Midsize noncoding RNAs in cancers: a new division that clarifies the world of noncoding RNA or an unnecessary chaos?

Most of the human genome is made out of noncoding RNAs (ncRNAs). These ncRNAs do not code for proteins but carry a vast number of important functions in human cells such as: modification and processing other RNAs (tRNAs, rRNAs, snRNAs, snoRNAs, miRNAs), help in the synthesis of ribosome proteins, initiation of DNA replication, regulation of transcription, processing of pre-messenger mRNA during its maturation and much more. The ncRNAs also have a significant impact on many events that occur during carcinogenesis in cancer cells, such as: regulation of cell survival, cellular signaling, apoptosis, proliferation or even influencing the metastasis process. The ncRNAs may be divided based on their length, into short and long, where 200 nucleotides is the “magic” border. However, a new division was proposed, suggesting the creation of the additional group called midsize noncoding RNAs, with the length ranging from 50–400 nucleotides. This new group may include: transfer RNA (tRNA), small nuclear RNAs (snRNAs) with 7SK and 7SL, small nucleolar RNAs (snoRNAs), small Cajal body-specific RNAs (scaRNAs) and YRNAs. In this review their structure, biogenesis, function and influence on carcinogenesis process will be evaluated. What is more, a question will be answered of whether this new division is a necessity that clears current knowledge or just creates an additional misunderstanding in the ncRNA world

Biological role of long non-coding RNA in head and neck cancers

AimHead and neck squamous cell carcinoma (HNSCC) are one of the worst prognosis cancers with high mortality of patients. The treatment strategy is primarily based on surgery and radiotherapy but chemotherapy is also used. Every year the knowledge concerning HNSCC biology is updated with new elements such as the recent discovered molecules – long non-coding RNAs. Long non-coding RNAs are involved in regulatory processes in the cells. It has been revealed that the expression levels of lncRNAs are disturbed in tumor cells what results in the acquisition of their specific phenotype. lncRNAs influence cell growth, cell cycle, cell phenotype, migration and invasion ability as well as apoptosis. Development of the lncRNA panel characteristic for HNSCC and validation of specific lncRNA functions are yet to be elucidated. In this work, we collected available data concerning lncRNAs in HNSCC and characterized their biological role. We believe that the tumor examination, in the context of lncRNA expression, may lead to understanding complex biology of the cancer and improve therapeutic methods in the future

Host gene and its guest: short story about relation of long-noncoding MIR31HG transcript and microRNA miR-31

Epigenetics is the changes in a cellular phenotype without changes in the genotype. This term is not limited only to the modification of chromatin and DNA but also relates to some RNAs, like non-coding RNAs (ncRNAs), both short and long RNAs (lncRNAs) acting as molecular modifiers. Mobile RNAs, as a free form or encapsulated in exosomes, can regulate neighboring cells or be placed in distant locations. It underlines the vast capacity of ncRNAs as epigenetic elements of transmission information and message of life. One of the amazing phenomena is long non-coding microRNA-host-genes (lnc-MIRHGs) whose processed transcripts function as lncRNAs and also as short RNAs named microRNAs (miRNAs). MIR31HG functions as a modulator of important biological and cellular processes including cell proliferation, apoptosis, cell cycle regulation, EMT process, metastasis, angiogenesis, hypoxia, senescence, and inflammation. However, in most cases, the role of MIR31HG is documented only by one study and there is a lack of exact description of molecular pathways implicated in these processes, and for some of them, such as response to irradiation, no studies have been done. In this review, MIR31HG, as an example of lnc-MIRHGs, was described in the context of its known function and its potential uses as a biomarker in oncology

Good or not good: Role of miR-18a in cancer biology

miR-18a is a member of primary transcript called miR-17-92a (C13orf25 or MIR17HG) which also contains five other miRNAs: miR-17, miR-19a, miR-20a, miR-19b and miR-92a. This cluster as a whole shows specific characteristics, where miR-18a seems to be unique. In contrast to the other members, the expression of miR-18a is additionally controlled and probably functions as its own internal controller of the cluster. miR-18a regulates many genes involved in proliferation, cell cycle, apoptosis, response to different kinds of stress, autophagy and differentiation. The disturbances of miR-18a expression are observed in cancer as well as in different diseases or pathological states. The miR-17-92a cluster is commonly described as oncogenic and it is known as ‘oncomiR-1’, but this statement is a simplification because miR-18a can act both as an oncogene and a suppressor.In this review we summarize the current knowledge about miR-18a focusing on its regulation, role in cancer biology and utility as a potential biomarker

