Publications by authors named "Andreas Scorilas"

292 Publications

Elevated levels of both microRNA 378 (miR-378) and kallikrein-related peptidase 4 (KLK4) mRNA are associated with an unfavorable prognosis in triple-negative breast cancer.

Am J Transl Res 2021 15;13(3):1594-1606. Epub 2021 Mar 15.

Clinical Research Unit, Department of Obstetrics and Gynecology, Technical University of Munich Germany.

Triple-negative breast cancer (TNBC) patients have the worst outcome among all breast cancer subtypes. In oral squamous carcinoma cells, miR-378 was reported to target the mRNA of kallikrein-related peptidase 4 (KLK4), resulting in inhibition of cell proliferation, migration and invasion, induction of apoptosis, and reduction of tumor growth . Similarly, a miR-378/KLK4 axis has been proposed in prostate cancer. Here, we analyzed the correlation between miR-378 and KLK4 mRNA expression and determined the prognostic impact of both factors in TNBC. miR-378 and KLK4 mRNA expression levels were determined by quantitative PCR in tumor tissue of TNBC patients (n=103) and correlated with clinical parameters and patients' survival. There was no significant correlation between miR-378 and KLK4 mRNA expression. In univariate Cox regression analysis, elevated miR-378 expression was significantly associated with shortened disease-free survival (DFS, P=0.047) and overall survival (OS, P=0.031), high KLK4 mRNA levels were linked to a worse DFS (P=0.033). Combination of KLK4 mRNA and miR-378 (KLK4+miR-378, low/low versus high and/or high) allowed even better discrimination between favorable and unfavorable prognosis (DFS, P=0.008; OS, P=0.025). In multivariable analysis, miR-378 and KLK4+miR-378 expression remained independent predictive factors for DFS (P=0.014, P=0.010, respectively) and OS (P=0.016, P=0.049, respectively), while KLK4 mRNA only showed a trend towards significance for DFS (P=0.061). Our findings suggest that in TNBC there is no significant impact of miR-378 on KLK4 expression. Both factors, miR-378 and, to a lesser extent, KLK4 mRNA represent unfavorable prognostic markers in TNBC patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014413PMC
March 2021

The Multifaceted Role and Utility of MicroRNAs in Indolent B-Cell Non-Hodgkin Lymphomas.

Biomedicines 2021 Mar 25;9(4). Epub 2021 Mar 25.

Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701 Athens, Greece.

Normal B-cell development is a tightly regulated complex procedure, the deregulation of which can lead to lymphomagenesis. One common group of blood cancers is the B-cell non-Hodgkin lymphomas (NHLs), which can be categorized according to the proliferation and spread rate of cancer cells into indolent and aggressive ones. The most frequent indolent B-cell NHLs are follicular lymphoma and marginal zone lymphoma. MicroRNAs (miRNAs) are small non-coding RNAs that can greatly influence protein expression. Based on the multiple interactions among miRNAs and their targets, complex networks of gene expression regulation emerge, which normally are essential for proper B-cell development. Multiple miRNAs have been associated with B-cell lymphomas, as the deregulation of these complex networks can lead to such pathological states. The aim of the present review is to summarize the existing information regarding the multifaceted role of miRNAs in indolent B-cell NHLs, affecting the main B-cell subpopulations. We attempt to provide insight into their biological function, the complex miRNA-mRNA interactions, and their biomarker utility in these malignancies. Lastly, we address the limitations that hinder the investigation of the role of miRNAs in these lymphomas and discuss ways that these problems could be overcome in the future.
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http://dx.doi.org/10.3390/biomedicines9040333DOI Listing
March 2021

SARS-CoV-2 Infection Is Asymptomatic in Nearly Half of Adults with Robust Anti-Spike Protein Receptor-Binding Domain Antibody Response.

Vaccines (Basel) 2021 Mar 2;9(3). Epub 2021 Mar 2.

First Department of Propaedeutic Internal Medicine, School of Medicine, Laiko General Hospital, NKUA, 15772 Athens, Greece.

Between June and November 2020, we assessed plasma antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein in 4996 participants (aged 18-82 years, 34.5% men) from the National and Kapodistrian University of Athens. The weighted overall prevalence was 1.6% and monthly prevalence correlated with viral RNA-confirmed SARS-CoV-2 infections in Greece, in the same period. Notably, 49% of seropositive cases reported no history of SARS-CoV-2 infection-related clinical symptoms and 33% were unsuspected of their previous infection. Additionally, levels of anti-SARS-CoV-2 antibodies against the spike-protein receptor-binding domain were similar between symptomatic and asymptomatic individuals, irrespective of age and gender. Using Food and Drug Administration Emergency Use Authorization-approved assays, these results support the need for such studies on pandemic evaluation and highlight the development of robust humoral immune responses even among asymptomatic individuals. The high percentage of unsuspected/asymptomatic active cases, which may contribute to community transmission for more days than that of cases who are aware and self-isolate, underscores the necessity of measures across the population for the efficient control of the pandemic.
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http://dx.doi.org/10.3390/vaccines9030207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998869PMC
March 2021

Jagged Ends of Cell-Free DNA: Rebranding Fragmentomics in Modern Liquid Biopsy Diagnostics.

Clin Chem 2021 Mar;67(4):576-578

Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.

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http://dx.doi.org/10.1093/clinchem/hvab036DOI Listing
March 2021

Multiple Myeloma Bone Disease: Implication of MicroRNAs in Its Molecular Background.

Int J Mol Sci 2021 Feb 27;22(5). Epub 2021 Feb 27.

Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece.

