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Molecular Biomarkers in Cancer and Metabolic Disease
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Molecular Biomarkers in Cancer and Metabolic Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 46427

Special Issue Editors

Prof. Dr. Elisabetta Ferretti

E-Mail Website
Guest Editor
Dipartimento di Medicina Sperimentale, Università di Roma "La Sapienza", Viale Regina Elena, 291, 00161 Rome, Italy
Interests: precision medicine; biomarkers; liquid biopsy; brain tumours; Hedgehog-Gli signaling; colorectal cancer; thyroid cancer; melanoma; obesity; diabetes
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Zein Mersini Besharat

E-Mail Website1 Website2
Guest Editor
Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena, 324, 00161 Rome, Italy
Interests: network medicine; bioinformatics; omics; data integration; cancer; diabetes
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Agnese Po

E-Mail Website1 Website2
Guest Editor
Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena, 291, 00161 Rome, Italy
Interests: targeted therapy; non-coding RNAs; lung cancer; cfDNA; microRNAs; cancer stem cells; tumour escape mechanisms; in vivo models; metabolic disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue will cover the role of molecular biomarkers in cancer and metabolic disease. In this era, where precision medicine is taking a central role in patient care, we finally have the tools to identify molecular biomarkers, which are ideal, as they are able to both reflect the disease and characterize each individual patient. The challenge today is not only to determine the biomarkers with increased specificity and sensitivity, but also to move them to a clinical setting, thus approaching translational medicine. This Issue is dedicated to some of the latest and most remarkable advances involving molecular biomarkers in different contexts. The selected studies that will be included in this Issue will cover molecular biomarkers detected in different biological samples and will include nucleic acid-based biomarkers, such as gene mutations and non-coding RNAs. Finally, the latest developments in how molecular biomarkers can be exploited in the development of new targeted therapies and in patients’ follow-up will be discussed. A number of selected reviews will address personalized medicine in the general notion of precision medicine and how the use of network medicine can contribute to our everlasting confrontation with disease. For this reason, we have put together scientists with long-standing experience in the field, as well as young scientists with innovative ideas, to share their precious contribution.

Prof. Dr. Elisabetta Ferretti
Prof. Dr. Zein Mersini Besharat
Prof. Dr. Agnese Po
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Precision medicine
  • Biomarkers
  • Cancer
  • Metabolic disease
  • Liquid biopsy
  • Targeted therapy
  • Risk stratification
  • Network medicine

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Published Papers (15 papers)

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Research

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17 pages, 3479 KiB  
Article
LINE-1 Cargo and Reverse Transcriptase Activity Profiles in Extracellular Vesicles from Lung Cancer Cells and Human Plasma
by Emma C. Bowers, Alexandre Motta, Ken Knox, Brian S. McKay and Kenneth S. Ramos
Int. J. Mol. Sci. 2022, 23(7), 3461; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073461 - 22 Mar 2022
Cited by 3 | Viewed by 2814
Abstract
Long Interspersed Element-1 (LINE-1) is an oncogenic human retrotransposon that ‘copies and pastes’ DNA into new locations via reverse transcription. Given that enzymatically active LINE-1 can be exported in extracellular vesicles (EVs), and that LINE-1 mRNA and its two encoded proteins, ORF1p and [...] Read more.
Long Interspersed Element-1 (LINE-1) is an oncogenic human retrotransposon that ‘copies and pastes’ DNA into new locations via reverse transcription. Given that enzymatically active LINE-1 can be exported in extracellular vesicles (EVs), and that LINE-1 mRNA and its two encoded proteins, ORF1p and ORF2p, are required for retrotransposition, the present study examined LINE-1 EV loading patterns relative to reverse transcriptase (RT) activity in vivo and in vitro. Density gradient ultracentrifugation identified conserved patterns of LINE-1 mRNA and protein distribution in EVs, with RT activity readily detected in EV fractions containing both LINE-1 mRNA and protein. Unlike whole cell and tissue lysates, the ORF1p in EVs was detected as a dimer. EVs from ostensibly healthy plasma donors showed variable but consistent ORF1p profiles, with residual levels of LINE-1 mRNA measured in some but not all samples. EVs from cancer cell lines had elevated mean LINE-1 levels and 5–85 times greater RT activity than EVs from normal cells or healthy plasma. EV RT activity was associated with EV LINE-1 mRNA content and was highest in cell lines that also expressed an elevated expression of ORF1p and ORF2p. Given that LINE-1 activation is a hallmark of many cancer types, our findings suggest that an EV LINE-1 ‘liquid biopsy’ may be developed to monitor LINE-1 activity during the course of malignant progression. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Metabolic Disease)
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22 pages, 17758 KiB  
Article
Identification of Fucosylated SERPINA1 as a Novel Plasma Marker for Pancreatic Cancer Using Lectin Affinity Capture Coupled with iTRAQ-Based Quantitative Glycoproteomics
by Chia-Chun Wu, Yu-Ting Lu, Ta-Sen Yeh, Yun-Hsin Chan, Srinivas Dash and Jau-Song Yu
Int. J. Mol. Sci. 2021, 22(11), 6079; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116079 - 04 Jun 2021
Cited by 12 | Viewed by 2524
Abstract
Pancreatic cancer (PC) is an aggressive cancer with a high mortality rate, necessitating the development of effective diagnostic, prognostic and predictive biomarkers for disease management. Aberrantly fucosylated proteins in PC are considered a valuable resource of clinically useful biomarkers. The main objective of [...] Read more.
