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Laryngeal squamous cell cancer (LSCC) accounts for almost 25–30% of all head and neck squamous cell cancers and is clustered according to the affected districts, as this determines distinct tendency to recur and metastasize. A major role for numerous genetic alterations in driving the onset and progression of this neoplasm is emerging. However, major efforts are still required for the identification of molecular markers useful for both early diagnosis and prognostic definition of LSCC that is still characterized by significant morbidity and mortality. Non-coding RNAs appear the most promising as they circulate in all the biological fluids allowing liquid biopsy determination, as well as due to their quick and characteristic modulation useful for non-invasive detection and monitoring of cancer. Other critical aspects are related to recent progress in circulating tumor cells and DNA detection, in metastatic status and chemo-refractoriness prediction, and in the functional interaction of LSCC with chronic inflammation and innate immunity. We review all these aspects taking into account the progress of the technologies in the field of next generation sequencing.

Salivary gland cancer (SGC) is an uncommon and heterogeneous disease that accounts for around 8.5% of all head and neck cancers. MicroRNAs (miRNAs) consist of a class of highly conserved, short, single-stranded segments (18–25 nucleotides) of noncoding RNA that represent key gene-transcription regulators in physiological and pathological human conditions. However, their role in SGC development and progression is not completely clear. This review aims to compile and summarize the recent findings on the topic, focusing on the prognostic and diagnostic value of the major modulated and validated microRNAs in SGC. Their differential expression could possibly aid the clinician in delivering an early diagnosis, therapeutic strategy and precision medicine.

Colorectal cancer (CRC) is the third most deadly cancer worldwide, and inflammatory bowel disease (IBD) is one of the critical factors in CRC carcinogenesis. IBD is responsible for an unphysiological and sustained chronic inflammation environment favoring the transformation. MicroRNAs (miRNAs) belong to a class of highly conserved short single-stranded segments (18–25 nucleotides) non-coding RNA and have been extensively discussed in both CRC and IBD. However, the role of miRNAs in the development of colitis-associated CRC (CAC) is less clear. The aim of this review is to summarize the major upregulated (miR-18a, miR-19a, miR-21, miR-31, miR-155 and miR-214) and downregulated (miR-124, miR-193a-3p and miR-139-5p) miRNAs in CAC, and their roles in genes’ expression modulation in chronic colonic-inflammation-induced carcinogenesis, including programmed cell-death pathways. These miRNAs dysregulation could be applied for early CAC diagnosis, to predict therapy efficacy and for precision treatment.

BACKGROUND: This study aimed to characterize programmed death ligand-1 (PD-L1) expression and CD8(+) tumor-infiltrating lymphocytes (TILs) density, and their impact on survival in patients with surgically resected small-cell lung cancer (SCLC). METHODS: Fifty-six patients with surgically resected SCLC were included. PD-L1 protein expression and CD8(+) TILs were tested by immunohistochemistry. A meta-analysis of 15 articles with 1,505 patients that investigated the prevalence and prognostic significance of PD-L1 expression in SCLC was conducted. RESULTS: Twenty-two (39.3%) patients had positive PD-L1 protein expression and 42 (75.0%) had high CD8(+) TILs density. PD-L1 expression level was not associated with CD8(+) TILs density (P=0.528). No any association between clinicopathological features and PD-L1 expression level or CD8(+) TILs density was observed. Positive PD-L1 expression [hazard ratio (HR) =0.374, P=0.002] and high CD8(+) TILs density (HR =0.429, P=0.008) were independently associated with significantly longer overall survival (OS), which remain the statistical significance in multivariate analyses (P=0.007, P=0.002; respectively). Meta-analysis showed that the prevalence of positive PD-L1 expression was 0.35 [95% confidence interval (CI), 0.22–0.48] and positive PD-L1 expression was correlated with markedly longer OS (HR =0.61; 95% CI, 0.31–0.91) in patients with SCLC. CONCLUSIONS: The prevalence of PD-L1 expression in surgically resected SCLC is lower than that published for NSCLC. There was no association between PD-L1 expression or CD8(+) TILs density and clinicopathological parameters. PD-L1 expression and CD8(+) TILs density was independently correlated with better outcome in patients with SCLC.