Multiple myeloma (MM) is a common hematological malignancy arising from terminally differentiated plasma cells. In the majority of cases, symptomatic disease is characterized by the presence of bone disease. Multiple myeloma bone disease (MMBD) is a result of an imbalance in the bone-remodeling process that leads to increased osteoclast activity and decreased osteoblast activity. The molecular background of MMBD appears intriguingly complex, as several signaling pathways and cell-to-cell interactions are implicated in the pathophysiology of MMBD. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the expression of their target mRNAs. Numerous miRNAs have been witnessed to be involved in cancer and hematological malignancies and their role has been characterized either as oncogenic or oncosuppressive. Recently, scientific research turned towards miRNAs as regulators of MMBD. Scientific data support that miRNAs finely regulate the majority of the signaling pathways implicated in MMBD. In this review, we provide concise information regarding the molecular pathways with a significant role in MMBD and the miRNAs implicated in their regulation. Moreover, we discuss their utility as molecular biomarkers and highlight the putative usage of miRNAs as novel molecular targets for targeted therapy in MMBD.
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http://dx.doi.org/10.3390/ijms22052375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956742PMC
February 2021

A 3' tRNA-derived fragment produced by tRNA and tRNA is associated with poor prognosis in B-cell chronic lymphocytic leukemia, independently of classical prognostic factors.

Eur J Haematol 2021 Mar 4. Epub 2021 Mar 4.

Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens Panepistimiopolis, Athens, Greece.

Objective: 3' tRNA-derived fragments (3' tRFs) are important epigenetic regulators in normal and pathological conditions. In this study, we aimed to explore the potential value of a 3' tRF as a prognostic and/or screening biomarker for B-cell chronic lymphocytic leukemia (B-CLL).

Methods: Publicly available next-generation sequencing data from 20 B-CLL cases were analyzed, followed by prediction of targets of the most abundantly and ubiquitously expressed 3' tRFs, leading to selection of tRF-Leu . PBMCs were isolated from blood samples of 91 B-CLL patients and 43 non-leukemic donors, followed by total RNA extraction, in-vitro polyadenylation, and first-strand cDNA synthesis. Next, a real-time quantitative PCR (qPCR) assay was developed for the accurate quantification of tRF-Leu and applied in all samples, prior to biostatistical analysis.

Results: High tRF-Leu levels are associated with inferior overall survival (OS) of B-CLL patients. The unfavorable significance of tRF-Leu was independent of established prognostic factors in B-CLL. Stratified Kaplan-Meier OS analysis uncovered the unfavorable prognostic role of high tRF-Leu levels for patients in Binet A or Rai I stage, negative CD38 expression, mutated, or unmutated IGHV genomic locus.

Conclusion: Our approach revealed the independent prognostic value of a particular 3' tRF, derived from tRNA and tRNA (tRF-Leu ) in B-CLL.
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http://dx.doi.org/10.1111/ejh.13613DOI Listing
March 2021

MicroRNAs: Tiny Regulators of Gene Expression with Pivotal Roles in Normal B-Cell Development and B-Cell Chronic Lymphocytic Leukemia.

Cancers (Basel) 2021 Feb 3;13(4). Epub 2021 Feb 3.

Second Department of Internal Medicine and Research Unit, University General Hospital "Attikon", 12462 Athens, Greece.

MicroRNAs (miRNAs) represent a class of small non-coding RNAs bearing regulatory potency. The implication of miRNAs in physiological cellular processes has been well documented so far. A typical process orchestrated by miRNAs is the normal B-cell development. A stage-specific expression pattern of miRNAs has been reported in the developmental procedure, as well as interactions with transcription factors that dictate B-cell development. Besides their involvement in normal hematopoiesis, miRNAs are severally implicated in hematological malignancies, a typical paradigm of which is B-cell chronic lymphocytic leukemia (B-CLL). B-CLL is a highly heterogeneous disease characterized by the accumulation of abnormal B cells in blood, bone marrow, lymph nodes, and spleen. Therefore, timely, specific, and sensitive assessment of the malignancy is vital. Several studies have attempted to highlight the remarkable significance of miRNAs as regulators of gene expression, biomarkers for diagnosis, prognosis, progression, and therapy response prediction, as well as molecules with potential therapeutic utility. This review seeks to outline the linkage between miRNA function in normal and malignant hematopoiesis by demonstrating the main benchmarks of the implication of miRNAs in the regulation of normal B-cell development, and to summarize the key findings about their value as regulators, biomarkers, or therapeutic targets in B-CLL.
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http://dx.doi.org/10.3390/cancers13040593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913321PMC
February 2021

tRNA-Derived Fragments (tRFs) in Bladder Cancer: Increased 5'-tRF-LysCTT Results in Disease Early Progression and Patients' Poor Treatment Outcome.

Cancers (Basel) 2020 Dec 6;12(12). Epub 2020 Dec 6.

Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 157 01 Athens, Greece.

The heterogeneity of bladder cancer (BlCa) prognosis and treatment outcome requires the elucidation of tumors' molecular background towards personalized patients' management. tRNA-derived fragments (tRFs), although originally considered as degradation debris, represent a novel class of powerful regulatory non-coding RNAs. analysis of the TCGA-BLCA project highlighted 5'-tRF-LysCTT to be significantly deregulated in bladder tumors, and 5'-tRF-LysCTT levels were further quantified in our screening cohort of 230 BlCa patients. Recurrence and progression for non-muscle invasive (NMIBC) patients, as well as progression and patient's death for muscle-invasive (MIBC) patients, were used as clinical endpoint events. TCGA-BLCA were used as validation cohort. Bootstrap analysis was performed for internal validation and the clinical net benefit of 5'-tRF-LysCTT on disease prognosis was assessed by decision curve analysis. Elevated 5'-tRF-LysCTT was associated with unfavorable disease features, and significant higher risk for early progression (multivariate Cox: HR = 2.368; = 0.033) and poor survival (multivariate Cox: HR = 2.151; = 0.032) of NMIBC and MIBC patients, respectively. Multivariate models integrating 5'-tRF-LysCTT with disease established markers resulted in superior risk-stratification specificity and positive prediction of patients' progression. In conclusion, increased 5'-tRF-LysCTT levels were strongly associated with adverse disease outcome and improved BlCa patients' prognostication.
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http://dx.doi.org/10.3390/cancers12123661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762106PMC
December 2020

Identification of Two Novel Circular RNAs Deriving from and Investigation of Their Potential Value as a Molecular Signature in Colorectal Cancer.

