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Special Issue "Oral Squamous Cell Carcinoma—Pathogenetic, Diagnostic and Therapeutic Perspectives"

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 29 November 2023 | Viewed by 7699

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Special Issue Editors

Dr. Ana Caruntu

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Guest Editor

1. Department of Oral and Maxillofacial Surgery, Carol Davila Central Military Emergency Hospital, 010825 Bucharest, Romania
2. Department of Oral and Maxillofacial Surgery, Faculty of Dental Medicine, Titu Maiorescu University, 031593 Bucharest, Romania
Interests: head and neck cancer; diagnosis and prognosis in head and neck cancer; biomarkers; reconstructive surgery; salivary gland pathology; tissue regeneration; tissue engineering
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Shun-Fa Yang

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Guest Editor

Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
Interests: cancer prevention; cancer biomarker; oral cancer; cancer metastasis; polymorphism; tumor microenvironment; matrix metalloproteinase
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Dr. Julio Acero

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Guest Editor

1. Department of Oral and Maxillofacial Surgery, Hospital Ramon y Cajal, 28034 Madrid, Spain
2. Hospital Universitario Puerta de Hierro, 28222 Majadahonda, Spain
Interests: head and neck cancer; head and neck reconstruction; tissue engineering; microvascular surgery; stem cells; oral cancer; oral surgery; orbital surgery; midfacial surgery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Oral Squamous Cell Carcinoma (OSCC), the most common form of head and neck cancer, remains one of the major challenges of modern medicine, despite all progressed made during the last decades in cancer control for other types of malignancies. Statistical data show that the incidence of OSCC is continuously rising, while the prognosis has not improved significantly, with important mortality rates, especially associated with advanced disease at the moment of diagnosis. Some aspects regarding the carcinogenesis process in OSCC have been elucidated. Today we know that lesions of OSCC imply multiple genetic alterations in combination with exposure to behaviour or environmental risk factors. However, the exact mechanisms leading to cancer development and, more importantly, the elements which influence the response to therapy are far from being unveiled. Several questions remain unanswered: Who will suffer from OSCC during their lifetime? or How to increase the response to therapy rate in OSCC patients?

This Special issue aims to gather the most recent research conducted in the complex domain of molecular mechanisms that impact carcinogenesis, response to therapy and prognosis in OSCC. Experimental studies, as well as clinical submissions with biomolecular experiments are within the scope of our Special issue and are welcomed for submission. All authors are invited to send their research related to the topic of our Special issue, both original and review articles, to be assessed and included in the peer review process of our journal.

Dr. Ana Caruntu
Prof. Dr. Shun-Fa Yang
Dr. Julio Acero
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

oral squamous cell carcinoma
molecular biology
pathology
microbiome
biomarkers
genetic alterations
biological behavior
diagnostics and therapeutics
reconstructive therapy
chemoresistance
radioresistantce

Published Papers (8 papers)

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Research

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Open AccessArticle

Salivary Chemical Barrier Proteins in Oral Squamous Cell Carcinoma—Alterations in the Defense Mechanism of the Oral Cavity

Gergő Kalló

Petra Magdolna Bertalan

Ildikó Márton

Csongor Kiss

and

Éva Csősz

Int. J. Mol. Sci. 2023, 24(17), 13657; https://doi.org/10.3390/ijms241713657 - 04 Sep 2023

Viewed by 627

Abstract

Oral squamous cell carcinoma (OSCC) is one of the most frequent types of head and neck cancer. Despite the genetic and environmental risk factors, OSCC is also associated with microbial infections and/or dysbiosis. The secreted saliva serves as the chemical barrier of the oral cavity and, since OSCC can alter the protein composition of saliva, our aim was to analyze the effect of OSCC on the salivary chemical barrier proteins. Publicly available datasets regarding the analysis of salivary proteins from patients with OSCC and controls were collected and examined in order to identify differentially expressed chemical barrier proteins. Network analysis and gene ontology (GO) classification of the differentially expressed chemical barrier proteins were performed as well. One hundred and twenty-seven proteins showing different expression pattern between the OSCC and control groups were found. Protein–protein interaction networks of up- and down-regulated proteins were constructed and analyzed. The main hub proteins (IL-6, IL-1B, IL-8, TNF, APOA1, APOA2, APOB, APOC3, APOE, and HP) were identified and the enriched GO terms were examined. Our study highlighted the importance of the chemical barrier of saliva in the development of OSCC. Full article

(This article belongs to the Special Issue Oral Squamous Cell Carcinoma—Pathogenetic, Diagnostic and Therapeutic Perspectives)

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Open AccessArticle

Serum and Saliva Level of miR-31-5p and miR-let 7a in EBV Associated Oropharyngeal Cancer

and

Małgorzata Polz-Dacewicz

Int. J. Mol. Sci. 2023, 24(15), 11965; https://doi.org/10.3390/ijms241511965 - 26 Jul 2023

Viewed by 445

Abstract

Epstein-Barr virus (EBV) has a well-documented association with head and neck neoplasms, including nasopharyngeal carcinoma (NPC). In the last few years, research aimed at elucidating the role of the miRs in the pathogenesis of head and neck cancer (HNC) has gained importance. The study of miRs expression has set new directions in the search for biomarkers with diagnostic and prognostic value, and even in the search for new therapeutic targets for various tumors, including HNC. The aim of current study was to approximate the importance of miR-31-5p and miR-let 7a in the pathogenesis of EBV associated oropharyngeal cancer. For this purpose, experiments were carried out to determine the level of mentioned miRs in serum among patients diagnosed with oropharyngeal cancer linked to EBV infection, depending on histological differentiation-grading (G1–G3) and TNM classification. All clinical specimens stratified by HPV status were HPV negative. The level of antibodies EBNA and EBVCA was also assessed. The obtained results showed a significantly increased serum level of miR-31-5p but decreased level of miR-let 7a in EBV positive oropharyngeal cancer patients. We demonstrated association between the level of tested miRs and clinical stage. Our findings showed that miR-31-5p and miR-let-7a may be involved in development and progression of EBV associated oropharyngeal cancer. Therefore, it seems important to further study these molecules, as well as to determine whether they could be important biomarkers in the diagnosis of oropharyngeal cancer associated with EBV infection. Full article

