8 Frequent misregulation of miRNAs in numerous cancers supports the hypothesis that mutation of these miRNAs may be initiating events in cancer, and that specific miRNAs misregulated in each cancer type may act as biomarkers as well as potential targets for future novel therapies.9 As miRNAs regulate hundreds of messenger RNAs, mutations in the miRNA itself or in its binding site could be http://www.selleckchem.com/products/tofacitinib-cp-690550.html associated with malignant transformation or disease progression. Oncomirs, which are miRNAs associated with cancer, may function as oncogenes or tumor-suppressor genes. Tumor-suppressor genes include let-7 in lung cancer, mir-125b in breast cancer, and miR-15a in B-cell chronic lymphocytic leukemia.10 Oncogenes include miR-155 in breast cancer,11 miR-21 in glioblastoma,12 and miR-155 in Burkitt and Hodgkin lymphoma.

13 In addition, miRNAs have been found to predict prognosis and response to therapy.10,14 There is evidence that SNPs in miRNA binding sites can be associated with disease. For example, a point mutation identified in several Tourette syndrome patients in the 3��UTR of SLITRK1 disrupts the binding of miR-189.15 Supporting evidence was demonstrated by He and colleagues7 and Landi and associates who confirmed that allele frequencies in the 3��UTR of many genes vary between cancerous and normal samples. The miRNA let-7 family, which functions as a tumor suppressor, negatively regulates the RAS pathway and HMGA2.16 Deregulation of the let-7 family occurs in several cancers, including lung, colon, breast, ovarian, pancreatic, and prostate.

17 KRAS-Variant We previously identified a germline single nucleotide polymorphism (rs61764370 T > G) in the let-7 complementary site 6 in the KRAS 3��UTR region. To assess the impact of the KRAS-variant on KRAS expression, A549 cells, a lung cancer cell line, were transfected with a luciferase reporter containing the KRAS-variant in the KRAS 3��UTR and with a luciferase reporter containing the wild-type KRAS 3��UTR. There was increased KRAS expression in the cells transfected with the KRAS variant than in cells transfected with the wild-type KRAS 3��UTR. Therefore, the KRAS-variant disrupts the binding of let-7 to KRAS, leading to increased KRAS expression, and is associated with lower let-7 levels in tumors. The let-7 family of miRNAs acts as a tumor suppressor. It has been demonstrated in lung cancer that let-7 is reduced in cancer tissue, and RAS is elevated.

18 The KRAS-variant is found in 5.3% of the world��s population, and in 12% of white populations of European descent, based on the genotyping of more than 2500 samples representing 46 geographic populations.18 Moreover, in patients with a moderate smoking history, defined as < 41 pack years, the KRAS-variant was associated Entinostat with a 1.4- to 2.3-fold increased risk (odds ratio [OR] 1.4; 95% confidence interval [CI], 1.1-1.7; P = .01; OR 2.3; 95% CI, 1.1�C4.6; P = .02) of non-small cell lung cancer.