Pancreatic cancer (PC) is an aggressive cancer with a high mortality rate, necessitating the development of effective diagnostic, prognostic and predictive biomarkers for disease management. Aberrantly fucosylated proteins in PC are considered a valuable resource of clinically useful biomarkers. The main objective of the present study was to identify novel plasma glycobiomarkers of PC using the iTRAQ quantitative proteomics approach coupled with Aleuria aurantia lectin (AAL)-based glycopeptide enrichment and isotope-coded glycosylation site-specific tagging, with a view to analyzing the glycoproteome profiles of plasma samples from patients with non-metastatic and metastatic PC and gallstones (GS). As a result, 22 glycopeptides with significantly elevated levels in plasma samples of PC were identified. Fucosylated SERPINA1 (fuco-SERPINA1) was selected for further validation in 121 plasma samples (50 GS and 71 PC) using an AAL-based reverse lectin ELISA technique developed in-house. Our analyses revealed significantly higher plasma levels of fuco-SERPINA1 in PC than GS subjects (310.7 ng/mL v.s. 153.6 ng/mL, p = 0.0114). Elevated fuco-SERPINA1 levels were associated with higher TNM stage (p = 0.024) and poorer prognosis for overall survival (log-rank test, p = 0.0083). The increased plasma fuco-SERPINA1 levels support the utility of this protein as a novel prognosticator for PC. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Metabolic Disease)
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25 pages, 5982 KiB  
Article
Molecular Analysis of ZNF71 KRAB in Non-Small-Cell Lung Cancer
by Qing Ye, Rehab Mohamed, Duaa Dakhlallah, Marieta Gencheva, Gangqing Hu, Martin C. Pearce, Siva Kumar Kolluri, Clay B. Marsh, Timothy D. Eubank, Alexey V. Ivanov and Nancy Lan Guo
Int. J. Mol. Sci. 2021, 22(7), 3752; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073752 - 04 Apr 2021
Cited by 12 | Viewed by 3999
Abstract
Our previous study found that zinc finger protein 71 (ZNF71) mRNA expression was associated with chemosensitivity and its protein expression was prognostic of non-small-cell lung cancer (NSCLC). The Krüppel associated box (KRAB) transcriptional repression domain is commonly present in human zinc finger proteins, [...] Read more.
Our previous study found that zinc finger protein 71 (ZNF71) mRNA expression was associated with chemosensitivity and its protein expression was prognostic of non-small-cell lung cancer (NSCLC). The Krüppel associated box (KRAB) transcriptional repression domain is commonly present in human zinc finger proteins, which are linked to imprinting, silencing of repetitive elements, proliferation, apoptosis, and cancer. This study revealed that ZNF71 KRAB had a significantly higher expression than the ZNF71 KRAB-less isoform in NSCLC tumors (n = 197) and cell lines (n = 117). Patients with higher ZNF71 KRAB expression had a significantly worse survival outcome than patients with lower ZNF71 KRAB expression (log-rank p = 0.04; hazard ratio (HR): 1.686 [1.026, 2.771]), whereas ZNF71 overall and KRAB-less expression levels were not prognostic in the same patient cohort. ZNF71 KRAB expression was associated with epithelial-to-mesenchymal transition (EMT) in both patient tumors and cell lines. ZNF71 KRAB was overexpressed in NSCLC cell lines resistant to docetaxel and paclitaxel treatment compared to chemo-sensitive cell lines, consistent with its association with poor prognosis in patients. Therefore, ZNF71 KRAB isoform is a more effective prognostic factor than ZNF71 overall and KRAB-less expression for NSCLC. Functional analysis using CRISPR-Cas9 and RNA interference (RNAi) screening data indicated that a knockdown/knockout of ZNF71 did not significantly affect NSCLC cell proliferation in vitro. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Metabolic Disease)
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15 pages, 2318 KiB  
Article
An Integrative Transcriptome-Wide Analysis of Amyotrophic Lateral Sclerosis for the Identification of Potential Genetic Markers and Drug Candidates
by Sungmin Park, Daeun Kim, Jaeseung Song and Jong Wha J. Joo
Int. J. Mol. Sci. 2021, 22(6), 3216; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063216 - 22 Mar 2021
Cited by 6 | Viewed by 3147
