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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.

Introduction Nuclear paraspeckle assembly transcript 1 (NEAT1) is considered an oncogene in various cancers, but the role in head and neck squamous cell carcinomas (HNSCC) is not clear. Material and methods Expression of NEAT1 in HNSCC patients' samples and cell lines was analysed using qRT-PCR. The TCGA expression data of NEAT1 were analysed depending on the clinicopathological parameters and tumour localisation. Correlation and gene set enrichment analysis (GSEA) were conducted, and the results were analysed using the REACTOME and GeneMANIA tools. All statistical analyses were carried out using GraphPad Prism 5 and Statistica 13. Results The NEAT1 was up-regulated in some patients' samples and HNSCC cell lines. Moreover, TCGA data analysis indicated that the expression of NEAT1 was up-regulated in tumour tissue in most of the analysed TCGA cancers, including HNSCC. There were no significant differences in levels of NEAT1 between various tumour localisations. Overall survival of individuals with high expression of NEAT1 was slightly longer than in the low-expression group (p = 0.0553). Analysis of genes that positively and negatively correlated with NEAT1 indicated that they are involved in mRNA metabolism and cellular transport. Moreover, the GSEA revealed that in patients with low NEAT1, the most up-regulated genes were in clusters associated with the cAMP-dependent pathway, the MYC pathway, unfolded protein response, the MTORC1 signalling pathway, oxidative phosphorylation, and DNA repair. Conclusions Patients with low expression of NEAT1 display worse overall survival, presumably due to up-regulation of certain oncogenic signalling pathways that are important for cancerogenesis.

Melanoma is the most aggressive skin cancer, with a growing number of incidents worldwide and with no effective cure in a metastatic stage so far. There are several pathways and processes engaged in melanoma pathogenesis that have been extensively explored in recent years. The emerging evidence suggests that oxidative stress (OS) is highly involved in melanin synthesis and melanoma formation. Melanoma is particularly susceptible to OS due to the involvement of melanin synthesis and UV radiation in the generation of reactive oxygen species. Oxidative stress influences melanoma immunity, the metastatic potential of melanoma cells and their resistance to therapy. In malignant melanocytes, the process of melanogenesis is frequently upregulated, suggesting possible therapeutic targets. This review describes the role of OS in melanin synthesis in melanocytes and explains how it affects melanoma cells. Better knowledge about the mechanisms involved in cancer progression may result in the development of better treatment strategies.

Simple Summary Transmembrane proteins (TMEM) are a large group of integral membrane proteins whose molecular and biological functions are not fully understood. It is known that some of them are involved in tumor formation and metastasis. Here, we performed a panel of TCGA data analyses to investigate the role of different TMEM genes in head and neck squamous cell carcinoma (HNSCC) and define their potential as biomarkers. Based on changes in the expression levels in HNSCC tumors, we selected four TMEM genes: ANO1, TMEM156, TMEM173, and TMEM213 and associated them with patient survival. We also demonstrated that the expression of those TMEMs highly correlates with the enrichment of genes involved in numerous biological processes, especially metastasis formation and immune response. Thus, we propose ANO1, TMEM156, TMEM173, and TMEM213 as new biomarkers and potential targets for personalized therapy of HNSCC. Abstract Background: Transmembrane proteins (TMEM) constitute a large family of proteins spanning the entirety of the lipid bilayer. However, there is still a lack of knowledge about their function or mechanism of action. In this study, we analyzed the expression of selected TMEM genes in patients with head and neck squamous cell carcinoma (HNSCC) to learn their role in tumor formation and metastasis. Materials and Methods: Using TCGA data, we analyzed the expression levels of different TMEMs in both normal and tumor samples and compared those two groups depending on clinical-pathological parameters. We selected four TMEMs whose expression was highly correlated with patient survival status and subjected them to further analysis. The pathway analysis using REACTOME and the gene set enrichment analysis (GSEA) were performed to evaluate the association of those TMEMs with genes involved in hallmarks of cancer as well as in oncogenic and immune-related pathways. In addition, the fractions of different immune cell subpopulations depending on TMEM expression were estimated in analyzed patients. The results for selected TMEMs were validated using GEO data. All analyses were performed using the R package, Statistica, and Graphpad Prism. Results: We demonstrated that 73% of the analyzed TMEMs were dysregulated in HNSCC and depended on tumor localization, smoking, alcohol consumption, or HPV infection. The expression levels of ANO1, TMEM156, TMEM173, and TMEM213 correlated with patient survival. The four TMEMs were also upregulated in HPV-positive patients. The elevated expression of those TMEMs correlated with the enrichment of genes involved in cancer-related processes, including immune response. Specifically, overexpression of TMEM156 and TMEM173 was associated with immune cell mobilization and better survival rates, while the elevated ANO1 expression was linked with metastasis formation and worse survival. Conclusions: In this work, we performed a panel of in silico analyses to discover the role of TMEMs in head and neck squamous cell carcinoma. We found that ANO1, TMEM156, TMEM173, and TMEM213 correlated with clinical status and immune responses in HNSCC patients, pointing them as biomarkers for a better prognosis and treatment. This is the first study describing such the role of TMEMs in HNSCC. Future clinical trials should confirm the potential of those genes as targets for personalized therapy of HNSCC.

