Novel Biomarkers and Therapeutic Targets for Human Cancers

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Oncology".

Deadline for manuscript submissions: closed (15 November 2021) | Viewed by 15384

Special Issue Editors

Department of Precision Medicine, University of Campania “L. Vanvitelli” via L. De Crecchio 7, 80138 Naples, Italy
Interests: target therapy; cell death mechanisms; microRNAs; long non-coding RNAs; biomarkers; nanotechnology; drug delivery; signal transduction; cancer; circulating tumor cells; glioblastoma; prostate cancer; hepatocellular cancer
Special Issues, Collections and Topics in MDPI journals
Department of Precision Medicine, University of Campania “L. Vanvitelli” via L. De Crecchio 7, 80138 Naples, Italy
Interests: microRNAs; long non-coding RNAs; extracellular vesicles; regulation of gene expression; cell death mechanisms; cell signaling; cancer therapy; drug delivery systems; target therapy; immunotherapy; prostate cancer; colorectal cancer; glioblastoma
Special Issues, Collections and Topics in MDPI journals
Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
Interests: oncology; biochemistry; nanotechnologies; RNA interference
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The discovery and development of novel biomarkers and therapeutic targets have greatly accelerated progress towards precision medicine in oncology. Multi-platforms for molecular characterization of tumors have given rise to new efforts in performing pathological, biochemical, molecular, and immunological research to study the mechanisms underlying carcinogenesis, with the final aim of finding the cancer biomarkers and molecular targets, which could be applied in clinical practice. Cancer biomarkers are of great interest for early diagnosis, prognosis, and prediction of treatment response and may aid in the development of new anti-cancer targeted therapies with proven benefits for treatment response and survival. However, plenty of research opportunity exists for discovering, developing, and validating cancer biomarkers and targets for improving the clinical outcomes of patients with malignant diseases. The present Special Issue aims to collect the most relevant research in the emerging areas of clinical molecular diagnostics, drug development, and targeting different signaling pathways involved in tumorigenesis.

Prof. Silvia Zappavigna
Prof. Amalia Luce
Dr. Marianna Abate
Guest Editors

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Keywords

  • Cancer Biomarker
  • Predictive biomarker
  • Prognosis
  • Diagnosis
  • Molecular target
  • Non-coding RNAs
  • Extracellular vesicles
  • Circulating tumor cells
  • Omic sciences
  • Drug design
  • Nanodrug

Published Papers (8 papers)

