MicroRNA‑21: A potential therapeutic target in lung cancer (Review)

Abstract

In this review, the role of microRNA‑21 (miRNA‑21) as an oncogene in lung cancer was investigated. Studies have shown that miRNA‑21 can promote the progression of lung cancer by targeting downstream target genes, and its expression can be modulated by transcription factors, DNA methylation or competitive endogenous RNA as an upstream regulator. This review highlights that miRNA‑21 can promote the progression of lung cancer through multiple signaling pathways, with a focus on the PI3K/AKT, MEK/ERK, TGF‑β/SMAD, Hippo, NF‑κB and STAT3 signaling pathways. Mechanistically, miRNA‑21 plays an important role in the progression of lung cancer by regulating multiple biological processes, such as proliferation, invasion, metastasis, apoptosis and angiogenesis in lung cancer cells. Higher expression of miRNA‑21 is associated with chemotherapy, radiotherapy and immune resistance in lung cancer. Targeting these molecular pathways may be a novel therapeutic strategy for treating lung cancer. Additionally, miRNA‑21 can serve as a biomarker for lung cancer diagnosis, prognosis and treatment response. This review also summarized the following: i) Current methods employed to inhibit the expression of miRNA‑21 in lung cancer, including CRISPR/Cas9 technology; ii) the application of natural anticancer agents, oligonucleotides, small molecules and miRNA sponges; and iii) the nano‑delivery systems developed for miRNA‑21 inhibitors. Finally, the advancements in research on miRNA mimics and inhibitors in clinical trials, which may promote the application of miRNA‑21 in clinical trials in lung cancer, were discussed. Given that lung cancer is a considerable public health challenge, these studies provide new ways of treating patients with lung cancer.

Keywords: biomarker; chemotherapy; lung cancer; miRNA‑21; proliferation; target.

Figure 1

Biosynthesis and regulation of the expression of miRNA-21. First, in the nucleus, the miRNA-21 gene is transcribed into pri-miRNA-21 in response to RNA Pol II. Pri-miRNA-21 is further processed into Pre-miRNA-21 via the Drosha enzyme-Dgcr8 complex. Pre-miRNA-21 is transported to the cytoplasm by Exportin-5. In the cytoplasm, Pre-miRNA-21 is discern and cleaved by the TRBP and Dicer enzyme into mature double-stranded miRNA-21, which is ~22 nucleotides in length. One strand (the guide strand) in the mature double-stranded miRNA-21 is subsequently loaded into the Argonaute protein to form an RISC that binds to the 3′-UTR of the target gene mRNA through sequence complementation. The target gene mRNA degrades if perfectly bound, whereas translational repression occurs if it is bound imperfectly. Pri-miRNA-21, primary microRNA-21; Pre-miRNA-21, precursor miRNA-21; RISC, RNA-induced silencing complex; RNA Pol, RNA polymerase; TRBP, trans-activation response RNA-binding protein.

Figure 2

MiRNA-21 targets downstream target genes to regulate PI3K/AKT, MEK/ERK, TGF-β/SMAD, Hippo, NF-κB and STAT3 pathways, which in turn promote the progression of lung cancer. MiRNA-21, microRNA-21. PTEN, phosphatase and tensin homolog; ASPP2, apoptosis stimulating protein 2 of p53; PDCD4, programmed cell death factor 4; SMAD7, Sma and Mad-related protein 7; KIBRA, kidney and brain expressed protein.

Figure 3

MiRNA-21 can promote lung cancer progression by directly targeting downstream target genes. However, miRNA-21 is regulated by a variety of lncRNAs and circRNAs that affect the expression of miRNA-21 or downstream target genes, which in turn regulates lung cancer progression. MiRNA-21, microRNA-21; circRNA, circular RNA; lncRNA, long non-coding RNA. LncRNA CASC2, lncRNA cancer susceptibility candidate 2; lncRNA PLAC2, lncRNA cancer susceptibility candidate 2; lncRNA GAS5, lncRNA growth arrest-specific transcript 5; LncRNA Erbb4-IR, LncRNA Erb-B2 receptor tyrosine kinase 4 IR; lncRNA ASBEL, lncRNA anti-sense transcript of BTG3 (B-cell translocation gene 3); PTEN, phosphatase and tensin homolog; RECK, reversion inducing cysteine rich protein with kazal motifs; IRF1, interferon-regulatory factors 1; HMSH2, human mutS homolog 2; ADSL, adenylosuccinate lyase; PDCD4, programmed cell death factor 4; LZTFL1, leucine zipper transcription factor-like 1; ASPP2, apoptosis stimulating protein 2 of p53.