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative neuromuscular disease. Although genome-wide association studies (GWAS) have successfully identified many variants significantly associated with ALS, it is still difficult to characterize the underlying biological mechanisms inducing ALS. In this study, we performed a transcriptome-wide association [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative neuromuscular disease. Although genome-wide association studies (GWAS) have successfully identified many variants significantly associated with ALS, it is still difficult to characterize the underlying biological mechanisms inducing ALS. In this study, we performed a transcriptome-wide association study (TWAS) to identify disease-specific genes in ALS. Using the largest ALS GWAS summary statistic (n = 80,610), we identified seven novel genes using 19 tissue reference panels. We conducted a conditional analysis to verify the genes’ independence and to confirm that they are driven by genetically regulated expressions. Furthermore, we performed a TWAS-based enrichment analysis to highlight the association of important biological pathways, one in each of the four tissue reference panels. Finally, utilizing a connectivity map, a database of human cell expression profiles cultured with bioactive small molecules, we discovered functional associations between genes and drugs to identify 15 bioactive small molecules as potential drug candidates for ALS. We believe that, by integrating the largest ALS GWAS summary statistic with gene expression to identify new risk loci and causal genes, our study provides strong candidates for molecular basis experiments in ALS. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Metabolic Disease)
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22 pages, 5903 KiB  
Article
Preclinical Evaluation of [18F]FACH in Healthy Mice and Piglets: An 18F-Labeled Ligand for Imaging of Monocarboxylate Transporters with PET
by Daniel Gündel, Masoud Sadeghzadeh, Winnie Deuther-Conrad, Barbara Wenzel, Paul Cumming, Magali Toussaint, Friedrich-Alexander Ludwig, Rareş-Petru Moldovan, Mathias Kranz, Rodrigo Teodoro, Bernhard Sattler, Osama Sabri and Peter Brust
Int. J. Mol. Sci. 2021, 22(4), 1645; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041645 - 06 Feb 2021
Cited by 1 | Viewed by 2379
Abstract
The expression of monocarboxylate transporters (MCTs) is linked to pathophysiological changes in diseases, including cancer, such that MCTs could potentially serve as diagnostic markers or therapeutic targets. We recently developed [18F]FACH as a radiotracer for non-invasive molecular imaging of MCTs by [...] Read more.
The expression of monocarboxylate transporters (MCTs) is linked to pathophysiological changes in diseases, including cancer, such that MCTs could potentially serve as diagnostic markers or therapeutic targets. We recently developed [18F]FACH as a radiotracer for non-invasive molecular imaging of MCTs by positron emission tomography (PET). The aim of this study was to evaluate further the specificity, metabolic stability, and pharmacokinetics of [18F]FACH in healthy mice and piglets. We measured the [18F]FACH plasma protein binding fractions in mice and piglets and the specific binding in cryosections of murine kidney and lung. The biodistribution of [18F]FACH was evaluated by tissue sampling ex vivo and by dynamic PET/MRI in vivo, with and without pre-treatment by the MCT inhibitor α-CCA-Na or the reference compound, FACH-Na. Additionally, we performed compartmental modelling of the PET signal in kidney cortex and liver. Saturation binding studies in kidney cortex cryosections indicated a KD of 118 ± 12 nM and Bmax of 6.0 pmol/mg wet weight. The specificity of [18F]FACH uptake in the kidney cortex was confirmed in vivo by reductions in AUC0–60min after pre-treatment with α-CCA-Na in mice (−47%) and in piglets (−66%). [18F]FACH was metabolically stable in mouse, but polar radio-metabolites were present in plasma and tissues of piglets. The [18F]FACH binding potential (BPND) in the kidney cortex was approximately 1.3 in mice. The MCT1 specificity of [18F]FACH uptake was confirmed by displacement studies in 4T1 cells. [18F]FACH has suitable properties for the detection of the MCTs in kidney, and thus has potential as a molecular imaging tool for MCT-related pathologies, which should next be assessed in relevant disease models. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Metabolic Disease)
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17 pages, 1971 KiB  
Article
Comparison of Proteomic Technologies for Blood-Based Detection of Colorectal Cancer
by Megha Bhardwaj, Tobias Terzer, Petra Schrotz-King and Hermann Brenner
Int. J. Mol. Sci. 2021, 22(3), 1189; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031189 - 26 Jan 2021
Cited by 5 | Viewed by 3668
Abstract
Blood-based protein biomarkers are increasingly being explored as supplementary or efficient alternatives for population-based screening of colorectal cancer (CRC). The objective of the current study was to compare the diagnostic potential of proteins measured with different proteomic technologies. The concentrations of protein biomarkers [...] Read more.