Background:Head and neck squamous cell carcinoma (HNSCC) is the most common malignant cancer occurring in the head and neck area, approximately 90% of the cases. Even in the cases of primary radical treatment (surgical, concomitant chemoradiotherapy or radiotherapy alone), subsequent local recurrence or distant metastases are often observed. In patients with recurrent disease who are unable to receive radical treatment, the results of palliative chemotherapy are not satisfactory. In this review, we summarized the standard treatment options, current development of new drugs and future perspectives in the treatment of patients with recurrent locally advanced and/or metastatic HNSCC.Methods:PubMed databases with words ‘head and neck cancer treatment’, ‘immunotherapy in head and neck cancer treatment’ were searched and yielded 186512 and 2249 papers respectively. We selected the most cited articles and reports presenting new immunotherapy agents and drug combinations in HNSCC.Results:Recently, two new agents been approved in the treatment of recurrent locally advanced and/or metastatic HNSCC. These are immune-checkpoint inhibitors targeting PD1 (nivolumab and pembrolizumab) which are the most active drugs in the second line treatment of advanced HNSCC. Still, the first line ‘golden standard’ is the chemotherapy regimen (cisplatin, 5-fluorouracyl) combined with cetuximab. Many phase 3 studies are currently ongoing, evaluating the efficacy of combinational treatment-anti-CTLA4 with anti-PD1 or anti-PDL1. Very encouraging results have been shown in early phase studies evaluating the combination of immunecheckpoint inhibitors with tumor microenvironment immunosuppressive inhibitors.Conclusion:Despite the huge progress in the systemic treatment of patients with recurrent locally advanced and/or metastatic HNSCC, the disease at this stage remains incurable. Undoubtedly, further research in the field of biomarkers for effective immunotherapy is needed in order to select a group of patients whose will benefit from this therapy, as the treatment is still ineffective in most patients.

Long non-coding RNAs (lncRNA) are dysregulated in many cancer types. Abnormal baseline levels of these lncRNAs display diagnostic and prognostic potential in cancer patients. The aim of this study was to evaluate the prognostic value of plasma lncRNAs in BRAF-mutant advanced melanoma patients treated with a BRAF inhibitor. Total RNA was isolated from plasma samples collected from 58 advanced BRAF-mutant melanoma patients and 15 healthy donors. The expression levels of 90 lncRNAs were estimated using the LncProfiler qPCR Array Kit (SBI) and LightCycler 96 (Roche). LncRNA expression levels correlated with responses to the BRAF inhibitor (vemurafenib) treatment. The patients were stratified into three groups based on their lncRNA levels with various lncRNA expressions (low, medium, and high). A Cox proportional hazards regression model was used to determine the lncRNAs that were significantly associated with both progression-free and overall survivals (PFS and OS, respectively) in patients receiving vemurafenib. The expression level of 12 lncRNAs was down-regulated, while five lncRNAs were up-regulated in melanoma patients compared to healthy donors. Kaplan-Meier analysis showed that upregulation or downregulation of 11 and 16 different lncRNAs were associated with longer median PFS and OS, respectively. Further analysis demonstrated that the baseline lncRNAs for IGF2AS, anti-Peg11, MEG3, Zeb2NAT are independent prognostic factors in BRAF-mutant advanced melanoma patients treated with vemurafenib. Evaluation of plasma lncRNAs expression level for advanced melanoma diagnosis and prognosis evaluation appears to be a safe and valuable method; however, this method requires further validation in larger cohorts and randomized trials.

