MicroRNA-1: Diverse role of a small player in multiple cancers

Abstract

The process of cancer initiation and development is a dynamic and complex mechanism involving multiple genetic and non-genetic variations. With the development of high throughput techniques like next-generation sequencing, the field of cancer biology extended beyond the protein-coding genes. It brought the functional role of noncoding RNAs into cancer-associated pathways. MicroRNAs (miRNAs) are one such class of noncoding RNAs regulating different cancer development aspects, including progression and metastasis. MicroRNA-1 (miR-1) is a highly conserved miRNA with a functional role in developing skeletal muscle precursor cells and cardiomyocytes and acts as a consistent tumor suppressor gene. In humans, two discrete genes, MIR-1-1 located on 20q13.333 and MIR-1-2 located on 18q11.2 loci encode for a single mature miR-1. Downregulation of miR-1 has been demonstrated in multiple cancers, including lung, breast, liver, prostate, colorectal, pancreatic, medulloblastoma, and gastric cancer. A vast number of studies have shown that miR-1 affects the hallmarks of cancer like proliferation, invasion and metastasis, apoptosis, angiogenesis, chemosensitization, and immune modulation. The potential therapeutic applications of miR-1 in multiple cancer pathways provide a novel platform for developing anticancer therapies. This review focuses on the different antitumorigenic and therapeutic aspects of miR-1, including how it regulates tumor development and associated immunomodulatory functions.

Keywords: Cancer therapeutics; Chemosensitivity; Immunoregulation; MiR-1; MiRNAs.

Figure 1:

Gene tree representing the alignment of human MIR-1–1 and MIR-1–2 gene with other species. The gene tree analysis showed the conserved pattern of miR-1 across the species. Gene tree was created using Ensembl genome database (Ensemble archives103) [180].

Figure 2:. Mechanism of miR-1 biogenesis and common mechanism of action.

In case of humans, two discrete genes, MIR1–1 located on 20q13.333 and MIR1–2 located on 18q11.2 loci encode for a single mature miR-1. The initial stem loop or primary miR-1–1/miR-1–2 (pri-miR-1–1/pri-miR-1–2) were transcribed by RNA-polymerase II and DROSHA processed them into pre-miR-1–1 or pre-miR-1–2. The pre-miR-1 sequences then transported from the nucleus through exportin-5. Reaching out form the nucleus to cytoplasm, the pre-miR-1 sequences were processed by DICER and a single mature miR-1 was generated from both types of pre-sequences. The mature miR-1 was loaded to AGO2 that form miR-1-RISC complex for specific gene targeting or translation inhibition.

Figure 3:. Schematic illustrations for miR-1 modulated cancer associated signaling pathways and other targets.

MiR-1 downregulation is implicated in the various oncogenic signaling pathways, and overexpression of miR-1 or miR-1-RISC complex decreases/inhibited the activation of transcription factors or other protein molecules in multiple pathways associated with cancer cell proliferation, cell-growth, survival, angiogenesis, metastasis, metabolism (aerobic glycolysis), and autophagy mediated networks.