Insight toward the microRNA profiling of laryngeal cancers: Biological role and clinical impact

Head and neck squamous cell carcinoma (HNSCC), a heterogeneous disease arising from various anatomical locations including the larynx, is a leading cause of death worldwide. Despite advances in multimodality treatment, the overall survival rate of the disease is still largely dismal. Early and accurate diagnosis of HNSCC is urgently demanded in order to prevent cancer progression and to improve the quality of the patient’s life. Recently, microRNAs (miRNAs), a family of small non-coding RNAs, have been widely reported as new robust tools for prediction, diagnosis, prognosis, and therapeutic approaches of human diseases. Abnormally expressed miRNAs are strongly associated with cancer development, resistance to chemo-/radiotherapy, and metastatic potential through targeting a large variety of genes. In this review, we summarize on the recent reports that emphasize the pivotal biological roles of miRNAs in regulating carcinogenesis of HNSCC, particularly laryngeal cancer. In more detail, we report the characterized miRNAs with an evident either oncogenic or tumor suppressive role in the cancers. In addition, we also focus on the correlation between miRNA deregulation and clinical relevance in cancer patients. On the basis of intriguing findings, the study of miRNAs will provide a new great opportunity to access better clinical management of the malignancies

The role of miRNA in diagnostics

Whilst the promise of RNA interference (RNAi) continues to expand in the therapeutic environment, the utility of the endogenous RNAi mechanism, microRNAs (miRNA), in diagnostics has been proven with the successful commercialization of a biopsy assay for the identification of cancer of unknown primary origin (CUP). The implications and consequences in personalized medicine arising from this highly sensitive and specific approach are substantial, however, the true potential is only beginning to be understood, as reports of disease-specific miRNA signatures in circulating lymphocytes, blood plasma/ serum, lung sputum, saliva and urine have been described, even in diseases where no diagnostic tools exist. This review summarizes the various approaches in miRNA biomarker discovery in addition to key findings in the field with the highest potential for clinical development

Identification of Prognostic Cancer Biomarkers through the Application of RNA-Seq Technologies and Bioinformatics

MicroRNAs (miRNAs) are short single-stranded RNAs that function as the guide sequence of the post-transcriptional regulatory process known as the RNA-induced silencing complex (RISC), which targets mRNA sequences for degradation through complementary binding to the guide miRNA. Changes in miRNA expression have been reported as correlated with numerous biological processes, including embryonic development, cellular differentiation, and disease manifestation. In the latter case, dysregulation has been observed in response to infection by human papillomavirus (HPV), which has also been established as both oncogenic in cervical cancers and oropharyngeal cancers and favorable for overall patient survival after tumor formation. The identification of dysregulated miRNAs associated with both HPV infection and cancer survival requires large datasets of high-throughput sequencing data, which were obtained through The Cancer Genome Atlas. By analyzing this public data, we have identified a series of proposed mechanisms for cancer formation and survival that is mediated through the miRNA-RISC regulatory mechanism in response to HPV infection. We have also identified a diverse set of miRNA biomarkers that have been incorporated into linear expression-based risk signatures that are prognostic for overall patient survival after tumor diagnosis in HPV-related cancers. The tools that were used to identify both miRNA biomarkers and proposed targets in public datasets, such as The Cancer Genome Atlas, have since been incorporated into an web-accessible resource, OncomiR.org, to streamline the process of biomarker identification for the cancer research community

Micro-RNAs as diagnostic or prognostic markers in human epithelial malignancies

Micro-RNAs (miRs) are important regulators of mRNA and protein expression; the ability of miR expression profilings to distinguish different cancer types and classify their sub-types has been well-described. They also represent a novel biological entity with potential value as tumour biomarkers, which can improve diagnosis, prognosis, and monitoring of treatment response for human cancers. This endeavour has been greatly facilitated by the stability of miRs in formalin-fixed paraffin-embedded (FFPE) tissues, and their detection in circulation. This review will summarize some of the key dysregulated miRs described to date in human epithelial malignancies, and their potential value as molecular bio-markers in FFPE tissues and blood samples. There remain many challenges in this domain, however, with the evolution of different platforms, the complexities of normalizing miR profiling data, and the importance of evaluating sufficiently-powered training and validation cohorts. Nonetheless, well-conducted miR profiling studies should contribute important insights into the molecular aberrations driving human cancer development and progression

Human salivary microRNAs in Cancer

Circulating microRNAs (miRNAs) have emerged as excellent candidates for cancer biomarkers. Several recent studies have highlighted the potential use of saliva for the identification of miRNAs as novel biomarkers, which represents a great opportunity to improve diagnosis and monitor general health and disease. This review summarises the mechanisms of miRNAs deregulation in cancer, the value of targeting them with a therapeutic intention and the evidence of the potential clinical use of miRNAs expressed in saliva for the detection of different cancer types. We also provide a comprehensive review of the different methods for normalising the levels of specific miRNAs present in saliva, as this is a critical step in their analysis, and the challenge to validate salivary miRNAs as a reality to manage cancer patientsThe authors would like to thank the Eugenio Rodríguez Pascual Foundation and the Fundación Dexeus Salud de la Mujer, for supporting the authors’ studies in the field of salivary biomarkersS

