ROLE OF CIRCULAR RNAS IN TUMORIGENESIS AND THEIR POSSIBLE APPLICATIONS IN CANCER DIAGNOSIS AND TREATMENT

Circular RNAs (circRNAs) play critical roles in the development and progression of diseases, especially in cancer. Thus, expanding our understanding of circRNAs will enrich knowledge of cancer and give new opportunities for cancer therapy. In this review, we discuss the genesis of circular RNAs, their types and epigenetic aspects in tumorigenesis of abnormal cellular proliferation. The possible applications of individual circRNAs as biological markers in laboratory diagnosis of cancer received considerable attention recently. CDR1as and circHIPK3 active cell proliferative through regulating EGFR; et al. promotecancer cells evading antigrowth signals by preventing expression or activation of tumor suppressors, such as PTEN and CDK; Hsa_circ_0007534 et al. promote cancer cells evading cell death via regulating cellular apoptosis or autophagy; Hsa-circ-0020397 limits replicative potential of cell trough regulating angiogenesis trough regulating VEGF; process and tissue invasion and


Regulating transcription or splicing:
Some circRNAs have been demonstrated to regulate gene transcription through combining with RNA polymerase IIcomplex and translating related proteins (Chen, 2016).

Translating proteins:
CircRNAswere initially defined asa distinct class of endogenous noncoding RNA that could nottranslateproteins, because of lacking 5′-3′ and polyadenylatedtails, as well as internal ribosome entry sites (IRES) (

Contribution to invasion and metastasis:
During metastasis process, the cellsmay undergo some alterations such as hypernomicproliferation, "epithelialmesenchymal-transition" (EMT) (Dwyer et al., 2017), and increased expression of matrixmetalloproteinase (MMP). CircRNAs play a role as sponges in the regulation of tumorcell invasion and metastasis.
CircRNA also impacts the invasion and metastasis of tumor cells by suppressingmiRNAs that directly target MMP, thereby up regulating the expression of MMP intissues. For example, in non-small cell lung cancer, circRNA_100876 acts as a spongefor miR-136, which binds to the 3'-UTR of MMP-13 mRNA and suppresses itstranscription (Yao et al., 2017).

Influence on angiogenesis:
Angiogenesis

Circrnas As Biomarkers In Cancer:-
CircRNAs can be potentially valuable prognosticand diagnostic biomarkers for cancer. Recently,many studies have demonstrated circRNAs may be stablyexpressed and present in relatively high quantities in humanbody fluids, such as saliva, plasma, serum andexosomes,which also makes circRNAs ideal candidates asnoninvasive liquid biopsy biomarkers for cancer (Kun-Peng et al., 2018).Examples of circ RNAs as biomarkers in cancer are listed below.  Huang et al., 2017). The expression level of hsa_circ_0000745 in GC tissues was correlated with tumordifferentiation,while the expression level in plasma wascorrelated with tumor-node metastasis stage.  (Bray et al., 2018).

Circ-ZEB:-
CircMTO1 is downregulated in HCC tissues,and correlated with the poor survival of patients. Aftersilencing circMTO1, the level of cell proliferation andinvasion is significantly increased, and the percentage ofapoptosis is reduced (Han et al., 2017).
CSMARCA5 isdecreased in HCC tissues, and correlated with aggressivebiological behaviors, such as poorer tumor differentiation, advanced tumor stage, tumor size and the presenceof microvascular invasion (Yu et al.,  2018).

Conclusion:-
In the past few years, the regulatory effects of circRNAs have been illustrated on pathophysiologic processes, including tumorigenesis. In this review, we briefly summarized the recent advances regarding circRNAs in the hallmarks and the possibility as biomarkers for cancer.

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The stability, universality, and specificity of circRNAs make it to be a potential valuable prognostic and diagnostic biomarker for cancer, and the functions and regulatory roles that circRNAs play in tumor cells make it possible to be a target for the treatment of cancer. However, the study of circRNAs is far from being able to be incorporated into clinical practice, and there are still problems requiring further investigation in this field. For example, further investigation is needed regarding the precise mechanisms, other than those of miRNA sponge activity, of circRNAs underlying the initiation and progression of cancer. Furthermore, more controlled and large-scale clinical studies are required before cancer-specific circRNAs can be recommended for diagnosis and treatment. Understanding circRNA willgenerate new hypotheses regarding cancer pathogenesis. We hope that the appropriate and precise use of circRNAs in clinical applications might eventually create breakthroughs for cancer therapy in the upcoming years.