Introduction Head and neck squamous carcinoma (HNSCC) is one of the most invasive types of cancer with high mortality. A previous study has indicated that low levels of let-7d and miR-205 in HNSCC patients are correlated with poor survival. Let-7d and miR-205 are tumor suppressors and regulators of epithelial-to-mesenchymal transition (EMT). However, it is unclear if let-7d and miR-205 together influence cancer cells. Aim To determine if let-7d and miR-205 expression levels influence HNSCC patient outcome. Methods The TCGA expression data for let-7d, miR-205 and their targets as well as clinical data were downloaded from cBioPortal and starBase v2.0 for 307 patients. The expression levels of let-7d and miR-205 were verified according to clinicopathological parameters. The let-7d and miR-205 high- and low-expression groups as well as disease-free survival (DFS), overall survival (OS) and expression levels of genes related to EMT, cancer stem cells, metastasis, cell cycle, drug response and irradiation response were investigated. Results Let-7d and miR-205 were frequently upregulated in HNSCC compared to normal samples, and ROC analysis showed high discrimination ability for let-7d and miR-205 (area 0.7369 and 0.7739, respectively; p

Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), is a disorder caused by an autosomal dominant heterozygous germline mutation in one of the DNA mismatch repair (MMR) genes. Individuals with LS are at an increased risk of developing colorectal and extracolonic cancers, such as endometrial, small bowel, or ovarian. In this review, the mutations involved with LS and their diagnostic methods are described and compared, as are their current uses in clinical decision making. Nowadays, LS diagnosis is based on a review of family medical history, and when necessary, microsatellite instability (MSI) or/and immunohistochemistry (IHC) analyses should be performed. In the case of a lack of MMR protein expression (dMMR) or MSI-H (MSI-High) detection in tumor tissue, molecular genetic testing can be undertaken. More and more genetic testing for LS is based mainly on next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA), which provide better and quicker information about the molecular profile of patients as well as individuals at risk. Testing based on these two methods should be the standard and commonly used. The identification of individuals with mutations provides opportunities for the detection of cancer at an early stage as well as the introduction of proper, more effective treatment, which will result in increased patient survival and reduced costs of medical care.

Background: Long non-coding RNA (lncRNA) are RNA molecules that are more than 200 nucleotides long and have the ability to modify the activity of genes. They can be found in both healthy and cancer tissues, as well as in plasma, saliva and other bodily fluids. They can also be used as biomarkers of early detection, prognosis and chemotherapy resistance in several cancer types. Treatment of head and neck squamous cell carcinoma (HNSCC) patients with locally advanced disease is still difficult, and choice of treatment should be based on more precise and available biomarkers, such as those obtained from a liquid biopsy. For improvement of treatment efficacy, identification and clinical implementation of new biomarkers are of the utmost importance. Methods: Plasma samples drawn before (p1) and three cycles post (p2) (TPF: docetaxel, cisplatin, 5-fluorouracil/PF: cisplatin, 5-fluorouracil) chemotherapy from 53 HNSCC patients (17 with locally advanced and 36 with metastatic disease) and 14 healthy volunteers were studied. Expression levels of 90 lncRNA expression were analyzed using the qRT-PCR method, and the obtained results were compared between proper groups. Statistical analyses were carried out using Jupyter Notebooks (5.7.2), Python (ver. 3.6) and GraphPad Prism 8. Results: The study demonstrated the differences between the expressions of several lncRNA in cancer patients&rsquo, and healthy volunteers&rsquo, plasma, as well as between locally advanced and metastatic patients&rsquo, groups. A correlation between the response to systemic therapy and lncRNA expression levels was observed. Patients with a (high/low) expression of Alpha 250 and Emx2os showed statistically significant differences in progression free survival (PFS), as well as for overall survival (OS) depending on the level of Alpha 250, snaR, SNHG1. The univariate and multivariate Cox regression model showed Alpha 250 as the best prognostic factor for HNSCC patients. Conclusions: Liquid biopsies based on lncRNAs are promising diagnostic tools that can be used to differentiate between those with cancer and healthy individuals. Additionally, they can also serve as biomarkers for chemotherapy resistance. An identified, circulating lncRNA Alpha 250 seems to prove the best prognostic biomarker, associated with extended PFS and OS, and should be validated in a larger cohort in the future.