Int J Mol Sci 2020 Nov 23;21(22). Epub 2020 Nov 23.

Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701 Athens, Greece.

The utility of circular RNAs (circRNAs) as molecular biomarkers has recently emerged. However, only a handful of them have already been studied in colorectal cancer (CRC). The purpose of this study was to identify new circRNAs deriving from , a member of the BCL2 apoptosis-related family, and investigate their potential as biomarkers in CRC. Total RNA extracts from CRC cell lines and tissue samples were reversely transcribed. By combining PCR with divergent primers and nested PCR followed by Sanger sequencing, we were able to discover two circRNAs. Subsequently, bioinformatical tools were used to predict the interactions of these circRNAs with microRNAs (miRNAs) and RNA-binding proteins (RBPs). Following a PCR-based pre-amplification, real-time qPCR was carried out for the quantification of each circRNA in CRC samples and cell lines. Biostatistical analysis was used to assess their potential prognostic value in CRC. Both novel circRNAs likely interact with particular miRNAs and RBPs. Interestingly, circ-BCL2L12-2 expression is inversely associated with TNM stage, while circ-BCL2L12-1 overexpression is associated with shorter overall survival in CRC, particularly among TNM stage II patients. Overall, we identified two novel circRNAs, one of which can further stratify TNM stage II patients into two subgroups with substantially distinct prognosis.
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http://dx.doi.org/10.3390/ijms21228867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709015PMC
November 2020

Analytical methodologies for the detection of SARS-CoV-2 in wastewater: Protocols and future perspectives.

Trends Analyt Chem 2021 Jan 20;134:116125. Epub 2020 Nov 20.

Laboratory of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Greece.

In March 2020 the World Health Organization announced a pandemic outbreak. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen for the coronavirus disease-19 (COVID-19) pandemic. The authorities worldwide use clinical science to identify infected people, but this approach is not able to track all symptomatic and asymptomatic cases due to limited sampling capacity of the testing laboratories. This drawback is eliminated by the Wastewater-Based Epidemiology (WBE) approach. In this review, we summarized the peer-reviewed published literature (available as of September 28, 2020), in the field of WBE. The commonly used steps (sampling, storage, concentration, isolation, detection) of the analytical protocols were identified. The potential limitations of each stage of the protocols and good practices were discussed. Finally, new methods for the efficient detection of SARS-CoV-2 were proposed.
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http://dx.doi.org/10.1016/j.trac.2020.116125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677696PMC
January 2021

Revised Exon Structure of l-DOPA Decarboxylase () Reveals Novel Splice Variants Associated with Colorectal Cancer Progression.

Int J Mol Sci 2020 Nov 13;21(22). Epub 2020 Nov 13.

Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701 Athens, Greece.

Colorectal cancer (CRC) is a highly heterogenous malignancy with an increased mortality rate. Aberrant splicing is a typical characteristic of CRC, and several studies support the prognostic value of particular transcripts in this malignancy. l-DOPA decarboxylase (DDC) and its derivative neurotransmitters play a multifaceted role in physiological and pathological states. Our recent data support the existence of 6 novel exons. In this study, we investigated the existence of additional novel exons and transcripts, and their potential value as biomarkers in CRC. Next-generation sequencing (NGS) in 55 human cell lines coupled with Sanger sequencing uncovered 3 additional novel exons and 20 splice variants, 7 of which likely encode new protein isoforms. Eight of these transcripts were detected in CRC. An in-house qPCR assay was developed and performed in TNM II and III CRC samples for the quantification of transcripts bearing novel exons. Extensive biostatistical analysis uncovered the prognostic value of specific novel exons for patients' disease-free and overall survival. The revised exon structure, the putative protein isoforms with distinct functions, and the prognostic value of novel exons highlight the pivotal role of DDC in CRC progression, indicating its potential utility as a molecular biomarker in CRC.
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http://dx.doi.org/10.3390/ijms21228568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697000PMC
November 2020

The interplay between miR-1245a and BRCA2 in colorectal cancer.

Ann Transl Med 2020 Sep;8(17):1043

Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.

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http://dx.doi.org/10.21037/atm-2020-113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575948PMC
September 2020

Next-generation sequencing reveals alternative L-DOPA decarboxylase (DDC) splice variants bearing novel exons, in human hepatocellular and lung cancer cells.

Gene 2021 Feb 23;768:145262. Epub 2020 Oct 23.

Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece. Electronic address:

The human L-DOPA decarboxylase (DDC) is an enzyme that displays a pivotal role in metabolic processes. It is implicated in various human disorders, including hepatocellular and lung cancer. Several splice variants of DDC have previously been described, most of which encode for protein isoforms of this enzyme. In the present study, we used next-generation sequencing (NGS) technology along with nested touchdown PCR and Sanger sequencing to identify new splice variants bearing novel exons of the DDC gene, in hepatocellular and lung cancer cell lines. Using an in-house-developed algorithm, we discovered seven novel DDC exons. Next, we determined the structure of ten novel DDC transcripts, three of which contain an open reading frame (ORF) and probably encode for three previously unknown protein isoforms of this enzyme. Future studies should focus on the elucidation of their role in cellular physiology and cancer pathobiology.
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http://dx.doi.org/10.1016/j.gene.2020.145262DOI Listing
February 2021

Contribution of miRNAs, tRNAs and tRFs to Aberrant Signaling and Translation Deregulation in Lung Cancer.

Cancers (Basel) 2020 Oct 20;12(10). Epub 2020 Oct 20.