Tumor microenvironment – Unknown niche with powerful therapeutic potential

Head and neck squamous cell carcinomas (HNSCC) are in a group of cancers that are the most resistant to treatment. The survival rate of HNSCC patients has been still very low since last 20 years. The existence of relationship between oncogenic and surrounding cells is probably the reason for a poor response to treatment. Fibroblasts are an important element of tumor stroma which increases tumor cells ability to proliferate. Another highly resistance, tumorigenic and metastatic cell population in tumor microenvironment are cancer initiating cells (CICs). The population of cancer initiating cells can be found regardless of differentiation status of cancer and they seem to be crucial for HNSCC development.In this review, we describe the current state of knowledge about HNSCC biological and physiological tumor microenvironment

cfRNAs as biomarkers in oncology – still experimental or applied tool for personalized medicine already?

Currently, the challenges of contemporary oncology are focused mainly on the development of personalized medicine and precise treatment, which could be achieved through the use of molecular biomarkers. One of the biological molecules with great potential are circulating free RNAs (cfRNAs) which are present in various types of body fluids, such as blood, serum, plasma, and saliva. Also, different types of cfRNA particles can be distinguished depending on their length and function: microRNA (miRNA), PIWI-interacting RNA (piRNA), tRNA-derived RNA fragments (tRFs), circular RNA (circRNA), long non-coding RNA (lncRNA), and messenger RNA (mRNA). Moreover, cfRNAs occur in various forms: as a free molecule alone, in membrane vesicles, such as exosomes, or in complexes with proteins and lipids. One of the modern approaches for monitoring patient's condition is a "liquid biopsy" that provides a non-invasive and easily available source of circulating RNAs. Both the presence of specific cfRNA types as well as their concentration are dependent on many factors including cancer type or even reaction to treatment. Despite the possibility of using circulating free RNAs as biomarkers, there is still a lack of validated diagnostic panels, defined protocols for sampling, storing as well as detection methods.In this work we examine different types of cfRNAs, evaluate them as possible biomarkers, and analyze methods of their detection. We believe that further research on cfRNA and defining diagnostic panels could lead to better and faster cancer identification and improve treatment monitoring

YRNAs: New Insights and Potential Novel Approach in Head and Neck Squamous Cell Carcinoma

YRNAs are a class of non-coding RNAs that are components of the Ro60 ribonucleoprotein particle and are essential for initiation of DNA replication. Ro60 ribonucleoprotein particle is a target of autoimmune antibodies in patients suffering from systemic lupus erythematosus and Sjögren’s syndrome. Deregulation of YRNAs has been confirmed in many cancer types, but not in head and neck squamous cell carcinoma (HNSCC). The main aim of this study was to determine the biological role of YRNAs in HNSCC, the expression of YRNAs, and their usefulness as potential HNSCC biomarkers. Using quantitative reverse transcriptase (qRT)-PCR, the expression of YRNAs was measured in HNSCC cell lines, 20 matched cancer tissues, and 70 FFPETs (Formaline-Fixed Paraffin-Embedded Tissue) from HNSCC patients. Using TCGA (The Cancer Genome Atlas) data, an analysis of the expression levels of selected genes, and clinical-pathological parameters was performed. The expression of low and high YRNA1 expressed groups were analysed using gene set enrichment analysis (GSEA). YRNA1 and YRNA5 are significantly downregulated in HNSCC cell lines. YRNA1 was found to be significantly downregulated in patients’ tumour sample. YRNAs were significantly upregulated in T4 stage. YRNA1 showed the highest sensitivity, allowing to distinguish healthy from cancer tissue. An analysis of TCGA data revealed that expression of YRNA1 was significantly altered in the human papilloma virus (HPV) infection status. Patients with medium or high expression of YRNA1 showed better survival outcomes. It was noted that genes correlated with YRNA1 were associated with various processes occurring during cancerogenesis. The GSEA analysis showed high expression enrichment in eight vital processes for cancer development. YRNA1 influence patients’ survival and could be used as an HNSCC biomarker. YRNA1 seems to be a good potential biomarker for HNSCC, however, more studies must be performed and these observations should be verified using an in vitro model