Blood-based protein biomarkers are increasingly being explored as supplementary or efficient alternatives for population-based screening of colorectal cancer (CRC). The objective of the current study was to compare the diagnostic potential of proteins measured with different proteomic technologies. The concentrations of protein biomarkers were measured using proximity extension assays (PEAs), liquid chromatography/multiple reaction monitoring–mass spectrometry (LC/MRM-MS) and quantibody microarrays (QMAs) in plasma samples of 56 CRC patients and 99 participants free of neoplasms. In another approach, proteins were measured in serum samples of 30 CRC cases and 30 participants free of neoplasm using immunome full-length functional protein arrays (IpAs). From all the measurements, 9, 6, 35 and 14 protein biomarkers overlapped for comparative evaluation of (a) PEA and LC/MRM-MS, (b) PEA and QMA, (c) PEA and IpA, and (d) LC/MRM-MS and IpA measurements, respectively. Correlation analysis was performed, along with calculation of the area under the curve (AUC) for assessing the diagnostic potential of each biomarker. DeLong’s test was performed to assess the differences in AUC. Evaluation of the nine biomarkers measured with PEA and LC/MRM-MS displayed correlation coefficients >+0.6, similar AUCs and DeLong’s p-values indicating no differences in AUCs for biomarkers like insulin-like growth factor binding protein 2 (IGFBP2), matrix metalloproteinase 9 (MMP9) and serum paraoxonase lactonase 3 (PON3). Comparing six proteins measured with PEA and QMA showed good correlation and similar diagnostic performance for only one protein, growth differentiation factor 15 (GDF15). The comparison of 35 proteins measured with IpA and PEA and 14 proteins analyzed with IpA and LC/MRM-MS revealed poor concordance and comparatively better AUCs when measured with PEA and LC/MRM-MS. The comparison of different proteomic technologies suggests the superior performance of novel technologies like PEA and LC/MRM-MS over the assessed array-based technologies in blood-protein-based early detection of CRC. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Metabolic Disease)
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15 pages, 1377 KiB  
Article
Phosphodiesterase Type-5 Inhibitor Tadalafil Modulates Steroid Hormones Signaling in a Prostate Cancer Cell Line
by Viviana M. Bimonte, Francesco Marampon, Ambra Antonioni, Simona Fittipaldi, Elisabetta Ferretti, Richard G. Pestell, Mariaignazia Curreli, Andrea Lenzi, Giovanni Vitale, Antonio Brunetti, Silvia Migliaccio and Antonio Aversa
Int. J. Mol. Sci. 2021, 22(2), 754; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020754 - 13 Jan 2021
Cited by 7 | Viewed by 2959
Abstract
Background: The androgen receptor (AR) plays a key role in normal prostate homeostasis and in prostate cancer (PCa) development, while the role of aromatase (Cyp19a1) is still unclear. We evaluated the effects of a treatment with Tadalafil (TAD) on both these proteins. Methods: [...] Read more.