Laryngeal cancer (LCa), a neoplasm of the head and neck region, is a leading cause of death worldwide. Surgical intervention remains the mainstay of LCa treatment, but a crucial point is represented by the possible nodal involvement. Therefore, it is urgently needed to develop biomarkers and therapeutic tools able to drive treatment approaches for LCa. In this study, we investigated deregulated microRNAs (miRNAs) in tissues from LCa patients with either lymph node metastases (N+) or not (N−). miRNA expression profiling was performed by a comprehensive PCR array and subsequent validation by RT-qPCR. Results showed a significant decrease of miR-449a expression in N+ compared to N− patients, and miR-133b down-modulation in LCa tissues compared to paired normal ones. Receiver operating characteristic (ROC) curve analysis revealed the potential diagnostic power of miR-133b for LCa detection. According to the validation results, we selected miR-449a for further in vitro studies. Ectopic miR-449a expression in the LCa cell line Hep-2 inhibited invasion and motility in vitro, slowed cell proliferation, and induced the downregulation of Notch1 and Notch2 as direct targets of miR-449a. Collectively, this study provides new promising biomarkers for LCa diagnosis and a new opportunity to use miR-449a for the treatment of nodal metastases in LCa patients., Graphical Abstract, The need to identify molecular markers for early detection of laryngeal cancer prompted Kawasaki et al. to define a miRNA signature of tumor transformation and spreading. They showed the diagnostic and predictive potential of miR-133b and miR-449a, respectively, and demonstrated miR-449a-mediated suppression of the metastatic factors Notch1 and Notch2.

// Donatella Malanga 1 , Carmela De Marco 1, 2 , Ilaria Guerriero 2 , Fabiana Colelli 2 , Nicola Rinaldo 2 , Marianna Scrima 1, 2 , Teresa Mirante 3 , Claudia De Vitis 7 , Pietro Zoppoli 2 , Michele Ceccarelli 1, 4 , Miriam Riccardi 1, 2 , Maria Ravo 5 , Alessandro Weisz 5 , Antonella Federico 6 , Renato Franco 7 , Gaetano Rocco 7 , Rita Mancini 8 , Antonia Rizzuto 3 , Elio Gulletta 9 , Gennaro Ciliberto 7 , Giuseppe Viglietto 1, 2 1 Dipartimento di Medicina Sperimentale e Clinica, Universita Magna Graecia, Catanzaro, Italy 2 Biogem scarl, Istituto di Ricerche Genetiche, Ariano Irpino (Avellino), Italy 3 Dipartimento di Scienze Mediche e Chirurgiche, Universita Magna Graecia, Catanzaro, Italy 4 Dipartimento di Scienze e Tecnologie, Universita del Sannio, Benevento, Italy 5 Dipartimento di Medicina e Chirurgia, Universita di Salerno, Baronissi, Italy 6 Dipartimento di Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita Federico II, Napoli, Italy 7 IRCCS Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, Italy 8 Dipartimento di Medicina Clinica e Molecolare, Universita di Roma “La Sapienza” Ospedale S. Andrea, Roma, Italy 9 Dipartimento di Scienze della Salute, Universita Magna Graecia, Catanzaro, Italy Correspondence to: Giuseppe Viglietto, e-mail: viglietto@unicz.it Keywords: NSCLC, tumor initiating cells, Akt1, IL-6, STAT3 Received: June 15, 2015 Accepted: September 09, 2015 Published: October 13, 2015 ABSTRACT Here we report that the PI3K/Akt1/IL-6/STAT3 signalling pathway regulates generation and stem cell-like properties of Non-Small Cell Lung Cancer (NSCLC) tumor initiating cells (TICs). Mutant Akt1, mutant PIK3CA or PTEN loss enhances formation of lung cancer spheroids (LCS), self-renewal, expression of stemness markers and tumorigenic potential of human immortalized bronchial cells (BEAS-2B) whereas Akt inhibition suppresses these activities in established (NCI-H460) and primary NSCLC cells. Matched microarray analysis of Akt1-interfered cells and LCSs identified IL-6 as a critical target of Akt signalling in NSCLC TICs. Accordingly, suppression of Akt in NSCLC cells decreases IL-6 levels, phosphorylation of IkK and IkB, NF-kB transcriptional activity, phosphorylation and transcriptional activity of STAT3 whereas active Akt1 up-regulates them. Exposure of LCSs isolated from NSCLC cells to blocking anti-IL-6 mAbs, shRNA to IL-6 receptor or to STAT3 markedly reduces the capability to generate LCSs, to self-renew and to form tumors, whereas administration of IL-6 to Akt-interfered cells restores the capability to generate LCSs. Finally, immunohistochemical studies in NSCLC patients demonstrated a positive correlative trend between activated Akt, IL-6 expression and STAT3 phosphorylation ( n = 94; p < 0.05). In conclusion, our data indicate that aberrant Akt signalling contributes to maintaining stemness in lung cancer TICs through a NF-kB/IL-6/STAT3 pathway and provide novel potential therapeutic targets for eliminating these malignant cells in NSCLC.

