Role of miRNA-Regulated Cancer Stem Cells in the Pathogenesis of Human Malignancies

Abstract

Recent biomedical discoveries have revolutionized the concept and understanding of carcinogenesis, a complex and multistep phenomenon which involves accretion of genetic, epigenetic, biochemical, and histological changes, with special reference to MicroRNAs (miRNAs) and cancer stem cells (CSCs). miRNAs are small noncoding molecules known to regulate expression of more than 60% of the human genes, and their aberrant expression has been associated with the pathogenesis of human cancers and the regulation of stemness features of CSCs. CSCs are the small population of cells present in human malignancies well-known for cancer resistance, relapse, tumorigenesis, and poor clinical outcome which compels the development of novel and effective therapeutic protocols for better clinical outcome. Interestingly, the role of miRNAs in maintaining and regulating the functioning of CSCs through targeting various oncogenic signaling pathways, such as Notch, wingless (WNT)/β-Catenin, janus kinases/ signal transducer and activator of transcription (JAK/STAT), phosphatidylinositol 3-kinase/ protein kinase B (PI3/AKT), and nuclear factor kappa-light-chain-enhancer of activated B (NF-kB), is critical and poses a huge challenge to cancer treatment. Based on recent findings, here, we have documented the regulatory action or the underlying mechanisms of how miRNAs affect the signaling pathways attributed to stemness features of CSCs, such as self-renewal, differentiation, epithelial to mesenchymal transition (EMT), metastasis, resistance and recurrence etc., associated with the pathogenesis of various types of human malignancies including colorectal cancer, lung cancer, breast cancer, head and neck cancer, prostate cancer, liver cancer, etc. We also shed light on the fact that the targeted attenuation of deregulated functioning of miRNA related to stemness in human carcinogenesis could be a viable approach for cancer treatment.

Cancer Stem Cells Regulation with a Sublingual Nanotherapy using Ultra Low Doses of Non-Coding RNAs

“…Several lines of evidence have shown the critical roles of ncRNAs in CSCs biology [13][14][15][16][17][18][19][20][21][22]. Accumulating evidence has provided insights into the importance of ncRNAs as regulators in several critical steps of cancer development, such as carcinogenesis, cancer invasion, and metastasis.…”

“…On a general level, miRNAs are associated with tumor initiation and development through regulating CSC characteristics including the ability of self-renewal, drug resistance, and tumorigenicity as shown on ( Figure 6) [13]. Figure 6: miRNAs in regulating cancer stem cells characteristics Key microRNAs have been described to affect the main signaling pathways regulating CSCs.…”

“…It was for example showed that different microRNAs affect [14]: -Wnt signaling → for instance miR-600 or miR-217 -Notch signaling → miR-34a or miR-141 -Hedgehog signaling → miR-324-5p or miR-326 miRNAs are key intracellular regulators of gene expression and play roles in tumor initiation and distant metastasis via controlling CSCs properties. Some of these miRNAs have tumor suppressor properties, whereas others act as oncogenes [13]. For example, miR-15a, miR-16-1, miR-34, miR-200c, and let-7 act as tumor suppressor in various types of CSCs and are commonly downregulated in different cancers [15].…”

Role of cancer stem cells in the development of giant cell tumor of bone

“…MicroRNAs are classified as small noncoding, singlestranded RNA molecules that trigger degradation or inhibit the translation process in mRNA molecule which results in the de-regulation of their target genes. Moderate or comprehensive binding of miRNAs to the 3′-untranslated region (3′-UTR) of their target mRNAs actually represents their function in which these molecules block the translation or degrade the mRNA [64]. 114], [126,129], [141,142] osteoclastogenesis [64].…”

“…Moderate or comprehensive binding of miRNAs to the 3′-untranslated region (3′-UTR) of their target mRNAs actually represents their function in which these molecules block the translation or degrade the mRNA [64]. 114], [126,129], [141,142] osteoclastogenesis [64]. Recent reports show that miR-NAs are usually needed in the process of osteoclastogenesis, which helps the researchers to understand the blockage of V-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) and RANK expression by ectopic expression of miR-148a and miR-503, which in turn leads to the inhibition of osteoclast differentiation.…”