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.

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.

Head 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.

Background The necessity of prediction and treatment outcome improvement of HNSCC needs to find new biomarkers. miRNAs seem to be good candidate for that. Objective Analysis of selected 5 miRNAs (let-7d, miR-18a, miR-21, miR-205 and miR-375) as potential biomarkers that allows to distinguish tumor and healthy tissue taken from HNSCC patients. Methods Tumor and normal epithelial tissues were obtained from 75 HNSCC patients to analyze selected miRNAs. Results Analysis indicated significant increase of miR-21 and miR-205 in tumor when compared with healthy tissue (p= 0.0069 and p= 0.0029, respectively). There was a significant correlation between let-7d and miR-18a. let-7d was down-regulated in 34.67% cases, miR-18a in 29.33%, miR-21 in 20%, miR-205 in 30.67% and miR-375 in 52% cases. At the same time over-expression of let-7d was detected in 18.67% cases, miR-18a in 22.67%, miR-21 in 48%, miR-205 in 41.33% and miR-375 in 52% cases. There was no correlation between miRNA expression and clinical data and the course of illness. Conclusion Our study indicated that miR-21 and miR-205 can be used to analyze the clarity of surgical margins and that concomitant changes in the expression of let-7 and miR-18a in tumor tissues might represent important future markers indicating the biology of HNSCC. These observations will help with developing personalization for HNSCC patients' treatment.

Background: Changes in expression profiles of the 5 selected miRNAs were analysed in a group of PC patients before treatment, after hormonotherapy and radiotherapy. Objective: Whether the expression profiles of the miRNAs may be useful for monitoring prostate cancer treatment. Methods: The initial study was carried out on 44 advanced prostate cancer patients and 41 healthy volunteers. The target group consisted of 39 PC patients. Blood for miRNA analysis was taken before treatment, after hormonotherapy and radiotherapy. The miRNAs were analysed by real-time PCR, followed by statistical analysis. Results: For the target group, the statistically significant differences in the expression level were found after radiotherapy: for miR-21 only in the group of patients above the cut-off value designed in the preliminary study (p=0.0369) and miR-100 for the whole group (p=0.0413) and for the above cut-off value group (p=0.0140). The differences between the levels of each miRNA between the high and low expression groups were statistically significant. The designed groups were stable during treatment. Inclusion to the high and low expression group levels did not influence the treatment result. Conclusion: The miRNAs studied in this work could not serve as biomarkers for the effectiveness of therapy for prostate cancer patients.

Head and neck squamous cell carcinomas are one of the worst prognosis cancers with high mortality of patients. The main methods of treatment are surgery, radiotherapy and chemotherapy. The improvement of currently applied therapeutic methods is seen in the use of molecular features of tumour marker that describes the behavior of cells after treatment. miRNAs are supposed to be a good diagnostic and prognostic biomarkers. They are small, non-coding RNAs which are involved in regulatory function in the cell. It has been revealed that the biogenesis and function of miRNAs are disturbed in tumour cells which results in the acquisition of specific phenotypic characteristics by tumour cells. The tumour examination in the context of miRNAs expression may allow to describe potential tumour ability to its growth, progression, radio – and chemosensitivity. Creation of the miRNA panel for the personalization of treatment is still at the research stage. In this work, we collected data concerning two miRNAs: let-7d and miR-18a. We have characterized them for potential use as miRbiomarkers.

