Tumor Suppressor miRNA in Cancer Cells and the Tumor Microenvironment: Mechanism of Deregulation and Clinical Implications

Abstract

MicroRNAs (miRNAs) are noncoding RNAs that have been identified as important posttranscriptional regulators of gene expression. miRNAs production is controlled at multiple levels, including transcriptional and posttranscriptional regulation. Extensive profiling studies have shown that the regulation of mature miRNAs expression plays a causal role in cancer development and progression. miRNAs have been identified to act as tumor suppressors (TS) or as oncogenes based on their modulating effect on the expression of their target genes. Upregulation of oncogenic miRNAs blocks TS genes and leads to tumor formation. In contrast, downregulation of miRNAs with TS function increases the translation of oncogenes. Several miRNAs exhibiting TS properties have been studied. In this review we focus on recent studies on the role of TS miRNAs in cancer cells and the tumor microenvironment (TME). Furthermore, we discuss how TS miRNA impacts the aggressiveness of cancer cells, with focus of the mechanism that regulate its expression. The study of the mechanisms of miRNA regulation in cancer cells and the TME may paved the way to understand its critical role in the development and progression of cancer and is likely to have important clinical implications in a near future. Finally, the potential roles of miRNAs as specific biomarkers for the diagnosis and the prognosis of cancer and the replacement of tumor suppressive miRNAs using miRNA mimics could be promising approaches for cancer therapy.

Keywords: cancer; functional regulation; microRNA; tumor microenvironment; tumor suppressor miRNA.

Figure 1

Summary of the mechanism of TS miRNA regulation in cancer. The mechanism controlling TS miRNAs occurs at different steps in cancer, including transcriptional and posttranscriptional regulation. A variety of posttranscriptional regulation occurs in the miRNA biogenesis machinery, which affects the components of miRNA processing. miRNA processing of some TS miRNAs is regulated at multiple levels: at the gene level, through genetic mutations in the miRNA gene and in other components of miRNA processing, such Dorsha, Dicer, and TRBP, and in the binding site of miRNA targets and exportin-5. In XPO mutations, several TS miRNAs are downregulated in cancer, such as miR-200 and let-7. The miRNA transcripts are altered at transcription by several oncogenes, such Myc and TGFB, or by epigenetic modification. LIN 28 proteins specifically block the processing of the pre-miRNA of Let-7. Several studies have highlighted that Dicer downregulation in cancer is caused by several factors, such as somatic mutations, Tap63, miR-360, and miR-103/107. EGFR suppresses the maturation of specific TS miRNAs through phosphorylation of AGO2 and prevents the association of AGO2 with Dicer.

Figure 2

Illustration of cancer cells and the tumor microenvironment-deregulated TS miRNAs that lead to tumor development and progression. In the tumor microenvironment, miRNAs regulate the interaction between cancer cells and their surrounding microenvironment by targeting several genes involved in this interaction. Several TS miRNAs are deregulated in the tumor microenvironment; for example, miR-29 and mR-148 are both downregulated in CAFs, and this deregulation promotes cancer cell invasion and metastasis. These miRNAs have been found to negatively target several genes that are crucial in enhancing cancer metastasis, such DNMT1 for miR-148 and ANGPTL4, PDF, LOX, MMP9, VEGF-A for miR-29. Hypoxia in the tumor microenvironment has a protumorigenic role by altering the expression of TS miRNAs, such as miR-200, miR-34, miR-29 and miR-15/16. Inhibition of miR-200 can significantly increase the expression of Ets-1, resulting in the promotion of angiogenesis. HIF-1 is one of the most studied genes in hypoxia that plays a crucial role in the tumor microenvironment and has been associated with the downregulation of miRNAs. CAFs play an important role in cancer cells during initial cancer and metastasis processes. miR-320 is a TS miRNA that is known to play a part in transforming NFs to CAFs. miR-320 targets ETS2, a cancer-specific transcription factor, resulting in increased oncogenic secretome secretion, and this oncogenic secretome converts NFs to CAFs in the tumor microenvironment (97).