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Research

20 pages, 8457 KiB  
Article
Monocyte Chemotactic Proteins (MCP) in Colorectal Adenomas Are Differently Expressed at the Transcriptional and Protein Levels: Implications for Colorectal Cancer Prevention
by Jarosław Wierzbicki, Artur Lipiński, Iwona Bednarz-Misa, Łukasz Lewandowski, Katarzyna Neubauer, Paulina Lewandowska and Małgorzata Krzystek-Korpacka
J. Clin. Med. 2021, 10(23), 5559; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10235559 - 26 Nov 2021
Cited by 2 | Viewed by 1485
Abstract
The expression of monocyte chemotactic proteins (MCPs) in colorectal polyps and their suitability as targets for chemoprevention is unknown, although MCP expression and secretion can be modulated by non-steroidal inflammatory drugs. This study was designed to determine the expression patterns of MCP-1/CCL2 [...] Read more.
The expression of monocyte chemotactic proteins (MCPs) in colorectal polyps and their suitability as targets for chemoprevention is unknown, although MCP expression and secretion can be modulated by non-steroidal inflammatory drugs. This study was designed to determine the expression patterns of MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7 at the protein (immunohistochemistry; n = 62) and transcriptional levels (RTqPCR; n = 173) in colorectal polyps with reference to the polyp malignancy potential. All chemokines were significantly upregulated in polyps at the protein level but downregulated at the transcriptional level by 1.4-(CCL2), 1.7-(CCL7), and 2.3-fold (CCL8). There was an inverse relation between the immunoreactivity toward chemokine proteins and the number of corresponding transcripts in polyps (CCL2 and CCL7) or in normal mucosa (CCL8). The downregulation of chemokine transcripts correlated with the presence of multiple polyps (CCL2 and CCL8), a larger polyp size (CCL2, CCL7, and CCL8), predominant villous growth patterns (CCL2, CCL7 and CCL8), and high-grade dysplasia (CCL2 and CCL8). In conclusion, MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7 chemokines are counter-regulated at the protein and transcriptional levels. Chemokine-directed chemopreventive strategies should therefore directly neutralize MCP proteins or target molecular pathways contributing to their enhanced translation or reduced degradation, rather than aiming at CCL2, CCL7 or CCL8 expression. Full article
(This article belongs to the Special Issue Novel Biomarkers and Therapeutic Targets for Human Cancers)
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16 pages, 2087 KiB  
Article
Prognostic Value of LC3B and p62 Expression in Small Intestinal Adenocarcinoma
by Jeong-Won Kim, Sun-Young Jun, Joon-Mee Kim, Young-Ha Oh, Ghilsuk Yoon, Seung-Mo Hong and Joon-Yong Chung
J. Clin. Med. 2021, 10(22), 5398; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10225398 - 19 Nov 2021
Cited by 5 | Viewed by 1722
Abstract
Autophagy, a mechanism that maintains cellular homeostasis, is involved in tumor cell growth and survival in cancer, and autophagy inhibitors have been tested clinical trials for anticancer therapy. To elucidate the clinical and prognostic implications of autophagy in small intestinal adenocarcinoma (SIAC), we [...] Read more.
Autophagy, a mechanism that maintains cellular homeostasis, is involved in tumor cell growth and survival in cancer, and autophagy inhibitors have been tested clinical trials for anticancer therapy. To elucidate the clinical and prognostic implications of autophagy in small intestinal adenocarcinoma (SIAC), we assessed the expression of autophagy markers, LC3B and p62, in 171 surgically resected primary SIACs using automated quantitative analysis. Positive LC3B, p62 nuclear (p62Nu), and p62 cytoplasmic (p62Cy) expression was observed in 23 (13.5%), 52 (30.4%), and 43 (25.1%) carcinomas, respectively. LC3B+ expression was correlated with undifferentiated carcinoma (p < 0.001) and high histologic grade (p = 0.029). The combined expression of LC3B and p62Nu (LC3+/p62Nu+) was related to the older age of patients (p = 0.017), undifferentiated carcinoma (p < 0.001), and high grade (p = 0.031). LC3B+ (p = 0.006), p62Cy+ (p = 0.041), or p62Nu+ (p = 0.006) expression were associated with worse survival. In addition, SIAC patients with either LC3B+/p62Nu+ (p = 0.001) or LC3B+/p62Cy+ (p = 0.002) expression had shorter survival times. In multivariate analysis, LC3B expression remained an independent prognostic factor (p = 0.025) for overall survival. In conclusion, autophagy may play a role in the tumorigenesis of SIACs, and LC3B and p62 could be used as prognostic biomarkers and potential therapeutic targets for SIACs. Full article