Background: The androgen receptor (AR) plays a key role in normal prostate homeostasis and in prostate cancer (PCa) development, while the role of aromatase (Cyp19a1) is still unclear. We evaluated the effects of a treatment with Tadalafil (TAD) on both these proteins. Methods: Androgen-sensitive human PCa cell line (LnCAP) was incubated with/without TAD (10−6 M) and bicalutamide (BCT) (10−4 M) to evaluate a potential modulation on cell proliferation, protein and mRNA expression of Cyp19a, AR and estrogen receptor-β (ERβ), respectively. Results: TAD increased early AR nuclear translocation (p < 0.05, after 15 min of exposure), and increased AR transcriptional activity (p < 0.05) and protein expression (p < 0.05) after 24 h. Moreover, after 24 h this treatment upregulated Cyp19a1 and ERβ mRNA (p < 0.05 and p < 0.005 respectively) and led to an increase in protein expression of both after 48 h (p < 0.05). Interestingly, TAD counteracted Cyp19a1 stimulation induced by BCT (p < 0.05) but did not alter the effect induced by BCT on the AR protein expression. Conclusion: We demonstrate for the first time that TAD can significantly modulate AR expression and activity, Cyp19a1 and ERβ expression in PCa cells, suggesting a specific effect of these proteins. In addition, TAD potentiates the antiproliferative activity of BCT, opening a new clinical scenario in the treatment of PCa. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Metabolic Disease)
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32 pages, 3828 KiB  
Article
Circular RNAs and Their Linear Transcripts as Diagnostic and Prognostic Tissue Biomarkers in Prostate Cancer after Prostatectomy in Combination with Clinicopathological Factors
by Hannah Rochow, Monika Jung, Sabine Weickmann, Bernhard Ralla, Carsten Stephan, Sefer Elezkurtaj, Ergin Kilic, Zhongwei Zhao, Klaus Jung, Annika Fendler and Antonia Franz
Int. J. Mol. Sci. 2020, 21(21), 7812; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217812 - 22 Oct 2020
Cited by 8 | Viewed by 2384
Abstract
As new biomarkers, circular RNAs (circRNAs) have been largely unexplored in prostate cancer (PCa). Using an integrative approach, we aimed to evaluate the potential of circRNAs and their linear transcripts (linRNAs) to act as (i) diagnostic biomarkers for differentiation between normal and tumor [...] Read more.
As new biomarkers, circular RNAs (circRNAs) have been largely unexplored in prostate cancer (PCa). Using an integrative approach, we aimed to evaluate the potential of circRNAs and their linear transcripts (linRNAs) to act as (i) diagnostic biomarkers for differentiation between normal and tumor tissue and (ii) prognostic biomarkers for the prediction of biochemical recurrence (BCR) after radical prostatectomy. In a first step, eight circRNAs (circATXN10, circCRIM1, circCSNK1G3, circGUCY1A2, circLPP, circNEAT1, circRHOBTB3, and circSTIL) were identified as differentially expressed via a genome-wide circRNA-based microarray analysis of six PCa samples. Additional bioinformatics and literature data were applied for this selection process. In total, 115 malignant PCa and 79 adjacent normal tissue samples were examined using robust RT-qPCR assays specifically established for the circRNAs and their linear counterparts. Their diagnostic and prognostic potential was evaluated using receiver operating characteristic curves, Cox regressions, decision curve analyses, and C-statistic calculations of prognostic indices. The combination of circATXN10 and linSTIL showed a high discriminative ability between malignant and adjacent normal tissue PCa. The combination of linGUCY1A2, linNEAT1, and linSTIL proved to be the best predictive RNA-signature for BCR. The combination of this RNA signature with five established reference models based on only clinicopathological factors resulted in an improved predictive accuracy for BCR in these models. This is an encouraging study for PCa to evaluate circRNAs and their linRNAs in an integrative approach, and the results showed their clinical potential in combination with standard clinicopathological variables. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Metabolic Disease)
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23 pages, 4068 KiB  
Article
Accumulation of 8-hydroxydeoxyguanosine, L-arginine and Glucose Metabolites by Liver Tumor Cells Are the Important Characteristic Features of Metabolic Syndrome and Non-Alcoholic Steatohepatitis-Associated Hepatocarcinogenesis
by Anna Kakehashi, Shugo Suzuki, Naomi Ishii, Takahiro Okuno, Yuko Kuwae, Masaki Fujioka, Min Gi, Vasily Stefanov and Hideki Wanibuchi
Int. J. Mol. Sci. 2020, 21(20), 7746; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207746 - 20 Oct 2020
Cited by 17 | Viewed by 3235
Abstract
To uncover mechanisms and explore novel biomarkers of obesity, type 2 diabetes (T2DM) and nonalcoholic steatohepatitis (NASH)-associated hepatocarcinogenesis, cellular and molecular alterations in the liver, and hepatocellular carcinomas (HCCs) were investigated in NASH model 60-week-old Tsumura, Suzuki, Obese Diabetic (TSOD) mice and NASH [...] Read more.
