SNPs in miRNAs and Target Sequences: Role in Cancer and Diabetes

Abstract

miRNAs are fascinating molecular players for gene regulation as individual miRNA can control multiple targets and a single target can be regulated by multiple miRNAs. Loss of miRNA regulated gene expression is often reported to be implicated in various human diseases like diabetes and cancer. Recently, geneticists across the world started reporting single nucleotide polymorphism (SNPs) in seed sequences of miRNAs. Similarly, SNPs are also reported in various target sequences of these miRNAs. Both the scenarios lead to dysregulated gene expression which may result in the progression of diseases. In the present paper, we explore SNPs in various miRNAs and their target sequences reported in various human cancers as well as diabetes. Similarly, we also present evidence of these mutations in various other human diseases.

Keywords: SNPs; cancer; diabetes mellitus; miRNA; microRNA; seed sequences; target genes.

FIGURE 1

SNPs reported in seed sequence of miRNA involved in cancer: miR-146 (rs2910164) targets include BRCA1, TRAF6, IRAKS, and NUMB gene and associated with cancer metastasis; miR-125a (rs1297533) found to be involved in invasion and metastasis and known targets include ERBB2, ERBB3, lin-40, and lin-28 gene; miR-499 (rs3746444) promotes invasion and inhibits cell apoptosis by targeting FOXO1A, FOXO4, PDCD4, PBX1, and SOX6 gene; miR-124 (rs34059726) has target genes DCC, CREB gene, and enhances invasion; miR-196-a2 (rs1614913) inhibits apoptosis and promotes invasion having target genes ANXA1 and HOX gene.

FIGURE 2

SNPs reported in 3′UTR region of the target gene involved in cancer: Due to SNPs in the BRCA gene (rs3092995, rs176318, rs12516) and RAD52 gene (rs7963551) binding site for miR-639, miR-1264, and miR-103 within BRCA and for let-7 within the RAD52 gene found to be disrupted and as tumor suppressor genes they promote cell apoptosis, decrease the DNA repair mechanism and maintain cell homeostasis; PALLD (rs1071738), IQGAP1 (rs1042538), ESR1 (rs9341070), and MDM4 (rs4245739) genes act as oncogenes and they are responsible for metastasis, cell migration, and invasion.

FIGURE 3

SNPs reported in seed sequence of miRNA involved in diabetes: (A) miR146a with SNP rs2910164 (C>G) raises vascular complications caused by upregulation of inflammatory factors (TNF associated factor 6 and IL1 associated kinase 1) in endothelial cells and induces apoptosis in pancreatic β-cells via NF-kB mediated pathway. (B) Reduced expression of miR499a due to SNP rs3746444 (A>G) provokes mitochondrial stress, impairs insulin signaling via PTEN mediated pathway, and promotes hepatic insulin resistance. (C) The miR124 rs34059726 (G>T) creates complimentary sequence for INSR; causing failure to transport GLUT4 transporter vesicle to outer membrane. This SNP also inhibits glycogenesis process via GSK-3β activation. (D) miR-3188 with rs7247237 (C>T) inhibits PI3K/AKT pathway dysregulating protein synthesis. Its target genes overexpression (GSTM1 and TRIB3) curtails nitric oxide pathway which increases vascular complications and induces β-cell apoptosis.

FIGURE 4

SNPs in 3′UTR of target genes associated with diabetes: (A) Downregulation of WFS1 due to SNPs rs1046322 (G>A) and rs9457 (G>C) via miRNAs miR185 and miR668 induces β-cell apoptosis and declines insulin secretion due to ER Ca⁺² stress. (B) SNP rs13702 (C>T) in LPL gene disrupts binding site for miR410. Its overexpression has pathological impact on liver and muscles leading to insulin resistance; whereas in adipose tissue it increases glucose metabolism. (C) SNP rs2229295 (C>A) of HNF1B creates new binding site for miR214-5p and miR550-5p, increasing glucose metabolism. (D) CDKN2B’s downregulation due to SNP rs1063192 (T>C) by miR323-5p maintains glucose homeostasis and promotes proliferation of β-cells. (E) Over-expression of FABP2 due to SNP rs11724758 (G>A) activates PPAR signaling pathway which in-turn leads to lipid metabolism.