miRNA on the Battlefield of Cancer: Significance in Cancer Stem Cells, WNT Pathway, and Treatment

Abstract

Carcinogenesis is a complex process characterized by intricate changes in organ histology, biochemistry, epigenetics, and genetics. Within this intricate landscape, cancer stem cells (CSCs) have emerged as distinct cell types possessing unique attributes that significantly contribute to the pathogenesis of cancer. The WNT signaling pathway plays a critical role in maintaining somatic stem cell pluripotency. However, in cancer, overexpression of WNT mediators enhances the activity of β-catenin, resulting in phenomena such as recurrence and unfavorable survival outcomes. Notably, CSCs exhibit heightened WNT signaling compared to bulk cancer cells, providing intriguing insights into their functional characteristics. MicroRNAs (miRNAs), as post-transcriptional gene expression regulators, modulate various physiological processes in numerous diseases including cancer. Upregulation or downregulation of miRNAs can affect the production of pro-oncogenic or anti-oncogenic proteins, influencing cellular processes that maintain tissue homeostasis and promote either apoptosis or differentiation, even in cancer cells. In order to understand the dysregulation of miRNAs, it is essential to examine miRNA biogenesis and any possible alterations at each step. The potential of a miRNA as a biomarker in prognosis, diagnosis, and detection is being assessed using technologies such as next-generation sequencing. Extensive research has explored miRNA expression profiles in cancer, leading to their utilization as diagnostic tools and the development of personalized and targeted cancer therapies. This review delves into the role of miRNAs in carcinogenesis in relation to the WNT signaling pathway along with their potential as druggable compounds.

Keywords: WNT signaling pathway; cancer stem cells; miRNA therapeutics; microRNA.

Figure 1

Transcription factors influencing the dysregulation of specific miRNAs resulting in a change in tumor cell properties. The up and down arrows are representative of the promotion and inhibition of the tumor cell property, respectively.

Figure 2

Normal process of miRNA biogenesis leading to translational inhibition, destabilization, or degradation of target mRNA.

Figure 3

Dysregulation of miRNA biogenesis resulting due to aberrant protein components of the miRNA biogenesis machinery. Aberrant proteins such as dysregulated WBP2, polyubiquitinated DDX17, mutated XPO5, and truncated DICER protein cause a reduction in processing of miRNA at various points in the biogenesis affecting their expression levels.

Figure 4

General overview of the WNT signaling pathway. The figure represents the WNT signaling pathway in the absence/presence of the WNT ligand. The absence of the WNT ligand causes the degradation of β-catenin via the destruction complex whereas in the presence of the WNT ligand, β-catenin activates the transcription of the WNT target genes.

Figure 5

miRNAs targeting different components of the WNT signaling pathway to promote tumorigenicity. The pro-oncogenic miRNAs like miR-92a, miR-217, miR-766, miR-1246, and miR-142 act on various levels of the WNT pathway to promote tumorigenicity. More commonly, these miRNAs negatively regulate the components of the destruction complex and WNT antagonists and promote WNT ligand production, thereby enabling the WNT signaling pathway.

Figure 6

miRNAs targeting different components of the WNT signaling pathway to inhibit tumorigenicity. The tumor suppressor miRNAs like miR-375, miR-148a, miR-133b, miR-506-3p, miR-137, miR-195, and miR-600 act on various levels of the WNT pathway to inhibit tumorigenicity. These miRNAs negatively regulate the WNT signaling pathway components such as the receptors, ligands, β-catenin, and transcription factors.