The aim of the present work was to identify protein tyrosine phosphatases (PTPs) as novel, candidate tumor suppressor genes in lung cancer. Among the 38 PTPs in the human genome that show specificity for phosphotyrosine, we identified six PTPs by quantitative RT-PCR whose mRNA expression levels were significantly down-regulated in lung cancer–derived cell lines (ie, PTPRE, PTPRF, PTPRU, PTPRK, PTPRD, and PTPN13). After validation in primary samples of non–small cell lung cancer (NSCLC), we selected PTPN13 for further studies. The results presented here demonstrate that PTPN13 is a candidate tumor suppressor gene that is frequently inactivated in NSCLC through the loss of either mRNA and protein expression (64/87, 73%) or somatic mutation (approximately 8%). Loss of PTPN13 expression was apparently due to the loss of one or both copies of the PTPN13 locus at 4q (approximately 26% double deletion and approximately 37% single deletion) but not to promoter methylation. Finally, the manipulation of PTPN13 expression in lung cancer cells (ie, NCI-H292, A549) demonstrated that PTPN13 negatively regulates anchorage-dependent and anchorage-independent growth in vitro and restrains tumorigenicity in vivo , possibly through the control of the tyrosine phosphorylation of both EGFR and HER2. In conclusion, the expression screening of PTPs in lung cancer reported here has identified PTPN13 as a novel candidate tumor suppressor in NSCLC whose loss increases signaling from epidermal growth factor receptor and HER2 tyrosine kinase receptors.

Loss of the PTEN tumor suppressor gene occurs frequently in non-small-cell lung carcinoma (NSCLC), although neither genetic alterations nor epigenetic silencing are significant predictors of PTEN protein levels. Since recent reports implicated neural precursor cell expressed, developmentally down-regulated 4-1 (NEDD4-1) as the E3 ubiquitin ligase that regulates PTEN stability, we investigated the role of NEDD4-1 in the regulation of PTEN expression in cases of NSCLC. Our findings indicate that NEDD4-1 plays a critical role in the development of NSCLC and provides novel insight on the mechanisms that contribute to inactivate PTEN in lung cancer. Immunohistochemical analysis on tissue microarrays containing 103 NSCLC resections revealed NEDD4-1 overexpression in 80% of tumors, which correlated with the loss of PTEN protein (n = 98; P < 0.001). Accordingly, adoptive NEDD4-1 expression in NSCLC cells decreased PTEN protein stability, whereas knock-down of NEDD4-1 expression decreased PTEN ubiquitylation and increased PTEN protein levels. In 25% of cases, NEDD4-1 overexpression was due to gene amplification at 15q21. In addition, manipulation of NEDD4-1 expression in different lung cell systems demonstrated that suppression of NEDD4-1 expression significantly reduced proliferation of NSCLC cells in vitro and tumor growth in vivo, whereas NEDD4-1 overexpression facilitated anchorage-dependent and independent growth in vitro of nontransformed lung epithelial cells that lack pRB and TP53 (BEAS-2B). NEDD4-1 overexpression also augmented the tumorigenicity of lung cancer cells that have an intact PTEN gene (NCI-H460 cells).