes: mediator of malignant propagation in liver cancer? Molecular Cancer. 2023, 22(1), 197. DOI: 10.1186/s12943-023-01891-y
Aquino-Jarquin G. CircRNA knockdown based on antisense strategies. Drug Discovery Today. 2024, 29(8), 104066. DOI: 10.1016/j.drudis.2024.104066
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