Oncogenic Role of ZFAS1 lncRNA in Head and Neck Squamous Cell Carcinomas

Background: Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with high mortality. The identification of specific HNSCC biomarkers will increase treatment efficacy and limit the toxicity of current therapeutic strategies. Long non-coding RNAs (lncRNAs) are promising biomarkers. Accordingly, here we investigate the biological role of ZFAS1 and its potential as a biomarker in HNSCC. Methods: The expression level of ZFAS1 in HNSCC cell lines was analyzed using qRT-PCR. Based on the HNSCC TCGA data, the ZFAS1 expression profile, clinicopathological features, and expression of correlated genes were analyzed in patient tissue samples. The selected genes were classified according to their biological function using the PANTHER tool. The interaction between lncRNA:miRNA and miRNA:mRNA was tested using available online tools. All statistical analyses were accomplished using GraphPad Prism 5. Results: The expression of ZFAS1 was up-regulated in the metastatic FaDu cell line relative to the less aggressive SCC-25 and SCC-040 and dysplastic DOK cell lines. The TCGA data indicated an up-regulation of ZFAS1 in HNSCCs compared to normal tissue samples. The ZFAS1 levels typically differed depending on the cancer stage and T-stage. Patients with a lower expression of ZFAS1 presented a slightly longer disease-free survival and overall survival. The analysis of genes associated with ZFAS1, as well its targets, indicate that they are linked with crucial cellular processes. In the group of patients with low expression of ZFAS1, we detected the up-regulation of suppressors and down-regulation of genes associated with epithelial-to-mesenchymal transition (EMT) process, metastases, and cancer-initiating cells. Moreover, the negative correlation between ZFAS1 and its host gene, ZNFX1, was observed. The analysis of interactions indicated that ZFAS1 has a binding sequence for miR-150-5p. The expression of ZFAS1 and miR-150-5p is negatively correlated in HNSCC patients. miR-150-5p can regulate the 3′UTR of EIF4E mRNA. In the group of patients with high expression of ZFAS1 and low expression of miR-150-5p, we detected an up-regulation of EIF4E. Conclusions: In HNSCC, ZFAS1 displays oncogenic properties, regulates important processes associated with EMT, cancer-initiating cells, and metastases, and might affect patients’ clinical outcomes. ZFAS1 likely regulates the cell phenotype through miR-150-5p and its downstream targets. Following further validation, ZFAS1 might prove a new and valuable biomarker

lncRNA in HNSCC: challenges and potential

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cause of cancer mortality in the world. Some progress has been made in the therapy of HNSCC, however treatment remains unsatisfactory. Recent studies have shown that different types of long non-coding RNAs (lncRNAs) are dysregulated in HNSCC and correlate with tumor progression, lymph node metastasis, clinical stage and poor prognosis. lncRNAs are a class of functional RNA molecules that can not be translated into proteins but can modulate the activity of transcription factors or regulate changes in chromatin structure. The lncRNAs might have potential of biomarker in HNSCC diagnosis, prognosis, prediction and targeted treatment. In this review we describe the potential role of lncRNAs as new biomarkers and discuss their features including source of origin, extraction methods, stability, detection methods and data normalization and potential function as biomarkers in HNSCC

Radio-lncRNAs: Biological Function and Potential Use as Biomarkers for Personalized Oncology

Long non-coding RNAs (lncRNAs) consist of at least 200 nucleotides. Although these molecules do not code proteins, they carry many regulatory functions in normal cells, as well as in cancer cells. For instance, many of these molecules have been previously correlated with tumorigenesis of different cancers and their reaction to various stress factors, such as radiotherapy, chemotherapy, or reactive oxygen species (ROS). The lncRNAs are associated not only with dysregulation in cancers after applied treatment but also with beneficial effects that may be achieved by modulating their expression, often significantly enhancing the patients’ outcomes. A multitude of these molecules was previously considered as potential biomarkers of tumor development, progression, or cells’ response to radio- or chemotherapy. Irradiation, which is often used in treating numerous cancer types, is not always sufficient due to cells gaining resistance in multiple ways. In this review, studies considering lncRNAs and their reaction to radiotherapy were examined. These molecules were divided regarding their role in specific processes strictly related to irradiation, and their influence on this type of treatment was explained, showing how vast an impact they have on IR-supported combat with the disease. This review aims to shed some light on potential future lncRNA-based biomarkers and therapeutic targets