The Role of Non-coding RNAs in Oncology

Abstract

For decades, research into cancer biology focused on the involvement of protein-coding genes. Only recently was it discovered that an entire class of molecules, termed non-coding RNA (ncRNA), plays key regulatory roles in shaping cellular activity. An explosion of studies into ncRNA biology has since shown that they represent a diverse and prevalent group of RNAs, including both oncogenic molecules and those that work in a tumor suppressive manner. As a result, hundreds of cancer-focused clinical trials involving ncRNAs as novel biomarkers or therapies have begun and these are likely just the beginning.

Figure 1.. Oncogenic ncRNAs and cancer-promoting mechanisms.

Simplified examples of pathways towards oncogenesis for the different classes of ncRNAs discussed in the review. (A) miRNA: miR-155 directly targets and decreases expression of SHIP1, a hematopoietic cell-specific phosphatase that hydrolyzes phosphatidylinositol-3,4,5-triphosphate [PI(3,4,5)P₃] to phosphatidylinositol-3,4-bisphosphate [PI(3,4)P₂]. Decreased SHIP1 levels can drive AKT signaling, proliferation, and survival, leading to lymphoma. As represented in the figure, clinical trials with anti-miR-155 (NCT02580522/NCT03713320) are underway. (Therapeutic clinical trials targeting the other classes of ncRNAs have yet to be initiated, and are, thus, not depicted.) (B) tsRNA: LeuCAG3’tsRNA (abbreviated Leu3’ in the figure) directly binds and enhances translation of RPS15 and RPS28 transcripts by unfolding of their secondary structures. LeuCAG3’tsRNA can, therefore, increase the levels of these small ribosomal proteins and biogenesis of ribosomes, promoting proliferation of hepatocellular carcinoma cells. (C) lncRNA: IGF2BP1 is an RNA binding protein that forms a messenger ribonucleoprotein (mRNP) complex with other proteins. Interaction of the lncRNA THOR with IGF2BP1 within the mRNP complex leads to stabilization and increased translation of IGF2BP1 target mRNAs (represented by gray curved lines). These proteins (represented as different color ovals) include known oncogenes with wide-reaching effects that can lead to cancers such as melanoma. (D) pseudogene: BRAFP1 acts as a competitive endogenous RNA for BRAF by binding shared miRNAs. This leads to increased BRAF expression and downstream proliferative MAPK signaling that can drive cancers like lymphoma. (E) circRNA: circCTNNBI binds to DDX3 and increases its interaction with YY1 transcription factors, resulting in enhanced transactivation of YY1 target promoters. This includes promoters for many genes involved in Wnt/β-catenin signaling.

Figure 2.. Tumor suppressive ncRNAs and pathways inhibiting tumor progression.

Examples of ncRNAs that can function as tumor suppressors and representative functional mechanisms of inhibition. Examples of tumor suppressive tsRNAs have not yet been mechanistically detailed and are, thus, not included in this figure. (A) miRNA: Among the targets of miR-16-1 are several transcripts that encode cyclins and cyclin-dependent kinases important for the G₀/G₁-S phase transition of the cell cycle. Decreased expression of these cell cycle regulators can prevent cancer development, and the locus encoding miR-16-1 is often deleted in chronic lymphocytic leukemia. A recent clinical trial (NCT02369198) examined the effects of replenishing this tumor suppressive miRNA in malignant pleural mesothelioma and non-small cell lung cancer using a TargomiR strategy. (B) lncRNA: MEG3 enhances the stability of p53 by directly binding to the protein. MEG3 can also inhibit expression of MDM2, which results in stabilization of p53. Both of these pathways lead to increased p53 activity, inhibition of proliferation, and activation of apoptosis. (C) pseudogene: PTENP1 functions as a competitive endogenous RNA for PTEN by sponging shared miRNA, thereby increasing levels of PTEN. Elevated PTEN levels can cause inhibition of AKT signaling, activation of apoptosis, inhibition of proliferation, and prevent malignancies such as renal cell carcinoma. (D) circRNA: circHIPK3 is an example of a tumor suppressive circRNA that acts as a sponge for miRNA (miR-558 in particular). miR-558 has been suggested to associate with the HPSE (heparanase) promoter and increase expression of heparanase. Therefore, sponging of miR-558 by circHIPK3 decreases heparanase levels which in turn leads to decreased MMP9 and VEGF. These changes result in decreased invasion, migration, and angiogenesis and can inhibit bladder cancer progression.