Novel role of microRNA-126 in digestive system cancers: From bench to bedside

Abstract

MicroRNAs (miRNAs) are ubiquitously expressed, small, non-coding RNAs that regulate the expression of approximately 30% of the human genes at the post-transcriptional level. miRNAs have emerged as crucial modulators in the initiation and progression of various diseases, including numerous cancer types. The high incidence rate of cancer and the large number of cancer-associated cases of mortality are mostly due to a lack of effective treatments and biomarkers for early diagnosis. Therefore there is an urgent requirement to further understand the underlying mechanisms of tumorigenesis. MicroRNA-126 (miR-126) is significantly downregulated in a number of tumor types and is commonly identified as a tumor suppressor in digestive system cancers (DSCs). miR-126 downregulates various oncogenes, including disintegrin and metalloproteinase domain-containing protein 9, v-crk sarcoma virus CT10 oncogene homolog and phosphoinositide-3-kinase regulatory subunit 2. These genes are involved in a number of tumor-associated signaling pathways, including angiogenesis, epithelial-mensenchymal transition and metastasis pathways. The aim of the current review was to summarize the role of miR-126 in DSCs, in terms of its dysregulation, target genes and associated signaling pathways. In addition, the current review has discussed the potential clinical application of miR-126 as a biomarker and therapeutic target for DSCs.

Keywords: clinical applications; digestive system cancers; microRNA-126; signaling pathways; target genes.

Figure 1.

Origin and structure of miR-126/miR-126*. The EGFL7 gene consists of nine introns located on human chromosome 9. A pre-miR structure is located within intron 7 of the EGFL7 gene from which miR-126 and miR-126* originate. miR or miRNA, microRNA; *, passenger strand; EGFL7, epidermal growth factor-like domain 7.

Figure 2.

The signaling pathways, including Ras/ERK, PI3K/AKT/mTOR, ADAM9/EGFR/AKT, RhoA/ROCK and Wnt/β-catenin, modulated by miR-126 in digestive system cancer types. These signaling cascades are involved in the regulation of angiogenesis and vascular integrity, as well as cell proliferation, migration and invasion. miR-126, microRNA-126; ERK, extracellular signal-regulated kinase; PI3K, phosphatidylinositol-3-kinase; mTOR, mammalian target of rapamycin; ADAM9, disintegrin and metalloproteinase domain-containing protein 9; EGFR, epidermal growth factor receptor; RhoA, ras homology gene family, member A; ROCK, Rho-associated protein kinase; LRP5/6, low density lipoprotein receptor related protein 5/6; GSK3, glycogen synthase kinase 3; DVL, dishevelled; RGS3, regulator of G protein signaling 3; Gα13, G protein α13; GTP, guanosine 5′-triphosphate; GDP, guanosine 5′-diphosphate; SDF-1, stromal cell-derived factor-1; CXCR4, CXC chemokine receptor type 4; PI3KR2, phosphoinositide-3-kinase regulatory subunit 2; IRS-1, insulin receptor substrate 1; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; SPRED1, sprouty-related EVH1 domain-containing protein 1; MEK, mitogen-activated protein kinase; HIF1, hypoxia-inducible factor 1.