miRNA in head and neck squamous cell carcinomas: promising but still distant future of personalized oncology

Head and neck squamous cell carcinoma is one of the most common and fatal cancers worldwide. Lack of appropriate preventive screening tests, late detection, and high heterogeneity of these tumors are the main reasons for the unsatisfactory effects of therapy and, consequently, unfavorable outcomes for patients. An opportunity to improve the quality of diagnostics and treatment of this group of cancers are microRNAs (miRNAs) — molecules with a great potential both as biomarkers and therapeutic targets. This review aims to present the characteristics of these short non-coding RNAs (ncRNAs) and summarize the current reports on their use in oncology focused on medical strategies tailored to patients’ needs

Angiotensin-converting enzyme inhibitors for ovarian cancer? — a new adjuvant option or a silent trap

Background: Ovarian cancer is a huge therapeutic and financial problem for which approved treatments have already achieved their limit of efficiency. A cost-effective strategy to extend therapeutic options in this malignancy is drug repurposing aimed at overcoming chemoresistance. Here, angiotensin-converting enzyme inhibitors (ACE-I) are worth considering. Material and methods: We searched literature for publications supporting the idea of adjuvant application of ACE-Is in ovarian malignancy. Then, we searched The Cancer Genome Atlas databases for relevant alternations of gene expression patterns. We also performed in silico structure-activity relationship evaluation for predicting ACE-Is’ cytotoxicity against ovarian cancer cell lines. Finally, we reviewed the potential obstacles in ACE-Is repurposing process. Results: The alternation of angiotensin receptor expression in ovarian cancer translates into poorer patient survival. This confirms the participation of the renin-angiotensin system in ovarian carcinogenesis. In observational studies, ACE-Is were shown synergize with both, platinum-based chemotherapy as well as with antiangiogenic therapy. Consistently, our in silico simulation showed that ACE-Is are probably cytotoxic against ovarian cancer cells. However, the publications on their chemopreventive properties were inconclusive. In addition, some reports correlated ACE-Is use with increased general cancer incidence. We hypothesized that this effect could be associated with mutagenic nitrosamine formation in ACE-Is’ pharmaceutical formulations, as was the case with angiotensin receptor blockers (ARBs) and other well-established pharmaceuticals. Conclusions: Available data warrant further research into repositioning ACE-Is to ovarian cancer as chemosensitizers. Prior to this, however, a special research program is needed to detect possible genotoxic contaminants of ACE-Is

Biological role and diagnostic utility of ribosomal protein L23a pseudogene 53 in cutaneous melanoma

Background: Skin melanoma is one of the deadliest types of skin cancer and develops from melanocytes. The genetic aberrations in protein-coding genes are well characterized, but little is known about changes in non-coding RNAs (ncRNAs) such as pseudogenes. Ribosomal protein pseudogenes (RPPs) have been described as the largest group of pseudogenes which are dispersed in the human genome. Materials and methids: We looked deeply at the role of one of them, ribosomal protein L23a pseudogene 53 (RPL23AP53), and its potential diagnostic use. The expression level of RPL23AP53 was profiled in melanoma cell lines using qRT-PCR and analyzed based on the Cancer Genome Atlas (TCGA) data depending on BRAF status and clinicopathological parameters. Cellular phenotype, which was associated with RPL23AP53 levels, was described based on the REACTOME pathway browser, Gene Set Enrichment Analysis (GSEA) analysis as well as Immune and ESTIMATE Scores. Results: We indicted in vitro changes in RPL23AP53 level depending on a cell line, and based on in silico analysis of TCGA samples demonstrated significant differences in RPL23AP53 expression between primary and metastatic melanoma, as well as correlation between  RPL23AP53 and overall survival. No differences depending on BRAF status were observed. RPL23AP53 is associated with several signaling pathways and cellular processes. Conclusions: This study showed that patients with higher expression of RPL23AP53 displayed changed infiltration of lymphocytes, macrophages, and neutrophils compared to groups with lower expression of RPL23AP53. RPL23AP53 pseudogene is differently expressed in melanoma compared with normal tissue and its expression is associated with cellular proliferation. Thus, it may be considered as an indicator of patients' survival and a marker for the immune profile assessment

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

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

lncRNA Expression after Irradiation and Chemoexposure of HNSCC Cell Lines

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cause of cancer mortality in the world. To improve the quality of diagnostics and patients’ treatment, new and effective biomarkers are needed. Recent studies have shown that the expression level of different types of long non-coding RNAs (lncRNAs) is dysregulated in HNSCC and correlates with many biological processes. In this study, the response of lncRNAs in HNSCC cell lines after exposure to irradiation and cytotoxic drugs was examined. The SCC-040, SCC-25, FaDu, and Cal27 cell lines were treated with different radiation doses as well as exposed to cisplatin and doxorubicin. The expression changes of lncRNAs after exposure to these agents were checked by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Target prediction was performed using available online tools and classified into specific biological processes and cellular pathways. The results indicated that the irradiation, as well as chemoexposure, causes changes in lncRNA expression and the effect depends on the cell line, type of agents as well as their dose. After irradiation using the dose of 5 Gy significant dysregulation of 4 lncRNAs, 10 Gy-5 lncRNAs, and 20 Gy-3 lncRNAs, respectively, were observed in all cell lines. Only lncRNAs Zfhx2as was down-regulated in all cell lines independently of the dose used. After cisplatin exposure, 14 lncRNAs showed lower and only two higher expressions. Doxorubicin resulted in lower expressions of eight and increased four of lncRNAs. Common effects of cytotoxic drugs were observed in the case of antiPEG11, BACE1AS, PCGEM1, and ST7OT. Analysis of the predicted targets for dysregulated lncRNAs indicated that they are involved in important biological processes, regulating cellular pathways connected with direct response to irradiation or chemoexposure, cellular phenotype, cancer initiating cells, and angiogenesis. Both irradiation and chemoexposure caused specific changes in lncRNAs expression. However, the common effect is potentially important for cellular response to the stress and survival. Further study will show if lncRNAs are useful tools in patients’ 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