To uncover mechanisms and explore novel biomarkers of obesity, type 2 diabetes (T2DM) and nonalcoholic steatohepatitis (NASH)-associated hepatocarcinogenesis, cellular and molecular alterations in the liver, and hepatocellular carcinomas (HCCs) were investigated in NASH model 60-week-old Tsumura, Suzuki, Obese Diabetic (TSOD) mice and NASH HCC patients. Markedly elevated lipid deposition, inflammation, fibrosis, and peroxisome proliferation in the liver, preneoplastic lesions, and HCCs of TSOD mice were accompanied by accumulation of polysaccharides in the cellular cytoplasm and nuclei and increase of oxidative DNA damage marker, 8-hydroxydeoxyguanosine (8-OHdG) formation in the liver and altered foci. Metabolomics of TSOD mice HCCs demonstrated significant elevation of the concentration of amino acid L-arginine, phosphocreatine, S-adenosylmethionine/S-adenosylhomocysteine ratio, adenylate, and guanylate energy charges in coordination with tremendous rise of glucose metabolites, mostly fructose 1,6-diphosphate. L-arginine accumulation in HCCs was associated with significant under-expression of arginase 1 (ARG1), suppression of the urea cycle, methionine and putrescine degradation pathways, activation of Ser and Thr kinase Akt AKT, phosphoinositide 3-kinase (PI3K), extracellular signal-regulated kinase 1/2 (ERK1/2) kinases, β-catenin, mammalian target of rapamycin (mTOR), and cell proliferation. Furthermore, clinicopathological analysis in 20 metabolic syndrome/NASH and 80 HCV-positive HCC patients demonstrated significant correlation of negative ARG1 expression with poor tumor differentiation, higher pathological stage, and significant decrease of survival in metabolic syndrome/NASH-associated HCC patients, thus indicating that ARG1 could become a potential marker for NASH HCC. From these results, formation of oxidative stress and 8-OHdG in the DNA and elevation of glucose metabolites and L-arginine due to ARG1 suppression in mice liver cells are the important characteristics of T2DM/NASH-associated hepatocarcinogenesis, which may take part in activating oxidative stress resistance, synthesis of phosphocreatine, cell signaling, methylation, and proliferation. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Metabolic Disease)
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20 pages, 2862 KiB  
Article
MicroRNA Expression in the Aqueous Humor of Patients with Diabetic Macular Edema
by Giuseppina Emanuela Grieco, Guido Sebastiani, Chiara Maria Eandi, Giovanni Neri, Laura Nigi, Noemi Brusco, Romina D'Aurizio, Matteo Posarelli, Tommaso Bacci, Elena De Benedetto, Mario Fruschelli, Maurizio Orlandini, Federico Galvagni, Francesco Dotta and Gian Marco Tosi
Int. J. Mol. Sci. 2020, 21(19), 7328; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197328 - 03 Oct 2020
Cited by 16 | Viewed by 2866
Abstract
We identified and compared secreted microRNA (miRNA) expression in aqueous humor (AH) and plasma samples among patients with: type 2 diabetes mellitus (T2D) complicated by non-proliferative diabetic retinopathy (DR) associated with diabetic macular edema (DME) (DME group: 12 patients); T2D patients without DR [...] Read more.
We identified and compared secreted microRNA (miRNA) expression in aqueous humor (AH) and plasma samples among patients with: type 2 diabetes mellitus (T2D) complicated by non-proliferative diabetic retinopathy (DR) associated with diabetic macular edema (DME) (DME group: 12 patients); T2D patients without DR (D group: 8 patients); and non-diabetic patients (CTR group: 10 patients). Individual patient AH samples from five subjects in each group were profiled on TaqMan Low Density MicroRNA Array Cards. Differentially expressed miRNAs identified from profiling were then validated in single assay for all subjects. The miRNAs validated in AH were then evaluated in single assay in plasma. Gene Ontology (GO) analysis was conducted. From AH profiling, 119 mature miRNAs were detected: 86 in the DME group, 113 in the D group and 107 in the CTR group. miRNA underexpression in the DME group was confirmed in single assay for let-7c-5p, miR-200b-3p, miR-199a-3p and miR-365-3p. Of these four, miR-199a-3p and miR-365-3p were downregulated also in the plasma of the DME group. GO highlighted 54 validated target genes of miR-199a-3p, miR-200b-3p and miR-365-3p potentially implied in DME pathogenesis. Although more studies are needed, miR-200b-3p, let-7c-5p, miR-365-3p and miR-199a-3p represent interesting molecules in the study of DME pathogenesis. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Metabolic Disease)
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13 pages, 467 KiB  
Article
The Association of dp-ucMGP with Cardiovascular Morbidity and Decreased Renal Function in Diabetic Chronic Kidney Disease
by Stefanos Roumeliotis, Athanasios Roumeliotis, Aikaterini Stamou, Konstantinos Leivaditis, Konstantia Kantartzi, Stylianos Panagoutsos and Vassilios Liakopoulos
Int. J. Mol. Sci. 2020, 21(17), 6035; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176035 - 21 Aug 2020
Cited by 21 | Viewed by 2783
Abstract
We aimed to investigate the possible association of the inactive, dephosphorylated, uncarboxylated matrix Gla protein (dp-ucMGP) with oxidized low-density lipoprotein (ox-LDL) and all-cause/cardiovascular (CV) mortality and renal function in diabetic chronic kidney disease (CKD). Ox-LDL and dp-ucMGP were determined in 66 diabetic CKD [...] Read more.