Department of Biochemistry, School of Medicine, University of Patras, 26504 Patras, Greece.

Transcriptomics profiles of miRNAs, tRNAs or tRFs are used as biomarkers, after separate examination of several cancer cell lines, blood samples or biopsies. However, the possible contribution of all three profiles on oncogenic signaling and translation as a net regulatory effect, is under investigation. The present analysis of miRNAs and tRFs from lung cancer biopsies indicated putative targets, which belong to gene networks involved in cell proliferation, transcription and translation regulation. In addition, we observed differential expression of specific tRNAs along with several tRNA-related genes with possible involvement in carcinogenesis. Transfection of lung adenocarcinoma cells with two identified tRFs and subsequent NGS analysis indicated gene targets that mediate signaling and translation regulation. Broader analysis of all major signaling and translation factors in several biopsy specimens revealed a crosstalk between the PI3K/AKT and MAPK pathways and downstream activation of eIF4E and eEF2. Subsequent polysome profile analysis and 48S pre-initiation reconstitution experiments showed increased global translation rates and indicated that aberrant expression patterns of translation initiation factors could contribute to elevated protein synthesis. Overall, our results outline the modulatory effects that possibly correlate the expression of important regulatory non-coding RNAs with aberrant signaling and translation deregulation in lung cancer.
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http://dx.doi.org/10.3390/cancers12103056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593945PMC
October 2020

The role of circular RNAs in therapy resistance of patients with solid tumors.

Per Med 2020 11 14;17(6):469-490. Epub 2020 Oct 14.

Department of Biochemistry & Molecular Biology, Faculty of Biology, National & Kapodistrian University of Athens, Athens 15701, Greece.

Circular RNAs (circRNAs) are a type of single-stranded RNA molecules forming a covalently closed, continuous structure, lacking 5'-3' polarity and polyadenylated tails. Recent advances in high-throughput sequencing technologies have revealed that these molecules are abundant, resistant to degradation and often expressed in a tissue- or developmental stage-specific manner. circRNAs are produced by back-splicing circularization of primary transcripts and exhibit a variety of functions, including regulation of transcription, translation and cellular localization. This review focuses on differentially expressed circRNAs conferring therapy resistance or sensitivity of solid tumors, such as carcinomas, sarcomas and lymphomas. Deregulated circRNAs can participate in the development of resistance to treatment by modulating regulatory pathways and cellular processes, including the mitogen-activated protein kinase pathway, epithelial-mesenchymal transition, apoptosis and autophagy.
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http://dx.doi.org/10.2217/pme-2020-0103DOI Listing
November 2020

Unraveling novel survivin mRNA transcripts in cancer cells using an in-house developed targeted high-throughput sequencing approach.

Genomics 2021 Jan 25;113(1 Pt 2):573-581. Epub 2020 Sep 25.

Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece. Electronic address:

The human baculoviral IAP repeat containing 5 (BIRC5), also known as survivin, is a conserved member of the inhibitor of apoptosis protein (IAPs) family, which is normally expressed during embryonic and fetal development. Although the expression levels of survivin are low in terminally differentiated cells and/or tissues, they can be found notably increased in certain pathological conditions including malignant tumors. Conventional cloning and sequencing techniques have already confirmed that alternative splicing events of the survivin pre-mRNA result in five distinct alternative transcript variants. In the present study, however, we implemented an innovative, in-house developed, targeted DNA-seq assay to identify novel survivin alternative transcript variants with increased depth and coverage that high-throughput sequencing approaches offer. Bioinformatics analysis of the derived NGS datasets unveiled several novel splice junctions between annotated exons of survivin gene as well as the existence of a novel exon of 117 nt, spanning between the annotated exons 3 and 3B. Validation of the NGS findings with PCR-based assays, using variant-specific primers, led to the identification of fourteen novel survivin alternative splice variants (BIRC5 v.4 - v.17), which demonstrate wide expression profiles in a broad established panel of human cell lines. Although the presented novel findings provide a crystal-clear overview of the survivin mRNAs that are actually generated from the pre-mRNA, future studies should focus on the impending necessity of characterizing the biological function of all novel alternative transcript variants as well as the putative protein isoforms. Such studies will further contribute to our understanding of how the balance between survivin isoforms regulate malignant cell proliferation and apoptosis, providing novel diagnostic, prognostic and predictive biomarkers as well as therapeutic targets.
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http://dx.doi.org/10.1016/j.ygeno.2020.09.053DOI Listing
January 2021

Seroprevalence of Antibodies against SARS-CoV-2 among the Personnel and Students of the National and Kapodistrian University of Athens, Greece: A Preliminary Report.

Life (Basel) 2020 Sep 21;10(9). Epub 2020 Sep 21.

Department of Clinical Therapeutics, School of Medicine, Alexandra General Hospital, NKUA, 11528 Athens, Greece.

Due to early implementation of public health measures, Greece had low number of SARS-CoV-2 infections and COVID-19 severe incidents in hospitalized patients. The National and Kapodistrian University of Athens (ΝΚUA), especially its health-care/medical personnel, has been actively involved in the first line of state responses to COVID-19. To estimate the prevalence of antibodies (Igs) against SARS-CoV-2 among NKUA members, we designed a five consecutive monthly serosurvey among randomly selected NKUA consenting volunteers. Here, we present the results from the first 2500 plasma samples collected during June-July 2020. Twenty-five donors were tested positive for anti-SARS-CoV-2 Igs; thus, the overall seroprevalence was 1.00%. The weighted overall seroprevalence was 0.93% (95% CI: 0.27, 2.09) and varied between males [1.05% (95% CI: 0.18, 2.92)] and females [0.84% (95% CI: 0.13, 2.49)], age-groups and different categories (higher in participants from the School of Health Sciences and in scientific affiliates/faculty members/laboratory assistants), but no statistical differences were detected. Although focused on the specific population of NKUA members, our study shows that the prevalence of anti-SARS-CoV-2 Igs for the period June-July 2020 remained low and provides knowledge of public health importance for the NKUA members. Given that approximately one in three infections was asymptomatic, continuous monitoring of the progression of the pandemic by assessing Ig seroprevalence is needed.
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http://dx.doi.org/10.3390/life10090214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555935PMC
September 2020

Circular RNAs: A New Piece in the Colorectal Cancer Puzzle.

