The Promising Role of miR-21 as a Cancer Biomarker and Its Importance in RNA-Based Therapeutics

Abstract

MicroRNAs are small noncoding transcripts that posttranscriptionally regulate gene expression via base-pairing complementarity. Their role in cancer can be related to tumor suppression or oncogenic function. Moreover, they have been linked to processes recognized as hallmarks of cancer, such as apoptosis, invasion, metastasis, and proliferation. Particularly, one of the first oncomiRs found upregulated in a variety of cancers, such as gliomas, breast cancer, and colorectal cancer, was microRNA-21 (miR-21). Some of its target genes associated with cancer are PTEN (phosphatase and tensin homolog), PDCD4 (programmed cell death protein 4), RECK (reversion-inducing cysteine-rich protein with Kazal motifs), and STAT3 (signal transducer activator of transcription 3). As a result, miR-21 has been proposed as a plausible diagnostic and prognostic biomarker, as well as a therapeutic target for several types of cancer. Currently, research and clinical trials to inhibit miR-21 through anti-miR-21 oligonucleotides and ADM-21 are being conducted. As all of the evidence suggests, miR-21 is involved in carcinogenic processes; therefore, inhibiting it could have effects on more than one type of cancer. However, whether miR-21 can be used as a tissue-specific biomarker should be analyzed with caution. Consequently, the purpose of this review is to outline the available information and recent advances regarding miR-21 as a potential biomarker in the clinical setting and as a therapeutic target in cancer to highlight its importance in the era of precision medicine.

Figure 1

The Genomic and Epigenomic Landscape of miR-21 (A) Genomic location of miR-21: miR-21 is located on chromosome 17 (17q.23.1) in the 10th intron of the TMEM49 gene precursor of the VMP1 protein. The site is recognized as a fragile site of the neuroblastoma histotype, where HPV16 integration events occur. (B) Epigenetic landscape of miR-21. H3K4me3 and H3K4m1 marks are associated with active transcription (in green), and chromatin immunoprecipitation sequencing (ChiP-seq) histograms (in blue) in the IMR90 cell line were retrieved from the Wash U Epigenome Browser (GRCh37). Chromatin marks such as H3K27me3 and H3K9me3 are completely absent from the miRNA promoter, whereas H3K4me3 and H3K4me1 marks, which are related to active transcription, are present on the promoter of miR-21. (C) Putative promoter region of miR-21 according to Fujita et al. (purple region). Transcription start sites for miR-21 described by Mudduluru et al. (blue arrow) and Fujita et al. (pink arrow) are found in the 10th intron of the VMP1 gene. Transcription start sites described by Cai et al. (orange arrow) and Löffler et al. (yellow arrow) are found on the 11th intron of the same gene. Transcription factor binding regions described by Fujita et al. at the putative promoter region are shown. The putative miRNA promoter region contains several binding sites for AP-1, Ets/PU.1, C/EBP, NFI, SRF, p53, and STAT3.

Figure 2

miR-21 Targets and Pathways Associated with the Hallmarks of Cancer The upregulation of miR-21 can lead to the downregulation of target genes involved in the carcinogenic process, such as SPRY2, PTEN, RECK, TIMP3, BCL2, and PDCD4. In addition, SPRY2 can negatively regulate the PI3K/AKT/mTOR and ERK/MAPK pathways by controlling the trafficking of EGFR and HER2 through the endosome and by inhibiting Raf1, respectively. Therefore, in its absence, uncontrolled proliferation is observed, but angiogenesis is suppressed. PTEN, another miR-21 target, can also control the PI3K/AKT/mTOR pathway by inhibiting AKT activation. In this case, AKT can inhibit FOXO3, which regulates cell survival, growth, and differentiation by inducing the expression of proapoptotic BCL2 family proteins and Fas and TRAIL ligands or by enhancing cyclin-dependent kinase inhibitors (CDKIs).^, Additionally, AKT can activate mTORC1 by the phosphorylation and inactivation of TSC2 or by the phosphorylation of PRAS40, which affects cell growth, proliferation, survival, and motility. Alternatively, RECK can negatively control two matrix metallopeptidases, MMP-2 and MMP-9, which inhibit angiogenesis and invasion.^, In addition, TIMP3 negatively regulates ADAM10 and ADAM17, two metalloproteinases that are upregulated in cancer, and receptor substrates such as Notch receptors, transforming growth factor β (TGF-β), HER2, HER4, and VEGFR2, among others. In contrast, BCL2 expression can be induced by miR-21 binding to its 3′ UTR, which decreases apoptosis and increases proliferation by dysregulating the BAX/BCL2 ratio. Finally, PDCD4, a miR-21 target, can interfere with JNK activation and lead to the upregulation of BLC2-like proteins and affect apoptosis, proliferation, and migration.

Figure 3

The Plausible Applications of miR-21 as a Diagnostic, Prognostic, and Predictive Biomarker in Several Types of Cancer Diagnostic biomarker applications (Dx) are shown in dark green and can be used in breast, pancreatic, colorectal, and prostate cancers. Plausible prognostic biomarkers are shown in light green, and their type is indicated by OS (overall survival), DFS (disease-free survival), BFS (biochemical-free survival), and RFS (recurrence-free survival). Prognosis parameters are found in breast, liver, lung, pancreatic, colorectal, and prostate cancers. Plausible predictive biomarkers are found in brain, breast, liver, ovarian, bladder, lung, pancreatic, and prostate cancers. The types of predictive biomarkers are also indicated in purple: TRAILR (tumor necrosis factor-related apoptosis-inducing ligand resistance), VM-26 R (teniposide resistance), PACR (paclitaxel resistance), TRAR (trastuzumab resistance), IFN-a/5-FY (interferon-α/5-fluorouracil resistance), DOXR (doxorubicin resistance), PRR (platinum resistance), GEMR (gemcitabine resistance).