We aimed to investigate the possible association of the inactive, dephosphorylated, uncarboxylated matrix Gla protein (dp-ucMGP) with oxidized low-density lipoprotein (ox-LDL) and all-cause/cardiovascular (CV) mortality and renal function in diabetic chronic kidney disease (CKD). Ox-LDL and dp-ucMGP were determined in 66 diabetic CKD patients. All patients were prospectively followed for seven years, or until the occurrence of death, or a composite renal outcome of 30% estimated glomerular filtration rate (eGFR) reduction or progression to end-stage renal disease (ESRD) requiring dialysis occurred. Secondary outcomes were the occurrence of CV events. Kaplan–Meier curves showed that patients with plasma dp-ucMGP levels above the median (≥656 pM) had a significantly higher risk for all study endpoints. After adjustment for several well-known cofounders, multivariate Cox analysis showed that high plasma dp-ucMGP levels were associated with all-cause mortality (Hazard ratio-HR = 2.63, 95% Confidence Interval-CI = 1.17–5.94, p = 0.02), CV mortality (HR = 2.82, 95% CI = 1.07–7.49, p = 0.037) and progression of CKD (HR = 4.02, 95% CI = 1.20–13.46, p = 0.024). Circulating dp-ucMGP is associated with mortality and decreased renal function in diabetic CKD. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Metabolic Disease)
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Review

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27 pages, 435 KiB  
Review
Circulating Nucleic Acid-Based Biomarkers of Type 2 Diabetes
by Felipe Padilla-Martinez, Gladys Wojciechowska, Lukasz Szczerbinski and Adam Kretowski
Int. J. Mol. Sci. 2022, 23(1), 295; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010295 - 28 Dec 2021
Cited by 6 | Viewed by 2890
Abstract
Type 2 diabetes (T2D) is a deficiency in how the body regulates glucose. Uncontrolled T2D will result in chronic high blood sugar levels, eventually resulting in T2D complications. These complications, such as kidney, eye, and nerve damage, are even harder to treat. Identifying [...] Read more.
Type 2 diabetes (T2D) is a deficiency in how the body regulates glucose. Uncontrolled T2D will result in chronic high blood sugar levels, eventually resulting in T2D complications. These complications, such as kidney, eye, and nerve damage, are even harder to treat. Identifying individuals at high risk of developing T2D and its complications is essential for early prevention and treatment. Numerous studies have been done to identify biomarkers for T2D diagnosis and prognosis. This review focuses on recent T2D biomarker studies based on circulating nucleic acids using different omics technologies: genomics, transcriptomics, and epigenomics. Omics studies have profiled biomarker candidates from blood, urine, and other non-invasive samples. Despite methodological differences, several candidate biomarkers were reported for the risk and diagnosis of T2D, the prognosis of T2D complications, and pharmacodynamics of T2D treatments. Future studies should be done to validate the findings in larger samples and blood-based biomarkers in non-invasive samples to support the realization of precision medicine for T2D. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Metabolic Disease)
16 pages, 781 KiB  
Review
Molecular Biomarkers for Pediatric Depressive Disorders: A Narrative Review
by Jongha Lee, Suhyuk Chi and Moon-Soo Lee
Int. J. Mol. Sci. 2021, 22(18), 10051; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221810051 - 17 Sep 2021
Cited by 4 | Viewed by 2579
Abstract
Depressive disorder in childhood and adolescence is a highly prevalent mood disorder that tends to recur throughout life. Untreated mood disorders can adversely impact a patient’s quality of life and cause socioeconomic loss. Thus, an accurate diagnosis and appropriate treatment is crucial. However, [...] Read more.
