Direct Interaction of miRNA and circRNA with the Oncosuppressor p53: An Intriguing Perspective in Cancer Research

Abstract

MicroRNAs (miRNAs) are linear single-stranded non-coding RNAs oligonucleotides, widely distributed in cells, playing a key role as regulators of gene expression at post-transcriptional level. Circular RNAs (circRNAs) are single-stranded RNA oligonucleotides forming a covalently closed continuous loop, which confers them a high structural stability and which may code for proteins or act as gene regulators. Abnormal levels or dysregulation of miRNA or circRNA are linked to several cancerous pathologies, so that they are receiving a large attention as diagnostic and prognostic tools. Some miRNAs and circRNAs are strongly involved in the regulatory networks of the transcription factor p53, which plays a pivotal role as tumor suppressor. Overexpression of miRNAs and/or circRNAs, as registered in a number of cancers, is associated to a concomitant inhibition of the p53 onco-suppressive function. Among other mechanisms, it was recently suggested that a functional inhibition of p53 could arise from a direct interaction between p53 and oncogenic miRNAs or circRNAs; a mechanism that might be reminiscent of the p53 inhibition by some E3 ubiquitin ligase such as MDM2 and COP1. Such evidence might deserve important implications for restoring the p53 anticancer functionality, and pave the way to intriguing perspectives for novel therapeutic strategies. In the present paper, the experimental evidence of the interaction between p53 and miRNAs and/or circRNAs is reviewed and discussed in connection with the development of new anticancer approaches.

Circular RNAs: implications of signaling pathways and bioinformatics in human cancer

“…The formation of a hetero-tetrameric mut-p53/wt-p53 complex inhibits the tumor suppression function of the remaining wt-p53, thus leading to tumor cell proliferation, survival, migration, and invasion. Interestingly, crosstalk between mut-p53 and circRNA has been reported 113 . For example, circPVT1 106 and circ-Ccnb1 114 are activated by mut-p53.…”

“…Circ-Ccnb1 dissociates the CyclinB1/Cdk1 mitotic complex, thereby suppressing cell invasion and tumorigenesis 114 . Mechanistically, a direct interaction between p53 and circRNAs has been speculated to prevent the destruction of p53, and this interaction may inhibit ubiquitination by E3 ubiquitin ligases (such as MDM2) and subsequent degradation of p53 113 . Binding of the circRNA CDR1as to p53 disrupts the p53/MDM2 complex, thus leading to p53 stabilization in glioblastoma 110 .…”

Exosomal circ-ADRM1 promotes lung adenocarcinoma progression and induces macrophage M2 polarization through regulating MMP14 mRNA and protein

“…As a noncoding endogenous RNA, circular RNA (circRNA) is characterized by the structure of a covalently closed continuous loop [7]. As reported, circRNAs can play a crucial role in the biological processes of LUAD cells.…”

The conformational heterogeneity of the tumor suppressor p53 is tuned by punctual mutations

“…[2][3][4][5] The p53 activity is finely tuned by different processes, including a direct interactions with some molecules, such as MDM2, S100, COP1 and, interestingly, miRNA. 6,7 When p53 does not work properly, for example as consequence of a mutation, a drastic increase of diseases, such as cancers, may occur. 8 In more than half of human cancers, mutations are located in the DBD portion; [9][10][11] this can strongly alter the capability of p53 to perform its tumour suppressive functions and sometimes leads p53 to acquire new functions, (gain-of-function, GOF) including transcriptional activation of different genes.…”