Cancers (Basel) 2020 Aug 31;12(9). Epub 2020 Aug 31.

Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, GR-15701 Athens, Greece.

Colorectal cancer (CRC) is the third most fatal type of malignancy, worldwide. Despite the advances accomplished in the elucidation of its molecular base and the existing CRC biomarkers introduced in the clinical practice, additional research is required. Circular RNAs (circRNAs) constitute a new RNA type, formed by back-splicing of primary transcripts. They have been discovered during the 1970s but were characterized as by-products of aberrant splicing. However, the modern high-throughput approaches uncovered their widespread expression; therefore, several questions were raised regarding their potential biological roles. During the last years, great progress has been achieved in the elucidation of their functions: circRNAs can act as microRNA sponges, transcription regulators, and interfere with splicing, as well. Furthermore, they are heavily involved in various human pathological states, including cancer, and could serve as diagnostic and prognostic biomarkers in several diseases. Particularly in CRC, aberrant expression of circRNAs has been observed. More specifically, these molecules either inhibit or promote colorectal carcinogenesis by regulating different molecules and signaling pathways. The present review discusses the characteristics and functions of circRNA, prior to analyzing the multifaceted role of these molecules in CRC and their potential value as biomarkers and therapeutic targets.
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http://dx.doi.org/10.3390/cancers12092464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564116PMC
August 2020

A novel, mitochondrial, internal tRNA-derived RNA fragment possesses clinical utility as a molecular prognostic biomarker in chronic lymphocytic leukemia.

Clin Biochem 2020 Nov 1;85:20-26. Epub 2020 Aug 1.

Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens GR-15701, Greece. Electronic address:

Objectives: Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults. The prognosis of CLL patients varies considerably. Transfer RNA-derived RNA fragments (tRFs) constitute a class of small non-coding RNA fragments excised from mature tRNAs and pre-tRNAs located in nuclei as well as in mitochondria. In this study, the clinical utility of i-tRF-Phe, a novel mitochondrial tRF, was investigated in CLL.

Design And Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 91 CLL patients and 43 non-leukemic controls. Total RNA was isolated from each sample, polyadenylated at the 3' end and reversely transcribed. An in-house developed real-time quantitative PCR assay was developed and applied, and the results were biostatistically analyzed. For the normalization of the i-tRF-Phe expression levels, the expression of a small nucleolar RNA (RNU48) was used as reference.

Results: Mann-Whitney U test showed that i-tRF-Phe can distinguish between CLL samples and normal controls (p < 0.001). As determined by Kaplan-Meier survival analysis, overexpression of i-tRF-Phe was related to poor overall survival of the CLL patients (p < 0.001). Univariate bootstrap Cox regression analysis exhibited a higher hazard ratio of 7.95 (95% CI = 2.37-26.72, p < 0.001) for patients with positive i-tRF-Phe expression status. Multivariate bootstrap Cox regression analysis showed that the prognostic value of this tRF is independent of clinical stage, mutational status of the immunoglobulin heavy chain variable (IGHV) genetic locus, and CD38 expression status (p = 0.010).

Conclusions: Our results show that i-tRF-Phe can serve as a molecular biomarker of poor prognosis in CLL, alongside with the existing factors for CLL prognosis.
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http://dx.doi.org/10.1016/j.clinbiochem.2020.07.005DOI Listing
November 2020

Identification and expression analysis of novel splice variants of the human carcinoembryonic antigen-related cell adhesion molecule 19 (CEACAM19) gene using a high-throughput sequencing approach.

Genomics 2020 11 11;112(6):4268-4276. Epub 2020 Jul 11.

Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece. Electronic address:

Alternative splicing is commonly involved in carcinogenesis, being highly implicated in differential expression of cancer-related genes. Recent studies have shown that the human CEACAM19 gene is overexpressed in malignant breast and ovarian tumors, possessing significant biomarker attributes. In the present study, 3' rapid amplification of cDNA ends (3' RACE) and next-generation sequencing (NGS) were used for the detection and identification of novel CEACAM19 transcripts. Bioinformatical analysis of our NGS data revealed novel splice junctions between previously annotated exons and ultimately new exons. Next, fifteen novel CEACAM19 transcripts were identified with Sanger sequencing. Additionally, their expression profile was investigated in a wide panel of human cell lines, using nested PCR with variant-specific primers. The broad expression pattern of the CEACAM19 gene, along with the fact that its overexpression has previously been associated with ovarian and breast cancer progression, indicate the potential of novel CEACAM19 transcripts as putative diagnostic and/or prognostic biomarkers.
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http://dx.doi.org/10.1016/j.ygeno.2020.06.043DOI Listing
November 2020

miR-181a overexpression predicts the poor treatment response and early-progression of serous ovarian cancer patients.

Int J Cancer 2020 12 1;147(12):3560-3573. Epub 2020 Aug 1.

Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.