Depressive disorder in childhood and adolescence is a highly prevalent mood disorder that tends to recur throughout life. Untreated mood disorders can adversely impact a patient’s quality of life and cause socioeconomic loss. Thus, an accurate diagnosis and appropriate treatment is crucial. However, until now, diagnoses and treatments were conducted according to clinical symptoms. Objective and biological validation is lacking. This may result in a poor outcome for patients with depressive disorder. Research has been conducted to identify the biomarkers that are related to depressive disorder. Cumulative evidence has revealed that certain immunologic biomarkers including brain-derived neurotrophic factor (BDNF) and cytokines, gastrointestinal biomarkers, hormones, oxidative stress, and certain hypothalamus-pituitary axis biomarkers are associated with depressive disorder. This article reviews the biomarkers related to the diagnosis and treatment of pediatric depressive disorders. To date, clinical biomarker tests are not yet available for diagnosis or for the prediction of treatment prognosis. However, cytokines such as Interleukin-2, interferon-gamma, tumor necrosis factor-alpha, and BDNF have shown significant results in previous studies of pediatric depressive disorder. These biomarkers have the potential to be used for diagnosis, prognostic assessment, and group screening for those at high risk. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Metabolic Disease)
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41 pages, 1148 KiB  
Review
MicroRNAs: The Link between the Metabolic Syndrome and Oncogenesis
by Adriana Fodor, Andrada Luciana Lazar, Cristina Buchman, Brandusa Tiperciuc, Olga Hilda Orasan and Angela Cozma
Int. J. Mol. Sci. 2021, 22(12), 6337; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126337 - 13 Jun 2021
Cited by 11 | Viewed by 3205
Abstract
Metabolic syndrome (MetS) represents a cluster of disorders that increase the risk of a plethora of conditions, in particular type two diabetes, cardiovascular diseases, and certain types of cancers. MetS is a complex entity characterized by a chronic inflammatory state that implies dysregulations [...] Read more.
Metabolic syndrome (MetS) represents a cluster of disorders that increase the risk of a plethora of conditions, in particular type two diabetes, cardiovascular diseases, and certain types of cancers. MetS is a complex entity characterized by a chronic inflammatory state that implies dysregulations of adipokins and proinflammatory cytokins together with hormonal and growth factors imbalances. Of great interest is the implication of microRNA (miRNA, miR), non-coding RNA, in cancer genesis, progression, and metastasis. The adipose tissue serves as an important source of miRs, which represent a novel class of adipokines, that play a crucial role in carcinogenesis. Altered miRs secretion in the adipose tissue, in the context of MetS, might explain their implication in the oncogenesis. The interplay between miRs expressed in adipose tissue, their dysregulation and cancer pathogenesis are still intriguing, taking into consideration the fact that miRNAs show both carcinogenic and tumor suppressor effects. The aim of our review was to discuss the latest publications concerning the implication of miRs dysregulation in MetS and their significance in tumoral signaling pathways. Furthermore, we emphasized the role of miRNAs as potential target therapies and their implication in cancer progression and metastasis. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Metabolic Disease)
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19 pages, 1688 KiB  
Review
The Emerging Regulatory Role of Circular RNAs in Periodontal Tissues and Cells
by Kexin Jiao, Laurence J. Walsh, Sašo Ivanovski and Pingping Han
Int. J. Mol. Sci. 2021, 22(9), 4636; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094636 - 28 Apr 2021
Cited by 32 | Viewed by 3275
Abstract
Periodontitis is a chronic complex inflammatory disease associated with a destructive host immune response to microbial dysbiosis, leading to irreversible loss of tooth-supporting tissues. Regeneration of functional periodontal soft (periodontal ligament and gingiva) and hard tissue components (cementum and alveolar bone) to replace [...] Read more.
Periodontitis is a chronic complex inflammatory disease associated with a destructive host immune response to microbial dysbiosis, leading to irreversible loss of tooth-supporting tissues. Regeneration of functional periodontal soft (periodontal ligament and gingiva) and hard tissue components (cementum and alveolar bone) to replace lost tissues is the ultimate goal of periodontal treatment, but clinically predictable treatments are lacking. Similarly, the identification of biomarkers that can be used to accurately diagnose periodontitis activity is lacking. A relatively novel category of molecules found in oral tissue, circular RNAs (circRNAs) are single-stranded endogenous, long, non-coding RNA molecules, with covalently circular-closed structures without a 5’ cap and a 3’ tail via non-classic backsplicing. Emerging research indicates that circRNAs are tissue and disease-specific expressed and have crucial regulatory functions in various diseases. CircRNAs can function as microRNA or RNA binding sites or can regulate mRNA. In this review, we explore the biogenesis and function of circRNAs in the context of the emerging role of circRNAs in periodontitis pathogenesis and the differentiation of periodontal cells. CircMAP3K11, circCDK8, circCDR1as, circ_0062491, and circ_0095812 are associated with pathological periodontitis tissues. Furthermore, circRNAs are expressed in periodontal cells in a cell-specific manner. They can function as microRNA sponges and can form circRNA–miRNA–mRNA networks during osteogenic differentiation for periodontal-tissue (or dental pulp)-derived progenitor cells. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Metabolic Disease)
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