Non-Coding RNAs in Cancer: Structure, Function, and Clinical Application

Abstract

We are on the brink of a paradigm shift in both theoretical and clinical oncology. Genomic and transcriptomic profiling, alongside personalized approaches that account for individual patient variability, are increasingly shaping discourse. Discussions on the future of personalized cancer medicine are mainly dominated by the potential of non-coding RNAs (ncRNAs), which play a prominent role in cancer progression and metastasis formation by regulating the expression of oncogenic or tumor suppressor proteins at transcriptional and post-transcriptional levels; furthermore, their cell-free counterparts might be involved in intercellular communication. Non-coding RNAs are considered to be promising biomarker candidates for early diagnosis of cancer as well as potential therapeutic agents. This review aims to provide clarity amidst the vast body of literature by focusing on diverse species of ncRNAs, exploring the structure, origin, function, and potential clinical applications of miRNAs, siRNAs, lncRNAs, circRNAs, snRNAs, snoRNAs, eRNAs, paRNAs, YRNAs, vtRNAs, and piRNAs. We discuss molecular methods used for their detection or functional studies both in vitro and in vivo. We also address the challenges that must be overcome to enter a new era of cancer diagnosis and therapy that will reshape the future of oncology.

Keywords: RNA; RNA detection; cancer; cancer diagnostics; cancer therapy; circRNA; lncRNA; miRNA; snRNA; snoRNA.

Figure 1

The role of various ncRNAs in the development of cancer. Non-coding RNAs influence the expression of proteins involved in pathways related to tumor progression at both transcriptional and post-transcriptional levels.

Figure 2

Methods for functional characterization of ncRNAs.

Figure 3

Summary of the clinical potential of ncRNAs. Some ncRNAs are promising biomarker candidates in cancer diagnostics in both tissue and liquid biopsy samples. Their application is also considered to be an effective tool in the personalized therapy of cancer by influencing the expression of proteins involved in cancer progression.

Figure 4

Molecular mechanisms of action of oncogenic and tumor suppressor miRNAs. (A) miR-21 has an oncogenic function by targeting PTEN, which supports cell proliferation [131]. (B) miR-200 family members are known tumor suppressors that inhibit epithelial–mesenchymal transition (EMT)-mediated tumor invasion by targeting ZEB1/2 [132].

Figure 5

Molecular mechanism of action of oncogenic and tumor suppressor lncRNAs. Long non-coding RNAs can exert their functions via DNA, protein, or RNA interactions. (A) The oncogenic REG1CP promotes tumorigenesis by forming an RNA–DNA triplex at the distal promoter region of REG3A, thus supporting its glucocorticoid receptor α (GRα)-mediated transcription by tethering FANCJ [194]. (B) DIRC3 is a nuclear-tumor-suppressor lncRNA that activates the expression of IGFBP5 by modulating chromatin structure and preventing SOX10 binding to the regulatory elements of the DIRC3 locus [198]. (C) HOTAIR effects its oncogenic potential by interacting with the androgen receptor (AR) protein, which blocks AR ubiquitination and leads to AR-mediated transcription [190]. (D) The tumor suppressor SATB2-AS1 serves as a scaffold for recruiting p300 protein, which promotes SATB2 transcription [195]. (E) MALAT1 exerts its oncogenic function by sponging miR-185-5p, which targets MDM4 [189]. (F) MEG3 acts as a tumor suppressor by sponging miR-708, leading to increased SOCS3 expression [201]. TSS: transcription start site.

Figure 6

Molecular mechanism of action of oncogenic and tumor suppressor circRNAs exerting their functions via protein and RNA interactions. (A) circ-CTNNB1 interacts with DDX3 protein, which facilitates its interaction with YY1 [220]. (B) circ-NOL10 inhibits cancer development by promoting the expression of SCML1 by inhibiting transcription factor ubiquitination. This affects the expression of humanin polypeptide (HN) family proteins [221]. (C) circ-FOXO3 exerts its oncogenic function by sponging miR-29a-3p, which leads to upregulation of SLC25A15 [222]. (D) circ-HIPK3 exerts its tumor suppressor function by suppressing heparanase expression by sponging miR-558. This prevents the transport of miR-558 to the nucleus, where it supports the transcription of HPSE [223].