(This article belongs to the Special Issue Novel Biomarkers and Therapeutic Targets for Human Cancers)
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10 pages, 508 KiB  
Article
Evaluation of the Differences in the Expression of Biogenic Amine-Related mRNAs and Proteins in Endometrioid Endometrial Cancer
by Michał Czerwiński, Anna Bednarska-Czerwińska, Nikola Zmarzły, Dariusz Boroń, Marcin Oplawski and Beniamin Oskar Grabarek
J. Clin. Med. 2021, 10(21), 4872; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10214872 - 22 Oct 2021
Cited by 3 | Viewed by 1725
Abstract
Biogenic amines, such as adrenaline, noradrenaline, histamine, dopamine, and serotonin are important neurotransmitters that also regulate cell viability. Their detection and analysis are helpful in the diagnosis of many diseases, including cancer. The aim of this study was to determine the expression profile [...] Read more.
Biogenic amines, such as adrenaline, noradrenaline, histamine, dopamine, and serotonin are important neurotransmitters that also regulate cell viability. Their detection and analysis are helpful in the diagnosis of many diseases, including cancer. The aim of this study was to determine the expression profile of the biogenic amine-related genes and proteins in endometrioid endometrial cancer compared to the control group. The material consisted of endometrial tissue samples and whole blood collected from 30 endometrioid endometrial cancer patients and 30 cancer-free patients. The gene expression was determined by the mRNA microarrays and validated by qRT-PCR. Protein levels were determined in the serum by the enzyme-linked immunosorbent assay (ELISA). Overexpression of histamine H1–H3 receptors and early growth response 1 and silencing of calmodulin, the histamine H4 receptor, and the dopamine D5 receptor have been reported in endometrioid endometrial cancer. The obtained results indicate disturbances in the signaling activated by histamine and dopamine receptors, which could potentially contribute to the progression of endometrioid endometrial cancer. Full article
(This article belongs to the Special Issue Novel Biomarkers and Therapeutic Targets for Human Cancers)
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9 pages, 1136 KiB  
Article
Protein Kinase A Detection in Human Urine Samples
by Angela Ragone, Alessia Salzillo, Annamaria Spina, Silvia Zappavigna, Michele Caraglia, Luigi Sapio and Silvio Naviglio
J. Clin. Med. 2021, 10(18), 4096; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10184096 - 10 Sep 2021
Cited by 1 | Viewed by 1358
Abstract
Actively involved in tumor maintenance, cAMP-dependent protein kinase A (PKA) has been proposed as a putative biomarker in cancer. Recently, an active PKA form has been identified in human sera and PKA autoantibodies have been detected in cancer patients. However, their serum functions, [...] Read more.
Actively involved in tumor maintenance, cAMP-dependent protein kinase A (PKA) has been proposed as a putative biomarker in cancer. Recently, an active PKA form has been identified in human sera and PKA autoantibodies have been detected in cancer patients. However, their serum functions, as well as diagnostic significance, remain largely unknown. Although several PKA detection assays have been developed, none refer to a laboratory diagnostic procedure. Among these, ELISA and Western blotting (WB) assays have been employed in PKA detection. Since, to the best of our knowledge, there are no data showing its presence in human urine samples, herein, we explore the possibility of PKA’s existence in this biological specimen. Interestingly, among the 30 screened urines by quantitative sandwich ELISA, we recognized detectable PKA levels in 5 different samples, and of those two exhibited a considerable high concentration. To corroborate these results, we also evaluated PKA’s presence in both positive and negative ELISA urines by WB. Remarkably, immunoblotting analysis confirmed PKA’s existence in certain, but not in all, human urine specimens. Despite being quite preliminary, these findings firstly identify PKA in urine samples and provide evidence for its potential clinic usage as a diagnostic analyte in laboratory medicine. Full article
(This article belongs to the Special Issue Novel Biomarkers and Therapeutic Targets for Human Cancers)
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11 pages, 2549 KiB  
Article
Upregulated MUC2 Is an Unfavorable Prognostic Indicator for Rectal Cancer Patients Undergoing Preoperative CCRT
by Chia-Lin Chou, Tzu-Ju Chen, Yu-Feng Tian, Ti-Chun Chan, Cheng-Fa Yeh, Wan-Shan Li, Hsin-Hwa Tsai, Chien-Feng Li and Hong-Yue Lai
J. Clin. Med. 2021, 10(14), 3030; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10143030 - 07 Jul 2021
