miR-199a: A Tumor Suppressor with Noncoding RNA Network and Therapeutic Candidate in Lung Cancer

Abstract

Lung cancer is the leading cause of cancer death worldwide. miR-199a, which has two mature molecules: miR-199a-3p and miR-199a-5p, plays an important biological role in the genesis and development of tumors. We collected recent research results on lung cancer and miR-199a from Google Scholar and PubMed databases. The biological functions of miR-199a in lung cancer are reviewed in detail, and its potential roles in lung cancer diagnosis and treatment are discussed. With miR-199a as the core point and a divergence outward, the interplay between miR-199a and other ncRNAs is reviewed, and a regulatory network covering various cancers is depicted, which can help us to better understand the mechanism of cancer occurrence and provide a means for developing novel therapeutic strategies. In addition, the current methods of diagnosis and treatment of lung cancer are reviewed. Finally, a conclusion was drawn: miR-199a inhibits the development of lung cancer, especially by inhibiting the proliferation, infiltration, and migration of lung cancer cells, inhibiting tumor angiogenesis, increasing the apoptosis of lung cancer cells, and affecting the drug resistance of lung cancer cells. This review aims to provide new insights into lung cancer therapy and prevention.

Keywords: drug resistance; glucose metabolism; interplay; lung cancer; miR-199a; non-coding RNAs.

Figure 1

Biogenesis and co-targeting of miR-199a. The gene encoding miR-199a in the nucleus is processed into pri-miRNA catalyzed by RNA poly Ⅱ. The pri-miRNA is then processed into a pre-miRNA by the shearing action of a complex composed of Drosha (a ribonuclease enzyme) and DGCR8 (Human Recombinant Protein (P01)). Pre-miRNA exits the nucleus into the cytoplasm with the help of Exportin 5 (Exporting protein 5) and Ran-GTP (Ras-like nuclear protein, GTPase). In the cytoplasm, Dicer (a ribonuclease enzyme) and TRBP (TAR-RNA binding protein) further process the pre-miRNA by excising the stem–loop structure at the end to form an unstable double-stranded RNA (dsRNA). DsRNA is unwound into single-stranded DNA by the action of Helicase, where one single strand is degraded and the other becomes a mature miRNA. The mature miRNA forms RISC (RNA-induced silencing complex) with TRBP, Argonaut protein and Dicer enzymes to perform biological functions.

Figure 2

The role of miR-199a in lung cancer and interplay with other ncRNAs. Promoter methylation and sponge adsorption of lncRNAs and circRNAs resulted in low expression levels of miR-199a. miR-199a acts as a tumor suppressor in lung cancer by targeting downstream genes. Overexpression of miR-199a could inhibit lung cancer cell proliferation, infiltration and migration, glycolytic pathway and tumor angiogenesis and increase lung cancer cell apoptosis. In some drug-resistant lung tumor cell lines, it also plays a sensitizing role.