The role of immune response is emerging as a key factor in the complex multistep process of cancer. Tumor microenvironment contains different types of immune cells, which contribute to regulate the fine balance between anti and protumor signals. In this context, mechanisms of crosstalk between cancer and immune cells remain to be extensively elucidated. Interestingly, microRNAs (miRNAs) have been demonstrated to function as crucial regulators of immune response in both physiological and pathological conditions. Specifically, different miRNAs have been reported to have a role in controlling the development and the functions of tumor-associated immune cells. This review aims to describe the most important miRNAs acting as critical modulators of immune response in the context of different solid tumors. In particular, we discuss recent studies that have demonstrated the existence of miRNA-mediated mechanisms regulating the recruitment and the activation status of specific tumor-associated immune cells in the tumor microenvironment. Moreover, various miRNAs have been found to target key cancer-related immune pathways, which concur to mediate the secretion of immunosuppressive or immunostimulating factors by cancer or immune cells. Modalities of miRNA exchange and miRNA-based delivery strategies are also discussed. Based on these findings, the modulation of individual or multiple miRNAs has the potential to enhance or inhibit specific immune subpopulations supporting antitumor immune responses, thus contributing to negatively affect tumorigenesis. New miRNA-based strategies can be developed for more effective immunotherapeutic interventions in cancer.

DNA methylation has a substantial impact on gene expression, affecting the prognosis of breast cancer (BC) patients dependent on molecular subtypes. In this study, we investigated the prognostic relevance of the expression of genes reported as aberrantly methylated, and the link between gene expression and DNA methylation in BC subtypes. The prognostic value of the expression of 144 aberrantly methylated genes was evaluated in ER1/HER22, HER21, and ER2/HER22 molecular BC subtypes, in a meta-analysis of two large transcriptomic cohorts of BC patients (n 5 1,938 and n 5 1,640). The correlation between gene expression and DNA methylation in distinct gene regions was also investigated in an independent dataset of 104 BCs. Survival and Pearson correlation analyses were computed for each gene separately. The expression of 48 genes was significantly associated with BC prognosis (p < 0.05), and 32 of these prognostic genes exhibited a direct expression-methylation correlation. The expression of several immune-related genes, including CD3D and HLA-A, was associated with both relapse-free survival (HR 5 0.42, p 5 3.5E-06; HR 5 0.35, p 5 1.7E-08) and overall survival (HR 5 0.50, p 5 5.5E-04; HR 5 0.68, p 5 4.5E-02) in ER-/HER2-BCs. On the overall, the distribution of both positive and negative expression-methylation correlation in distinct gene regions have different effects on gene expression and prognosis in BC subtypes. This large-scale metaanalysis allowed the identification of several genes consistently associated with prognosis, whose DNA methylation could represent a promising biomarker for prognostication and clinical stratification of patients with distinct BC subtypes.Breast cancer (BC) represents a heterogeneous disease, which includes several subtypes with different molecular and clinical features. 1 Distinct gene pathways, genomic aberrations, and gene expression profiles have been associated with pathological processes and prognosis in different BC subtypes. 1-4 Epigenetic alterations have recently emerged as a common hallmark of human cancer, including BC. 5,6 In particular, DNA methylation, which most frequently occurs at CpG dinucleotides, has been associated with clinicopathological features of BC patients, such as tumor stage, histological grade, and TP53 status. 7-10 Furthermore, DNA hypomethylation and hypermethylation can influence BC progression and prognosis, contributing to the overexpression of oncogenes and downregulation of tumor suppressor genes, respectively. 5

MicroRNAs (miRNAs) represent a class of small, non-coding RNAs that control gene expression by targeting mRNA and triggering either translational repression or RNA degradation. The objective of our study was to evaluate the involvement of miRNAs in human medullary thyroid carcinoma (MTC) and to identify the markers of metastatic cells and aggressive tumour behaviour. Using matched primary and metastatic tumour samples, we identified a subset of miRNAs aberrantly regulated in metastatic MTC. Deregulated miRNAs were confirmed by quantitative real-time PCR and validated by in situ hybridisation on a large independent set of primary and metastatic MTC samples. Our results uncovered ten miRNAs that were significantly expressed and deregulated in metastatic tumours: miR-10a, miR-200b/-200c, miR-7 and miR-29c were down-regulated and miR-130a, miR-138, miR-193a-3p, miR-373 and miR-498 were up-regulated. Bioinformatic approaches revealed potential miRNA targets and signals involved in metastatic MTC pathways. Migration, proliferation and invasion assays were performed in cell lines treated with miR-200antagomirs to ascertain a direct role for this miRNA in MTC tumourigenesis. We show that the members of miR-200 family regulate the expression of E-cadherin by directly targeting ZEB1 and ZEB2 mRNA and through the enhanced expression of tumour growth factor b (TGFb)-2 and TGFb-1.Overall, the treated cells shifted to a mesenchymal phenotype, thereby acquiring an aggressive phenotype with increased motility and invasion. Our data identify a robust miRNA signature associated with metastatic MTC and distinct biological processes, e.g., TGFb signalling pathway, providing new potential insights into the mechanisms of MTC metastasis.