Cited by 6 | Viewed by 1639
Abstract
For locally advanced rectal cancer patients, introducing neoadjuvant concurrent chemoradiotherapy (CCRT) before radical resection allows tumor downstaging and increases the rate of anus retention. Since accurate staging before surgery and sensitivity prediction to CCRT remain challenging, a more precise genetic biomarker is urgently [...] Read more.
For locally advanced rectal cancer patients, introducing neoadjuvant concurrent chemoradiotherapy (CCRT) before radical resection allows tumor downstaging and increases the rate of anus retention. Since accurate staging before surgery and sensitivity prediction to CCRT remain challenging, a more precise genetic biomarker is urgently needed to enhance the management of such situations. The epithelial mucous barrier can protect the gut lumen, but aberrant mucin synthesis may defend against drug penetration. In this study, we focused on genes related to maintenance of gastrointestinal epithelium (GO: 0030277) and identified mucin 2 (MUC2) as the most significantly upregulated gene correlated with CCRT resistance through a public rectal cancer transcriptome dataset (GSE35452). We retrieved 172 records of rectal cancer patients undergoing CCRT accompanied by radical resection from our biobank. We also assessed the expression level of MUC2 using immunohistochemistry. The results showed that upregulated MUC2 immunoexpression was considerably correlated with the pre-CCRT and post-CCRT positive nodal status (p = 0.001 and p < 0.001), advanced pre-CCRT and post-CCRT tumor status (p = 0.022 and p < 0.001), vascular invasion (p = 0.015), and no or little response to CCRT (p = 0.006). Upregulated MUC2 immunoexpression was adversely prognostic for all three endpoints, disease-specific survival (DSS), local recurrence-free survival (LRFS), and metastasis-free survival (MeFS) (all p < 0.0001), at the univariate level. Moreover, upregulated MUC2 immunoexpression was an independent prognostic factor for worse DSS (p < 0.001), LRFS (p = 0.008), and MeFS (p = 0.003) at the multivariate level. Collectively, these results imply that upregulated MUC2 expression is characterized by a more advanced clinical course and treatment resistance in rectal cancer patients undergoing CCRT, revealing the potential prognostic utility of MUC2 expression. Full article
(This article belongs to the Special Issue Novel Biomarkers and Therapeutic Targets for Human Cancers)
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21 pages, 2224 KiB  
Article
Methylation Status of Corticotropin-Releasing Factor (CRF) Receptor Genes in Colorectal Cancer
by Maria Panagopoulou, Antonia Cheretaki, Makrina Karaglani, Ioanna Balgkouranidou, Eirini Biziota, Kyriakos Amarantidis, Nikolaos Xenidis, Stylianos Kakolyris, Stavroula Baritaki and Ekaterini Chatzaki
J. Clin. Med. 2021, 10(12), 2680; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10122680 - 18 Jun 2021
Cited by 8 | Viewed by 2064
Abstract
The corticotropin-releasing factor (CRF) system has been strongly associated with gastrointestinal pathophysiology, including colorectal cancer (CRC). We previously showed that altered expression of CRF receptors (CRFRs) in the colon critically affects CRC progression and aggressiveness through regulation of colonic inflammation. Here, we aimed [...] Read more.
The corticotropin-releasing factor (CRF) system has been strongly associated with gastrointestinal pathophysiology, including colorectal cancer (CRC). We previously showed that altered expression of CRF receptors (CRFRs) in the colon critically affects CRC progression and aggressiveness through regulation of colonic inflammation. Here, we aimed to assess the potential of CRFR methylation levels as putative biomarkers in CRC. In silico methylation analysis of CRF receptor 1 (CRFR1) and CRF receptor 2 (CRFR2) was performed using methylome data derived by CRC and Crohn’s disease (CD) tissues and CRC-derived circulating cell-free DNAs (ccfDNAs). In total, 32 and 33 differentially methylated sites of CpGs (DMCs) emerged in CRFR1 and CRFR2, respectively, between healthy and diseased tissues. The methylation patterns were verified in patient-derived ccfDNA samples by qMSP and associated with clinicopathological characteristics. An automated machine learning (AutoML) technology was applied to ccfDNA samples for classification analysis. In silico analysis revealed increased methylation of both CRFRs in CRC tissue and ccfDNA-derived datasets. CRFR1 hypermethylation was also noticed in gene body DMCs of CD patients. CRFR1 hypermethylation was further validated in CRC adjuvant-derived ccfDNA samples, whereas CRFR1 hypomethylation, observed in metastasis-derived ccfDNAs, was correlated to disease aggressiveness and adverse prognostic characteristics. AutoML analysis based on CRFRs methylation status revealed a three-feature high-performing biosignature for CRC diagnosis with an estimated AUC of 0.929. Monitoring of CRFRs methylation-based signature in CRC tissues and ccfDNAs may be of high diagnostic and prognostic significance in CRC. Full article
