MicroRNA-128-3p-mediated depletion of Drosha promotes lung cancer cell migration.

Alteration in microRNAs (miRNAs) expression is a frequent finding in human cancers. In particular, widespread miRNAs down-regulation is a hallmark of malignant transformation. In the present report, we showed that the miR-128-3p, which is up-regulated in lung cancer tissues, has Drosha and Dicer, two key enzymes of miRNAs processing, as the main modulation targets leading to the widespread down-regulation of miRNA expression. We observed that the miRNAs downregulation induced by miR-128-3p contributed to the tumorigenic properties of lung cancer cells. In particular, miR-128-3p-mediated miRNAs down-regulation contributed to aberrant SNAIL and ZEB1 expression thereby promoting the epithelial-to-mesenchymal transition (EMT) program. Drosha also resulted to be implicated in the control of migratory phenotype as its expression counteracted miR-128-3p functional effects. Our study provides mechanistic insights into the function of miR-128-3p as a key regulator of the malignant phenotype of lung cancer cells. This also enforces the remarkable impact of Drosha and Dicer alteration in cancer, and in particular it highlights a role for Drosha in non-small-cell lung cancer cells migration.

MiRNA-513a-5p inhibits progesterone receptor expression and constitutes a risk factor for breast cancer: the hOrmone and Diet in the ETiology of breast cancer prospective study.

MicroRNAs (miRNAs) might be considered both predictors and players of cancer development. The aim of the present report was to investigate whether many years before the diagnosis of breast cancer miRNA expression is already disregulated. In order to test this hypothesis, we compared miRNAs extracted from leukocytes in healthy women who later developed breast cancer and in women who remain healthy during the whole 15-year follow-up time. Accordantly, we used a case-control study design nested in the hOrmone and Diet in the ETiology of breast cancer (ORDET) prospective cohort study addressing the possibility that miRNAs can serve as both early biomarkers and components of the hormonal etiological pathways leading to breast cancer development in premenopausal women. We compared leukocyte miRNA profiles of 191 incident premenopausal breast cancer cases and profiles of 191 women who remained healthy over a follow-up period of 20 years. The analysis identified 20 differentially expressed miRNAs in women candidate to develop breast cancer versus control women. The upregulated miRNAs, miR-513-a-5p, miR-513b-5p and miR-513c-5p were among the most significantly deregulated miRNAs. In multivariate analysis, miR-513a-5p upregulation was directly and statistically significant associated with breast cancer risk (OR = 1.69; 95% CI 1.08-2.64; P = 0.0293). In addition, the upregulation of miR-513-a-5p displayed the strongest direct association with serum progesterone and testosterone levels. The experimental data corroborated the inhibitory function of miR-513a-5p on progesterone receptor expression confirming that progesterone receptor is a target of miR-513a-5p. The identification of upregulated miR-513a-5p with its oncogenic potential further validates the use of miRNAs as long-term biomarker of breast cancer risk.

Oncogenic MicroRNAs: Key Players in Malignant Transformation.

MicroRNAs (miRNAs) represent a class of non-coding RNAs that exert pivotal roles in the regulation of gene expression at the post-transcriptional level. MiRNAs are involved in many biological processes and slight modulations in their expression have been correlated with the occurrence of different diseases. In particular, alterations in the expression of miRNAs with oncogenic or tumor suppressor functions have been associated with carcinogenesis, malignant transformation, metastasis and response to anticancer treatments. This review will mainly focus on oncogenic miRNAs whose aberrant expression leads to malignancy.

Epigenetic silencing of miR-145-5p contributes to brain metastasis.

Brain metastasis is a major cause of morbidity and mortality of lung cancer patients. We assessed whether aberrant expression of specific microRNAs could contribute to brain metastasis. Comparison of primary lung tumors and their matched metastatic brain disseminations identified shared patterns of several microRNAs, including common down-regulation of miR-145-5p. Down-regulation was attributed to methylation of miR-145's promoter and affiliated elevation of several protein targets, such as EGFR, OCT-4, MUC-1, c-MYC and, interestingly, tumor protein D52 (TPD52). In line with these observations, restored expression of miR-145-5p and selective depletion of individual targets markedly reduced in vitro and in vivo cancer cell migration. In aggregate, our results attribute to miR-145-5p and its direct targets pivotal roles in malignancy progression and in metastasis.

Risk of differentiated thyroid carcinoma and polymorphisms within the susceptibility cancer region 8q24.

BACKGROUND: Genome-wide association studies have shown that the 8q24 region harbours multiple independent cancer susceptibility loci and it was also defined as the "susceptibility cancer region." Thus, it could be hypothesized that genetic variants within this region could play a role in the risk of differentiated thyroid carcinoma (DTC). METHODS: Six single-nucleotide polymorphisms within 8q24 were analyzed, previously associated with the risk of cancer (i.e., rs6983267, rs1447295, rs10808556, rs7000448, rs13254738, and rs13281615) in a population of 1,250 patients affected by DTC and 1,250 controls from Central and Southern Italy. RESULTS: A strong association between smoking habit and risk of DTC was found [OR, 1.63; 95% confidence interval (CI), 1.39-1.91; P < 10(-6)]. The polymorphisms rs10808556 and rs1447295 showed an association with the risk of DTC (the strongest were the heterozygotes with OR, 1.38; 95% CI, 1.13-1.68 and OR, 1.35; 95% CI, 1.02-1.78, respectively), but, overall, they were unable to reach the statistically significant threshold following Bonferroni's correction. CONCLUSIONS: Present study suggested a limited involvement of polymorphisms within 8q24 region in relation to the risk of DTC in Central and Southern Italians. IMPACT: The exclusion of a relationship between DTC and 8q24 among Italians further highlights the tissue-specificity of this chromosomal segment in relation to human cancer and stresses the importance of other population-specific cofactors.