Ovarian cancer (OC) remains a leading cause of gynecological cancer-related death worldwide, characterized by poor 5-year survival. Molecular markers could serve as crucial tools of personalized prognosis and therapy. Herein, we present miR-181a as novel predictor of OC prognosis, using five independent OC cohorts. In particular, a screening (n = 81) and an institutionally independent validation (n = 100, OVCAD multicenter study) serous OC (SOC) cohorts were analyzed. Bagnoli et al (2016) OC179 (n = 124) to OC133 (n = 100) and TCGA (n = 489) served as external validation cohorts. Patients' survival and disease progression were assessed as clinical endpoint events. Bootstrap analysis was performed for internal validation and decision curve analysis was utilized to evaluate clinical benefit. miR-181a overexpression was unveiled as powerful and independent molecular predictor of patients' poor survival and higher risk for disease progression after debulking surgery and platinum-based chemotherapy. Analysis of the OVCAD institutionally independent cohort, as well as of Bagnoli et al. and TCGA external cohorts further confirmed the unfavorable prognostic nature of miR-181a overexpression in SOC. Strikingly, multivariate prognostic models incorporating miR-181a with established disease markers clearly improved patients' risk-stratification and offered superior clinical benefit in OC prognostication. Conclusively, miR-181a evaluation could augment prognostic accuracy and support precision medicine decisions in OC.
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http://dx.doi.org/10.1002/ijc.33182DOI Listing
December 2020

Complex transcriptional regulation of the BCL2L12 gene: Novel, active promoter in K562 cells.

Gene 2020 Aug 5;750:144723. Epub 2020 May 5.

Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia. Electronic address:

The BCL2L12, one of the latest discovered members of the BCL2 family, has both pro- and anti-apoptotic roles that are cell-type-dependent. Its role in tumorigenesis is highly implicated. Sixty-three splice variants of this gene have been identified so far, with significant differences in expression patterns between various cancer cell lines. Presently, little is known regarding the regulation of expression of the BCL2L12 gene. For the vast majority of BCL2L12 gene splice variants, the 5'- and 3'-untranslated regions as well as their transcriptional regulation have not been determined yet. The aim of this study was to get insight into the regulation of the BCL2L12 gene transcription in human chronic myelogenous leukemia (K562) cell line. Our results point to the activity of novel transcription start site of the BCL2L12 gene and indicate that Sp1 and GATA-1 transcription factors could be involved in the regulation of BCL2L12 gene expression in K562 cells. The previously reported active promoter of BCL2L12 gene differs from the one we described in our study. If this novel BCL2L12 promoter is confirmed to be active in other malignancies, transcripts generated from this region could be considered as new cancer-specific biomarkers. The results of our study contribute to the better understanding of the transcriptional regulation of the BCL2L12 gene.
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http://dx.doi.org/10.1016/j.gene.2020.144723DOI Listing
August 2020

Blood-based analysis of 84 microRNAs identifies molecules deregulated in individuals with type-2 diabetes, risk factors for the disease or metabolic syndrome.

Diabetes Res Clin Pract 2020 Jun 1;164:108187. Epub 2020 May 1.

Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK; Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus. Electronic address:

Aim: Micro-RNAs (miRNAs) are implicated in insulin-signaling and the development of type-2 diabetes (T2D). Their deregulated expression is mostly described in the pancreas, liver, skeletal muscle, or adipose tissue of diabetic animals. Relevant studies in humans are limited due to difficulties in accessing tissue-biopsies. Though, circulating miRNAs are indicators of organ-specific pathophysiological events and could potentially serve as disease biomarkers. We explored the profile of 84 T2D-related miRNAs in peripheral blood of subjects with or without the disease.

Methods: An RT-qPCR array screening 84 T2D-related miRNAs was applied in samples of T2D (n = 6) versus non-T2D (n = 6) subjects. The deregulated miRNAs were thereafter analyzed in peripheral blood samples of a validation cohort of 40 T2D and 37 non-T2D individuals [16 controls and 21 subjects with metabolic syndrome (Met-S) and/or T2D risk factors (T2D-RF)], using specific RT-qPCR assays. Correlations with clinicopathological parameters and risk factors were evaluated.

Results: Subjects with the disease displayed decreased levels of miR-214-3p, miR-24-3p and let-7f-5p, compared to those without. MiRNA levels correlated with serum insulin and HbA1c levels in individuals with T2D or Met-S/T2D-RF, and with higher BMI, dyslipidemia and family history in controls.

Conclusions: Blood levels of miR-214-3p, miR-24-3p and let-7f-5p are down-regulated in T2D- and Met-S/T2D-RF subjects. Future studies are needed to evaluate their potential as disease biomarkers and elucidate the associated tissue-specific pathogenetic mechanisms.
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http://dx.doi.org/10.1016/j.diabres.2020.108187DOI Listing
June 2020

Identification of six novel alternative transcripts of the human kallikrein-related peptidase 15 (KLK15), using 3'RACE and high-throughput sequencing.

Gene 2020 Jul 22;749:144708. Epub 2020 Apr 22.

Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, 15701 Athens, Greece. Electronic address:

The kallikrein-related peptidase 15 (KLK15) gene is a member of the largest cluster of serine proteases in the human genome. Exhibiting trypsin-like activity, KLK15 is most likely involved in the activation of prostate-specific antigen (PSA; also known as KLK3), an established biomarker for the diagnosis and screening of prostate cancer. High mRNA expression levels of KLK15 have already been reported in ovarian and prostate cancer, in contrast with breast cancer, where KLK15 has been proposed as a biomarker of favorable prognosis. In this study, we exploited the next-generation sequencing (NGS) technology along with 3' rapid amplification of cDNA ends (3' RACE) to discover alternative KLK15 splice variants. Extensive computational analysis of the obtained NGS data revealed the existence of novel splice junctions, thus supporting the existence of novel KLK15 transcripts. Six novel KLK15 splice variants were identified and verified by Sanger sequencing. Two of them (KLK15 v.11 and v.12) contain an open reading frame and are hence predicted to encode two novel KLK15 protein isoforms. Expression analysis of each KLK15 splice variant in sixteen cDNA pools from malignant cell lines and in normal cell lines (HEK293, HaCaT, and BJ cells) revealed very different expression profiles of particular KLK15 transcripts. Moreover, the new KLK15 splice variants were shown to be expressed in breast, ovarian, prostate, urinary bladder, colon, and renal tissue specimens. Due to the prominent clinical value of KLK15 mRNA expression, the novel KLK15 transcripts appear as candidate cancer biomarkers for diagnostic and/or prognostic purposes and, therefore, merit further investigation.
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http://dx.doi.org/10.1016/j.gene.2020.144708DOI Listing
July 2020

JQ1 inhibits tumour growth in combination with cisplatin and suppresses JAK/STAT signalling pathway in ovarian cancer.

