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Lung cancer remains one of the leading causes of cancer-related deaths worldwide. It is classified into two main histological groups: non-small cell lung cancer (NSCLC) and small cell lung cancer. Improving the outcome of cancer patients could be possible by enhancing the early diagnosis. In the current study, we evaluated the levels of three microRNAs - miR-21-5p, miR-155-5p, and miR-181a-5p in tumor (TT) vs adjacent normal tissue (NT), as well as their expression levels in plasma and extracellular vesicles (EVs) from plasma in lung squamous cell carcinoma (LUSC) male patients vs healthy individuals as means to identify a panel of miRNAs that could serve as novel biomarkers for the diagnosis of LUSC in male patients. Matched paired tissue samples from male LUSC (n=40) patients were used for miRNA expression analysis. MiR-21-5p and miR-155-5p in tumor tissue were overexpressed, while underexpression of miR-181a-5p was observed in LUSC TT vs NT. These results were further validated in the TCGA LUSC dataset, considering 279 male samples. These alterations of miR-21-5p, miR-181a-5p, and miR-155-5p in tumor tissue are also present in plasma and plasma extracellular vesicles in LUSC male patients. In addition, ROC curves were performed to assess the sensitivity and specificity of different combinations of these miRNAs, confirming a high diagnostic accuracy for LUSC of up to 88 % in male subjects. The expression levels in tissue samples and the abundance in plasma and plasma EVs of the three miRNAs combined - miR-21-5p, miR-155-5p and miR-181a-5p – could be considered for further studies on biomarkers for the early detection of LUSC in male subjects.

Most hepatocellular carcinomas (HCCs) arise in the context of chronic liver disease and/or cirrhosis. Thus, chemoprevention in individuals at risk represents an important but yet unproven approach. In this study, we investigated the ability of microRNA (miRNA)-based molecules to prevent liver cancer development in a cirrhotic model. To this end, we developed a mouse model able to recapitulate the natural progression from fibrosis to HCC, and then we tested the prophylactic activity of an miRNA-based approach in the model. The experiments were carried out in the TG221 transgenic mouse, characterized by the overexpression of miR-221 in the liver and predisposed to the development of liver tumors. TG221 as well as wild-type mice were exposed to the hepatotoxin carbon tetrachloride (CCl4) to induce chronic liver damage. All mice developed liver cirrhosis, but only TG221 mice developed nodular lesions in 100% of cases within 6 months of age. The spectrum of lesions ranged from dysplastic foci to carcinomas. To investigate miRNA-based prophylactic approaches, anti-miR-221 oligonucleotides or miR-199a-3p mimics were administered to TG221 CCl4-treated mice. Compared to control animals, a significant reduction in number, size, and, most significantly, malignant phenotype of liver nodules was observed, thus demonstrating an important prophylactic action of miRNA-based molecules. In summary, in this article, we not only report a simple model of liver cancer in a cirrhotic background but also provide evidence for a potential miRNA-based approach to reduce the risk of HCC development. Keywords: hepatocellular carcinoma, HCC, cirrhosis, carbon tetrachloride, CCl4, transgenic animals, microRNAs, prophylaxis

Summary: Endocrine therapy (ET) is the standard of care for estrogen receptor-positive (ER+) breast cancers. Despite its efficacy, ∼40% of women relapse with ET-resistant (ETR) disease. A global transcription analysis in ETR cells reveals a downregulation of the neutral and basic amino acid transporter SLC6A14 governed by enhanced miR-23b-3p expression, resulting in impaired amino acid metabolism. This altered amino acid metabolism in ETR cells is supported by the activation of autophagy and the enhanced import of acidic amino acids (aspartate and glutamate) mediated by the SLC1A2 transporter. The clinical significance of these findings is validated by multiple orthogonal approaches in a large cohort of ET-treated patients, in patient-derived xenografts, and in in vivo experiments. Targeting these amino acid metabolic dependencies resensitizes ETR cells to therapy and impairs the aggressive features of ETR cells, offering predictive biomarkers and potential targetable pathways to be exploited to combat or delay ETR in ER+ breast cancers. : Bacci et al. find that endocrine-resistant ER+ breast cancers are characterized by enhanced miR-23b-3p, autophagy activation, and import of aspartate and glutamate that fuel catabolic and anabolic pathways, which are essential for their aggressive features. The molecular players involved in this metabolic scenario are of clinical significance and have prognostic and predictive value. Keywords: endocrine therapy, resistance, metabolic reprogramming, estrogen receptor, amino acid transporters, aspartate, glutamate, miRNA, SLCs

Long noncoding RNAs (lncRNAs) significantly influence the development and regulation of genome expression in cells. Here, we demonstrate the role of lncRNA ceruloplasmin (NRCP) in cancer metabolism and elucidate functional effects leading to increased tumor progression. NRCP was highly upregulated in ovarian tumors, and knockdown of NRCP resulted in significantly increased apoptosis, decreased cell proliferation, and decreased glycolysis compared with control cancer cells. In an orthotopic mouse model of ovarian cancer, siNRCP delivered via a liposomal carrier significantly reduced tumor growth compared with control treatment. We identified NRCP as an intermediate binding partner between STAT1 and RNA polymerase II, leading to increased expression of downstream target genes such as glucose-6-phosphate isomerase. Collectively, we report a previously unrecognized role of the lncRNA NRCP in modulating cancer metabolism. As demonstrated, DOPC nanoparticle-incorporated siRNA-mediated silencing of this lncRNA in vivo provides therapeutic avenue toward modulating lncRNAs in cancer.