Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies with a high incidence and mortality rate. An essential challenge in colorectal cancer management is to identify new prognostic factors that could better estimate the evolution and treatment responses of this disease. Considering their role in cancer development, progression and metastasis, miRNAs have become an important class of molecules suitable for cancer biomarkers discovery. We performed a systematic search of studies investigating the role of miRNAs in colorectal progression and liver metastasis published until October 2018. In this review, we present up-to-date information regarding the specific microRNAs involved in CRC development, considering their roles in alteration of Wnt/βcatenin, EGFR, TGFβ and TP53 signaling pathways. We also emphasize the role of miRNAs in controlling the epithelial–mesenchymal transition of CRC cells, a process responsible for liver metastasis in a circulating tumor cell-dependent manner. Furthermore, we discuss the role of miRNAs transported by CRC-derived exosomes in mediating liver metastases, by preparing the secondary pre-metastatic niche and in inducing liver carcinogenesis in a Dicer-dependent manner.

BackgroundAdvanced squamous cervical cancer, one of the most commonly diagnosed cancers in women, still remains a major problem in oncology due to treatment failure and distant metastasis. Antitumor therapy failure is due to both intrinsic and acquired resistance; intrinsic resistance is often decisive for treatment response. In this study, we investigated the specific pathways and molecules responsible for baseline therapy failure in locally advanced squamous cervical cancer.MethodsTwenty-one patients with locally advanced squamous cell carcinoma were enrolled in this study. Primary biopsies harvested prior to therapy were analyzed for whole human gene expression (Agilent) based on the patient’s 6 months clinical response. Ingenuity Pathway Analysis was used to investigate the altered molecular function and canonical pathways between the responding and non-responding patients. The microarray results were validated by qRT-PCR and immunohistochemistry. An additional set of 24 formalin-fixed paraffin-embedded cervical cancer samples was used for independent validation of the proteins of interest.ResultsA 2859-gene signature was identified to distinguish between responder and non-responder patients. ‘DNA Replication, Recombination and Repair’ represented one of the most important mechanisms activated in non-responsive cervical tumors, and the ‘Role of BRCA1 in DNA Damage Response’ was predicted to be the most significantly altered canonical pathway involved in intrinsic resistance (p = 1.86E-04, ratio = 0.262). Immunohistological staining confirmed increased expression of BRCA1, BRIP1, FANCD2 and RAD51 in non-responsive compared with responsive advanced squamous cervical cancer, both in the initial set of 21 cervical cancer samples and the second set of 24 samples.ConclusionsOur findings suggest that FA/BRCA pathway plays an important role in treatment failure in advanced cervical cancer. The assessment of FANCD2, RAD51, BRCA1 and BRIP1 nuclear proteins could provide important information about the patients at risk for treatment failure.

Melanoma represents the most aggressive skin cancer, with an unpredictable and often treatment resistant behavior. The etiology of melanoma is multifactorial and includes both environmental and genetic factors. Recent evidence indicates that vitamin D has a role in the development and progression of melanoma. The biologically active form of vitamin D/1,25-dihydroxyvitamin D3 acts by binding to a intranuclear receptor; vitamin D receptor (VDR). Single nucleotide polymorphisms (SNPs) in the vitamin D receptor gene may alter the expression or the function of the VDR protein leading to various diseases, including melanoma. More than 600 SNPs have been identified in the VDR gene, but only a few have been analyzed in relation to melanoma risk: FokI, TaqI, BsmI, ApaI, Cdx2, EcoRV, and BglI. Individual studies carried on small cohorts of patients reported controversial results. In an attempt to clarify the available data in the literature on this subject, we elaborated a systematic review in which we analyzed the relationship between VDR gene polymorphisms and melanoma risk and progression. We concluded that vitamin D pathway is important for the pathogenesis and the progression of cutaneous melanoma, illustrating the gene-environment interactions, but well-designed prospective studies that include data on both genotypes and phenotypes of vitamin D metabolism are essential in order to understand the mechanisms underlying the association between vitamin D and melanoma.

Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are classical myeloproliferative neoplasms (MPN), characterized by specific somatic mutations in JAK2, CALR or MPL genes. JAK2 46/1 and TERT rs2736100 polymorphisms are known to significantly predispose to MPN. This study aimed to establish the additional contribution of the recently described MECOM rs2201862, HBS1L-MYB rs9376092 and THRB-RARB rs4858647 polymorphisms to the occurrence of MPN. These three polymorphisms, along with JAK2 46/1 and TERT rs2736100 were genotyped in 939 MPN patients (454 with ET, 337 with PV and 148 with PMF) and 483 controls. MECOM rs2201862 associated significantly with each MPN entity, except for ET, and with all major molecular sub-types, especially those CALR-mutated (OR = 1.4; 95% CI = 1.1-1.8; P-value = .005). HBS1L-MYB rs9376092 associated only with JAK2 V617F-mutated ET (OR = 1.4; 95% CI = 1.1-1.7; P-value = .003). THRB-RARB rs4858647 had a weak association with PMF only (OR = 1.5; 95% CI = 1-2.1; P-value = .04). Surprisingly, JAK2 46/1 haplotype was associated significantly not only with JAK2 V617F-mutated MPN, but also with CALR-mutated MPN (OR = 1.4; 95% CI = 1.1-1.8; P-value = .01). TERT rs2736100 was associated equally strong with all MPN, regardless of phenotype or molecular sub-type. In conclusion, JAK2 46/1, TERT rs2736100 and MECOM rs2201862 are the chief predisposing polymorphisms to MPN.