The implication of the let-7 family in cancer development is multifaceted. The family acts as tumor suppressor miRNA although overexpression of let-7 has also been described in many types of cancer, including head and neck squamous cell carcinoma (HNSCC). The aim of this study includes whether different expression levels of let-7d has an influence on chemo- and radiosensitivity. FaDu cell line models with a gradually increased level of let-7d (models from A to E) were generated with the lentiviral system. Expression levels of pluripotency, chemo-radioresistance/apoptosis, and targets of mRNAs were analyzed by real-time reverse transcription-PCR (qRT-PCR). Radiosensitivity was analyzed using a clonogenic assay after irradiation. Response to cisplatin, 5-FU, doxorubicin, and paclitaxel was done with MTT assay. Statistically significant decrease of K-RAS (p = 0.0369) and CASPASE3 (p = 0.0342) were observed with the growing expression level of let-7d. Cisplatin, 5-FU and doxorubicin caused similar decreased of cell survival with the increase of let-7d level (p = 0.004, post-trend p = 0.046; p = 0.004, post trend p = 0.0005 and p

The squamous cell carcinomas represent about 90 % of all head and neck cancers, ranking the sixth most common human cancer. Approximately 450,000 of new cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed every year. Unfortunately, because of diagnosis at the advanced stages and early metastasis to the lymph nodes, the HNSCC is associated with very high death rate. Identification of signature biomarkers and molecularly targeted therapies could provide more effective and specific cancer treatment, prevent recurrence, and increase survival rate. We used paired tumor and adjacent normal tissue samples to screen with RT² Profiler™ PCR Array Human Cancer PathwayFinderTM . Total of 20 up-regulated genes and two down-regulated genes were screened out. Out of 22 genes, 12 genes were subsequently validated to be significantly altered in the HNSCC; the samples were from all 41 patients. Five year survival and recurrence selected genes that could represent the biomarkers of survival and recurrence of the disease. We believe that comprehensive understanding of the unique genetic characteristics of HNSCC could provide novel diagnostic biomarkers and meet the requirement for molecular-targeted therapy for the HNSCC.

miRNAs belong to a class of small non-coding RNAs which can modulate gene expression. Disturbances in their expression and function may cause cancer formation, progression and cell response to various types of stress. The let-7 family is one of the most studied groups of miRNAs. The family contains 13 members with similar sequences and a wide spectrum of target genes. In this paper, we mostly focus on one member of the family – let-7d. This miRNA is dysregulated in many types of cancers. It can be over- or down-expressed, and it acts as a tumor suppressor or oncogene. It regulates various genes such as LIN28, C-MYC, K-RAS, HMGA2 and IMP-1. Moreover, let-7d has a significant impact on epithelial-to-mesenchymal transition (EMT) and formation of cancer initiating cells which are resistant to irradiation and chemical exposure and responsible for cancer metastasis. Let-7d can serve as a prognostic and predictive marker for personalization of the treatment. Let-7d is a small RNA with great power, but in different cell genetic backgrounds it acts in different ways, which makes this molecule still mysterious.

The Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common human cancer, causing 350,000 individuals die worldwide each year. The overall prognosis in HNSCC patients has not significantly changed for the last decade. Complete understanding of the molecular mechanisms in HNSCC carcinogenesis could allow an earlier diagnosis and the use of more specific and effective therapies. In the present study we used deep sequencing to characterize small non-coding RNAs (sncRNAs) in serum from HNSCC patients and healthy donors. We identified, for the first time, a multi-marker signature of 3 major classes of circulating sncRNAs in HNSCC, revealing the presence of circulating novel and known miRNAs, and tRNA- and YRNA-derived small RNAs that were significantly deregulated in the sera of HNSCC patients compared to healthy controls. By implementing a triple-filtering approach we identified a subset of highly biologically relevant miRNA-mRNA interactions and we demonstrated that the same genes/pathways affected by somatic mutations in cancer are affected by changes in the abundance of miRNAs. Therefore, one important conclusion from our work is that during cancer development, there seems to be a convergence of oncogenic processes driven by somatic mutations and/or miRNA regulation affecting key cellular pathways.