(This article belongs to the Special Issue Novel Biomarkers and Therapeutic Targets for Human Cancers)
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12 pages, 2082 KiB  
Article
Poorly Differentiated Neuroendocrine Larynx Carcinoma: Clinical Features and miRNAs Signature—A New Goal for Early Diagnosis and Therapy?
by Filippo Ricciardiello, Michela Falco, Giuseppe Tortoriello, Ferdinando Riccardi, Raul Pellini, Brigida Iorio, Giuseppe Russo, Giuseppe Longo, Ciro Coppola, Takashi Takeuchi, Anna Grimaldi, Marianna Abate, Marianna Scrima, Alessia Maria Cossu, Raffaele Addeo, Alessandro Ottaiano, Alfonso Scarpa, Amedeo Boscaino, Giovanni Motta, Michele Caraglia, Marco Bocchetti and Gabriella Missoadd Show full author list remove Hide full author list
J. Clin. Med. 2021, 10(9), 2019; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10092019 - 08 May 2021
Cited by 5 | Viewed by 1834
Abstract
Laryngeal neuroendocrine carcinomas (LNECs) are rare and highly heterogeneous malignancies presenting a wide range of pathological and clinical manifestations. Herein, we retrospectively characterize ten patients diagnosticated with LNEC, five of which were defined as well-moderately differentiated neuroendocrine carcinomas, and five that were defined [...] Read more.
Laryngeal neuroendocrine carcinomas (LNECs) are rare and highly heterogeneous malignancies presenting a wide range of pathological and clinical manifestations. Herein, we retrospectively characterize ten patients diagnosticated with LNEC, five of which were defined as well-moderately differentiated neuroendocrine carcinomas, and five that were defined as poorly differentiated neuroendocrine carcinomas, according to the latest WHO classification. Clinical features were analyzed and compared between the two subgroups together with a microRNA study which evidenced a peculiar signature likely related to poorly differentiated larynx neuroendocrine carcinomas. These findings may offer new useful insights for clinicians to improve diagnosis efficiency, therapy response, and patients’ outcome for this aggressive neoplasm. Full article
(This article belongs to the Special Issue Novel Biomarkers and Therapeutic Targets for Human Cancers)
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9 pages, 482 KiB  
Communication
Epigenetic Regulation of Mitochondrial Quality Control Genes in Multiple Myeloma: A Sequenom MassARRAY Pilot Investigation on HMCLs
by Patrizia D’Aquila, Domenica Ronchetti, Maria Eugenia Gallo Cantafio, Katia Todoerti, Elisa Taiana, Fernanda Fabiani, Alberto Montesanto, Antonino Neri, Giuseppe Passarino, Giuseppe Viglietto, Dina Bellizzi and Nicola Amodio
J. Clin. Med. 2021, 10(6), 1295; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10061295 - 21 Mar 2021
Cited by 5 | Viewed by 2164
Abstract
The mitochondrial quality control network includes several epigenetically-regulated genes involved in mitochondrial dynamics, mitophagy, and mitochondrial biogenesis under physiologic conditions. Dysregulated expression of such genes has been reported in various disease contexts, including cancer. However, their expression pattern and the possible underlying epigenetic [...] Read more.
The mitochondrial quality control network includes several epigenetically-regulated genes involved in mitochondrial dynamics, mitophagy, and mitochondrial biogenesis under physiologic conditions. Dysregulated expression of such genes has been reported in various disease contexts, including cancer. However, their expression pattern and the possible underlying epigenetic modifications remain to be defined within plasma cell (PC) dyscrasias. Herein, we compared the mRNA expression of mitochondrial quality control genes from multiple myeloma, plasma cell leukemia patients and human myeloma cell lines (HMCLs) with healthy plasma cells; moreover, by applying the Sequenom MassARRAY EpiTYPER technology, we performed a pilot investigation of their CpG methylation status in HMCLs. Overall, the results provided indicate dysregulated expression of several mitochondrial network’s genes, and alteration of the CpG methylation profile, underscoring novel potential myeloma biomarkers deserving in-depth functional investigation in the future. Full article
(This article belongs to the Special Issue Novel Biomarkers and Therapeutic Targets for Human Cancers)
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