Eur J Cancer 2020 02 9;126:125-135. Epub 2020 Jan 9.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Greece. Electronic address:

Background: Overexpression of c-Myc is commonly seen in human ovarian cancers, and this could be a potentially novel therapeutic target for this disease. JQ1, a selective small-molecule BET (Bromodomain and extraterminal domain family) bromodomain (BRDs) inhibitor, has been found to suppress tumour progression in several cancer cell types.

Results: Using a panel of ovarian cancer cell lines and primary cell cultures from human ovarian cancer ascites, we demonstrated that JQ1 significantly suppressed cell proliferation and induced apoptosis in an ovarian cancer cell by targeting BRD4 and c-Μyc. In addition, JQ1 sensitized ovarian cancer cells to cisplatin, the most commonly used chemotherapeutic agent in ovarian cancer. Importantly, this effect was observed in ovarian cells, which exhibited resistance to cisplatin alone. Finally, we show that JQ1 interacts with the JAK-STAT signalling pathway, a pathway important in supporting ovarian cancer cell survival by suppressing or inducing genes involved in cell survival and apoptosis, respectively.

Conclusion: Our data, taken together, suggest that JQ1 is an attractive antitumour candidate for further investigation in the treatment of ovarian cancer, as it associates with cell proliferation, apoptosis, and alterations in the JAK-STAT signalling pathway, especially in patients with a platinum-resistant profile or in patients with relapsed disease.
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http://dx.doi.org/10.1016/j.ejca.2019.11.017DOI Listing
February 2020

The emergence of drug resistance to targeted cancer therapies: Clinical evidence.

Drug Resist Updat 2019 12 26;47:100646. Epub 2019 Sep 26.

Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Greece. Electronic address:

For many decades classical anti-tumor therapies included chemotherapy, radiation and surgery; however, in the last two decades, following the identification of the genomic drivers and main hallmarks of cancer, the introduction of therapies that target specific tumor-promoting oncogenic or non-oncogenic pathways, has revolutionized cancer therapeutics. Despite the significant progress in cancer therapy, clinical oncologists are often facing the primary impediment of anticancer drug resistance, as many cancer patients display either intrinsic chemoresistance from the very beginning of the therapy or after initial responses and upon repeated drug treatment cycles, acquired drug resistance develops and thus relapse emerges, resulting in increased mortality. Our attempts to understand the molecular basis underlying these drug resistance phenotypes in pre-clinical models and patient specimens revealed the extreme plasticity and adaptive pathways employed by tumor cells, being under sustained stress and extensive genomic/proteomic instability due to the applied therapeutic regimens. Subsequent efforts have yielded more effective inhibitors and combinatorial approaches (e.g. the use of specific pharmacologic inhibitors with immunotherapy) that exhibit synergistic effects against tumor cells, hence enhancing therapeutic indices. Furthermore, new advanced methodologies that allow for the early detection of genetic/epigenetic alterations that lead to drug chemoresistance and prospective validation of biomarkers which identify patients that will benefit from certain drug classes, have started to improve the clinical outcome. This review discusses emerging principles of drug resistance to cancer therapies targeting a wide array of oncogenic kinases, along with hedgehog pathway and the proteasome and apoptotic inducers, as well as epigenetic and metabolic modulators. We further discuss mechanisms of resistance to monoclonal antibodies, immunomodulators and immune checkpoint inhibitors, potential biomarkers of drug response/drug resistance, along with possible new therapeutic avenues for the clinicians to combat devastating drug resistant malignancies. It is foreseen that these topics will be major areas of focused multidisciplinary translational research in the years to come.
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http://dx.doi.org/10.1016/j.drup.2019.100646DOI Listing
December 2019

Heat shock protein beta 3 (HSPB3) is an unfavorable molecular biomarker in colorectal adenocarcinoma.

Mol Carcinog 2020 01 10;59(1):116-125. Epub 2019 Nov 10.

Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.

Small heat shock proteins (sHSPs) participate in numerous cellular functions including cell signaling, differentiation, and apoptosis. Deregulation of the physiological expression level of sHSPs has been associated with several malignancies. Heat shock protein beta 3 (HSPB3) is the third member of the sHSP family in human and is mainly expressed in skeletal and smooth muscles. In this study, we investigated the potential prognostic significance of HSPB3 expression in colorectal adenocarcinoma, the most frequent type of colorectal cancer. For this purpose, we isolated total RNA from 188 colorectal adenocarcinoma specimens and 68 paired noncancerous ones. After reverse transcription of 2 μg total RNA, we quantified HSPB3 levels by using an in-house-developed real-time quantitative polymerase chain reaction method, based on the SYBR Green chemistry. Comparison of HSPB3 levels among 68 pairs of colorectal tumors and their adjacent noncancerous mucosae uncovered the downregulation of HSPB3 expression in the majority of malignant colorectal tumors. More importantly, high HSPB3 expression is associated with poor relapse-free survival (RFS) and overall survival (OS) of patients with colorectal adenocarcinoma. Multivariable Cox regression analysis revealed that HSPB3 overexpression could serve as an adverse prognostic biomarker in colorectal adenocarcinoma, independent of tumor location, histological grade, and TNM stage. Patients' stratification according to tumor location, histological grade, and TNM stage revealed that high HSPB3 messenger RNA expression retains its unfavorable prognostic potential regarding OS, in particular groups of patients with substantially different prognosis. In conclusion, high HSPB3 expression is associated with poor RFS and OS of patients with colorectal adenocarcioma, independently of clinicopathological prognosticators.
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http://dx.doi.org/10.1002/mc.23133DOI Listing
January 2020

High clusterin (CLU) mRNA expression levels in tumors of colorectal cancer patients predict a poor prognostic outcome.