Evaluation of the Expression of miR-486-3p, miR-548-3p, miR-561-5p and miR-509-5p in Tumor Biopsies of Patients with Oral Squamous Cell Carcinoma

Background and objective: Oral squamous cell carcinoma (OSCC) is the most common head and neck malignancy. Expression patterns of microRNAs (miRNAs) can direct us in identifying valuable biomarkers for the prognosis of different neoplasms. Inappropriate regulation of miRNAs during physiological procedures can result in malignancies including OSCC. The aim of the present study was to evaluate the expression of miR-486-3p, miR-561-5p, miR-548-3p, and miR-509-5p in tissue biopsy samples with and without OSCC. Materials and methods: This case-control study was conducted on 17 healthy and 17 OSCC tissue biopsy samples. The expression of miRNAs was assessed using quantitative real-time PCR (q-RT-PCR) after RNA extraction from normal and cancer tissues and cDNA synthesis. Results: The means of miRNA-486-3p, miR-561-5p, and miR-548-3p expression were significantly different between OSCC and control groups (p < 0.001), but there was no significant difference in means of miR-509-5p expression between OSCC and control groups (p = 0.179). Conclusions: The findings of this study revealed that the expression of miR-486-3p and miR-561-5p was significantly lower in cancer samples compared to normal tissue samples. On the other hand, miR-548-3p expression increased in the OSCC group compared to the control group

MicroRNA as Biomarkers in Cancer Diagnostics and Therapy

This Special Issue celebrates the 25th anniversary of the discovery of the first microRNA. The size of the microRNome and complexity of animal body plans and organ systems suggests a role for microRNAs in cell fate determination and differentiation. More than 2000 sequences have been proposed to represent unique microRNA genes in humans, with an increasing number of mechanistic roles identified in developmental, physiological, and pathological processes. Thus, dysregulation of a few key microRNAs can have a profound global effect on the gene expression and molecular programs of a cell. This great potential for clinical intervention has captured the interest and imagination of researchers in many fields. However, very few fields have been as prolific as the field of cancer research. This Special Issue provides but a glimpse of the large body of literature of microRNA biology in cancer research, containing 4 original research studies and 4 review articles that focus on specific hematologic or solid tumors in disease. Collectively, these articles highlight state-of-the-art approaches and methodologies for microRNA detection in tissue, blood, and other body fluids in a range of biomarkers applications, from early cancer detection to prognosis and treatment response. The articles also address some of the challenges regarding clinical implementation

Repression of Esophageal Neoplasia and Inflammatory Signaling by Anti-miR-31 Delivery In Vivo.

BACKGROUND: Overexpression of microRNA-31 (miR-31) is implicated in the pathogenesis of esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary zinc deficiency. Using a rat model that recapitulates features of human ESCC, the mechanism whereby Zn regulates miR-31 expression to promote ESCC is examined. METHODS: To inhibit in vivo esophageal miR-31 overexpression in Zn-deficient rats (n = 12-20 per group), locked nucleic acid-modified anti-miR-31 oligonucleotides were administered over five weeks. miR-31 expression was determined by northern blotting, quantitative polymerase chain reaction, and in situ hybridization. Physiological miR-31 targets were identified by microarray analysis and verified by luciferase reporter assay. Cellular proliferation, apoptosis, and expression of inflammation genes were determined by immunoblotting, caspase assays, and immunohistochemistry. The miR-31 promoter in Zn-deficient esophagus was identified by ChIP-seq using an antibody for histone mark H3K4me3. Data were analyzed with t test and analysis of variance. All statistical tests were two-sided. RESULTS: In vivo, anti-miR-31 reduced miR-31 overexpression (P = .002) and suppressed the esophageal preneoplasia in Zn-deficient rats. At the same time, the miR-31 target Stk40 was derepressed, thereby inhibiting the STK40-NF-κΒ-controlled inflammatory pathway, with resultant decreased cellular proliferation and activated apoptosis (caspase 3/7 activities, fold change = 10.7, P = .005). This same connection between miR-31 overexpression and STK40/NF-κΒ expression was also documented in human ESCC cell lines. In Zn-deficient esophagus, the miR-31 promoter region and NF-κΒ binding site were activated. Zn replenishment restored the regulation of this genomic region and a normal esophageal phenotype. CONCLUSIONS: The data define the in vivo signaling pathway underlying interaction of Zn deficiency and miR-31 overexpression in esophageal neoplasia and provide a mechanistic rationale for miR-31 as a therapeutic target for ESCC

Noncoding RNAs as Predictive Biomarkers of Therapeutic Response to Tyrosine Kinase Inhibitors in Metastatic Cancer

Since their discovery, noncoding RNAs have acquired extensive attention due to their eminent role in the regulation of gene expression and thus also in the pathogenesis of many diseases. Currently, strong evidence is showing that noncoding RNAs are integral parts of key cancer-related cellular pathways, and the deregulation of their levels is pathogenetic on one hand but feasible as a biomarker of pathogenesis itself on the other hand. In cancer, diagnosis, prognosis, and prediction of therapy outcome can be derived from levels of various noncoding RNAs. This chapter is focused on potential application of noncoding RNAs in prediction of therapeutic response to tyrosine kinase inhibitors commonly used as targeted therapy in a wide range of metastatic cancers