MicroRNAs at the Crossroad between Immunoediting and Oncogenic Drivers in Hepatocellular Carcinoma

Treatments aimed to reverse the tumor-induced immune tolerance represent a promising approach for advanced hepatocellular carcinoma (HCC). Notwithstanding, primary nonresponse, early, and late disease reactivation still represent major clinical challenges. Here, we focused on microRNAs (miRNAs) acting both as modulators of cancer cell hallmarks and immune system response. We outlined the bidirectional function that some oncogenic miRNAs play in the differentiation and program activation of the immune system development and, at the same time, in the progression of HCC. Indeed, the multifaceted spectrum of miRNA targets allows the modulation of both immune-associated factors and oncogenic or tumor suppressor drivers at the same time. Understanding the molecular changes contributing to disease onset, progression, and resistance to treatments might help to identify possible novel biomarkers for selecting patient subgroups, and to design combined tailored treatments to potentiate antitumor approaches. Preliminary findings seem to argue in favor of a bidirectional function of some miRNAs, which enact an effective modulation of molecular pathways driving oncogenic and immune-skipping phenotypes associated with cancer aggressiveness. The identification of these miRNAs and the characterization of their 'dual' role might help to unravel novel biomarkers identifying those patients more likely to respond to immune checkpoint inhibitors and to identify possible therapeutic targets with both antitumor and immunomodulatory functions. In the present review, we will focus on the restricted panel of miRNAs playing a bidirectional role in HCC, influencing oncogenic and immune-related pathways at once. Even though this field is still poorly investigated in HCC, it might represent a source of candidate molecules acting as both biomarkers and therapeutic targets in the setting of immune-based treatments

The nucleolar size is associated to the methylation status of ribosomal DNA in breast carcinomas.

BACKGROUND: There is a body of evidence that shows a link between tumorigenesis and ribosome biogenesis. The precursor of mature 18S, 28S and 5.8S ribosomal RNAs is transcribed from the ribosomal DNA gene (rDNA), which exists as 300-400 copies in the human diploid genome. Approximately one half of these copies are epigenetically silenced, but the exact role of epigenetic regulation on ribosome biogenesis is not completely understood. In this study we analyzed the methylation profiles of the rDNA promoter and of the 5' regions of 18S and 28S in breast cancer. METHODS: We analyzed rDNA methylation in 68 breast cancer tissues of which the normal counterpart was partially available (45/68 samples) using the MassARRAY EpiTYPER assay, a sensitive and quantitative method with single base resolution. RESULTS: We found that rDNA locus tended to be hypermethylated in tumor compared to matched normal breast tissues and that the DNA methylation level of several CpG units within the rDNA locus was associated to nuclear grade and to nucleolar size of tumor tissues. In addition we identified a subgroup of samples in which large nucleoli were associated with very limited or absent rDNA hypermethylation in tumor respect to matched normal tissue. CONCLUSIONS: In conclusion, we suggest that rDNA is an important target of epigenetic regulation in breast tumors and that rDNA methylation level is associated to nucleolar size

Dyskerin depletion increases VEGF mRNA internal ribosome entry site-mediated translation.

Dyskerin is a nucleolar protein encoded by the DKC1 gene that (i) stabilizes the RNA component of the telomerase complex, and (ii) drives the site-specific pseudouridilation of rRNA. It is known that the partial lack of dyskerin function causes a defect in the translation of a subgroup of mRNAs containing internal ribosome entry site (IRES) elements such as those encoding for the tumor suppressors p27 and p53. In this study, we aimed to analyze what is the effect of the lack of dyskerin on the IRES-mediated translation of mRNAs encoding for vascular endothelial growth factor (VEGF). We transiently reduced dyskerin expression and measured the levels of the IRES-mediated translation of the mRNA encoding for VEGF in vitro in transformed and primary cells. We demonstrated a significant increase in the VEGF IRES-mediated translation after dyskerin knock-down. This translational modulation induces an increase in VEGF production in the absence of a significant upregulation in VEGF mRNA levels. The analysis of a list of viral and cellular IRESs indicated that dyskerin depletion can differentially affect IRES-mediated translation. These results indicate for the first time that dyskerin inhibition can upregulate the IRES translation initiation of specific mRNAs

A statistical model predicting high hepatocyte proliferation index and the risk of developing hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis

none12noneAzzaroli F; Colecchia A; Lodato F; Trere D; Bacchi Reggiani ML; Festi D; Prati GM; Accogli E; Casanova S; Derenzini M; Roda E; Mazzella GAzzaroli F; Colecchia A; Lodato F; Trere D; Bacchi Reggiani ML; Festi D; Prati GM; Accogli E; Casanova S; Derenzini M; Roda E; Mazzella

Triple-negative breast cancer: investigating potential molecular therapeutic target

Introduction: Triple-negative breast cancer (TNBC) makes up about 10 - 20% of all breast cancers and the lack of hormone receptors and human epidermal growth factor receptor-2/Neu expression is responsible for poor prognosis, no targeted therapies and trouble in the clinical management. Tumor heterogeneity, also within the same tumor, is a major cause for this difficulty. Based on the introduction of new biological drugs against different kinds of tumor, many efforts have been made for classification of genetic alterations present in TNBC, leading to the identification of several oncogenes and tumor suppressor genes involved in breast cancer carcinogenesis. Areas covered: In this review we investigated the molecular alteration present in TNBC which could lead to the creation of new targeted therapies in the future, with the aim to counteract this disease in the most effective way. Expert opinion: In this context some hormone receptors like G-proteincoupled receptor 30 and androgen receptors may be a fascinating area to investigate; also, angiogenesis, represented not only by the classical VEGF/VEGFR relationship, but also by other molecules, like semaphorins, fibroblast growth factor and heparin-binding-EGF-like, is a mechanism in which new developments are expected. In this perspective, one technique that may show promise is the gene therapy; in particular the gene transfer could correct abnormal genetic function in cancer cells