Clin Biochem 2020 Jan 28;75:62-69. Epub 2019 Oct 28.

Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens GR-15701, Greece. Electronic address:

Objectives: Clusterin (CLU) is a multifunctional intra-/extra-cellular molecular chaperone with indications of serving as a promising prognostic biomarker for colorectal cancer (CRC). Several studies have examined the potential prognostic value of the CLU protein in CRC; however, our research follows an alternative approach, focusing on the CLU mRNA expression.

Design And Methods: Total RNA from 172 cancerous tissue specimens and 39 paired non-cancerous ones was isolated and 2 μg of this were subjected to reverse transcription with an oligo-dT primer. The single stranded DNA, which was synthesized, was amplified with an in-house developed highly sensitive and precise qPCR method, using specific pair of primers for the CLU molecule. Finally, an extensive biostatistical analysis took place for the assessment of the results.

Results: Patients with tumors expressing high CLU mRNA levels had a higher probability for poor outcome (relapse and death), comparing to those with CLU mRNA-negative tumors. This association between CLU mRNA expression status and both disease-free survival (DFS) and overall survival (OS) is evident in Cox regression analysis and is also depicted in the Kaplan-Meier survival curves. Consistently, the aforementioned associations and the CLU mRNA expression levels are significantly enhanced as CRC tumors progress from TNM stage I to IV, further supporting the functional implication of CLU in tumorigenesis.

Conclusions: High CLU mRNA levels in CRC tumors can act as a new adverse prognostic biomarker of DFS and OS for CRC, independent of clinicopathological and biological features of the patient.
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http://dx.doi.org/10.1016/j.clinbiochem.2019.10.008DOI Listing
January 2020

Identification of a novel, internal tRNA-derived RNA fragment as a new prognostic and screening biomarker in chronic lymphocytic leukemia, using an innovative quantitative real-time PCR assay.

Leuk Res 2019 12 11;87:106234. Epub 2019 Oct 11.

Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Panepistimiopolis, 15701, Athens, Greece. Electronic address:

Chronic lymphocytic leukemia (CLL) is one of the most common types of leukemia in adults. Several studies have identified various prognostic biomarkers in CLL. In this study, we investigated the potential value of an internal fragment of the tRNAs bearing the Glycine anticodon CCC (i-tRF-GlyCCC), which is a small non-coding RNA, as a prognostic and screening biomarker in CLL. For this purpose, blood samples were collected from 90 CLL patients and 43 non-leukemic blood donors. Peripheral blood mononuclear cells (PBMCs) were isolated, total RNA was extracted and in-vitro polyadenylated, and first-strand cDNA was synthesized using an oligo-dT-adaptor primer. A real-time quantitative PCR assay was developed and applied for the quantification of i-tRF-GlyCCC in our samples. The biostatistical analysis revealed that i-tRF-GlyCCC levels are significantly lower in PBMCs of CLL patients, compared to PBMCs of non-leukemic controls, and that i-tRF-GlyCCC could be considered as a screening biomarker. Kaplan-Meier overall survival (OS) analysis revealed reduced OS for CLL patients with positive i-tRF-GlyCCC expression (P = 0.001). Multivariate Cox regression confirmed its independent unfavorable prognostic power with regard to OS. In conclusion, i-tRF-GlyCCC may constitute a promising molecular biomarker in CLL, for screening and prognostic purposes.
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http://dx.doi.org/10.1016/j.leukres.2019.106234DOI Listing
December 2019

The miR-200 family as prognostic markers in clear cell renal cell carcinoma.

Urol Oncol 2019 12 19;37(12):955-963. Epub 2019 Oct 19.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada. Electronic address:

Objectives: microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by mRNA cleavage or translational repression. The miR-200 family is involved in the regulation of various tumor biologic processes including apoptosis, proliferation, invasion, and metastasis. They function mainly as tumor suppressors. In this study, we aim to validate the prognostic significance of miR-200 family using large cohort of primary clear cell renal cell carcinoma (ccRCC) and matched normal tissue and to explore the role of miR-200 family in RCC pathogenesis and progression.

Materials And Methods: We analyzed the expression of 3 members of the miR-200 family; miR-141, miR-200b, and miR-200c, between primary ccRCC, matched normal renal tissues, and nonmatched metastatic RCC. We compared clinicopathologic parameter including disease-free survival to miR-200 family expression. Additionally, we validated our results using The Cancer Genome Atlas dataset. We explored functional role of these miRNAs by bioinformatics analyses.

Results And Conclusions: Expression of miR-200 family significantly decreased in cancer compared to non-neoplastic tissues. miR-141 and miR-200b were significantly down-regulated in metastatic than primary tumors. There was statistically significant negative association between all 3 miRNAs and tumor size and stage. As binary variables, univariate analyses revealed that miR-141, miR-200b, and miR-200c-positive ccRCC patients have a statistically significant lower chance of disease-recurrence or relapse and multivariate analyses showed miR-200b and miR-200c-positive patients have longer disease-free survival. We could predict disease-free survival better when 2 or more miRNAs were used as a combination. Overall survival analysis using The Cancer Genome Atlas data revealed that miR-200b-positive patients have significantly better survival. These results suggest that miR-141, miR-200b, and miR-200c are independent prognostic markers for ccRCC. Targets of these miRNAs are associated with pathways related to cancer invasion and metastasis, including TRAIL pathway, VEGF and VEGFR signaling network, and epithelial-mesenchymal transition.
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http://dx.doi.org/10.1016/j.urolonc.2019.08.008DOI Listing
December 2019