(This article belongs to the Special Issue Oral Squamous Cell Carcinoma—Pathogenetic, Diagnostic and Therapeutic Perspectives)

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Open AccessArticle

Identification of Somatic Mutations in Plasma Cell-Free DNA from Patients with Metastatic Oral Squamous Cell Carcinoma

and

Int. J. Mol. Sci. 2023, 24(12), 10408; https://doi.org/10.3390/ijms241210408 - 20 Jun 2023

Viewed by 887

Abstract

The accurate diagnosis and treatment of oral squamous cell carcinoma (OSCC) requires an understanding of its genomic alterations. Liquid biopsies, especially cell-free DNA (cfDNA) analysis, are a minimally invasive technique used for genomic profiling. We conducted comprehensive whole-exome sequencing (WES) of 50 paired OSCC cell-free plasma with whole blood samples using multiple mutation calling pipelines and filtering criteria. Integrative Genomics Viewer (IGV) was used to validate somatic mutations. Mutation burden and mutant genes were correlated to clinico-pathological parameters. The plasma mutation burden of cfDNA was significantly associated with clinical staging and distant metastasis status. The genes TTN, PLEC, SYNE1, and USH2A were most frequently mutated in OSCC, and known driver genes, including KMT2D, LRP1B, TRRAP, and FLNA, were also significantly and frequently mutated. Additionally, the novel mutated genes CCDC168, HMCN2, STARD9, and CRAMP1 were significantly and frequently present in patients with OSCC. The mutated genes most frequently found in patients with metastatic OSCC were RORC, SLC49A3, and NUMBL. Further analysis revealed that branched-chain amino acid (BCAA) catabolism, extracellular matrix–receptor interaction, and the hypoxia-related pathway were associated with OSCC prognosis. Choline metabolism in cancer, O-glycan biosynthesis, and protein processing in the endoplasmic reticulum pathway were associated with distant metastatic status. About 20% of tumors carried at least one aberrant event in BCAA catabolism signaling that could possibly be targeted by an approved therapeutic agent. We identified molecular-level OSCC that were correlated with etiology and prognosis while defining the landscape of major altered events of the OSCC plasma genome. These findings will be useful in the design of clinical trials for targeted therapies and the stratification of patients with OSCC according to therapeutic efficacy. Full article

(This article belongs to the Special Issue Oral Squamous Cell Carcinoma—Pathogenetic, Diagnostic and Therapeutic Perspectives)

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Open AccessArticle

The Concordant Disruption of B7/CD28 Immune Regulators Predicts the Prognosis of Oral Carcinomas

and

Int. J. Mol. Sci. 2023, 24(6), 5931; https://doi.org/10.3390/ijms24065931 - 21 Mar 2023

Viewed by 976

Abstract

Immune modulation is a critical factor in determining the survival of patients with malignancies, including those with oral squamous cell carcinoma (OSCC) and head and neck SCC (HNSCC). Immune escape or stimulation may be driven by the B7/CD28 family and other checkpoint molecules, forming ligand–receptor complexes with immune cells in the tumor microenvironment. Since the members of B7/CD28 can functionally compensate for or counteract each other, the concomitant disruption of multiple members of B7/CD28 in OSCC or HNSCC pathogenesis remains elusive. Transcriptome analysis was performed on 54 OSCC tumors and 28 paired normal oral tissue samples. Upregulation of CD80, CD86, PD-L1, PD-L2, CD276, VTCN1, and CTLA4 and downregulation of L-ICOS in OSCC relative to the control were noted. Concordance in the expression of CD80, CD86, PD-L1, PD-L2, and L-ICOS with CD28 members was observed across tumors. Lower ICOS expression indicated a worse prognosis in late-stage tumors. Moreover, tumors harboring higher PD-L1/ICOS, PD-L2/ICOS, or CD276/ICOS expression ratios had a worse prognosis. The survival of node-positive patients was further worsened in tumors exhibiting higher ratios between PD-L1, PD-L2, or CD276 and ICOS. Alterations in T cell, macrophage, myeloid dendritic cell, and mast cell populations in tumors relative to controls were found. Decreased memory B cells, CD8⁺ T cells, and Tregs, together with increased resting NK cells and M0 macrophages, occurred in tumors with a worse prognosis. This study confirmed frequent upregulation and eminent co-disruption of B7/CD28 members in OSCC tumors. The ratio between PD-L2 and ICOS is a promising survival predictor in node-positive HNSCC patients. Full article

(This article belongs to the Special Issue Oral Squamous Cell Carcinoma—Pathogenetic, Diagnostic and Therapeutic Perspectives)

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Open AccessArticle

Semilicoisoflavone B Induces Apoptosis of Oral Cancer Cells by Inducing ROS Production and Downregulating MAPK and Ras/Raf/MEK Signaling

Mosleh Mohammad Abomughaid

Ming-Chang Hsieh

and

Mu-Kuan Chen

Int. J. Mol. Sci. 2023, 24(5), 4505; https://doi.org/10.3390/ijms24054505 - 24 Feb 2023

Viewed by 965

Abstract

Oral squamous cell carcinoma (OSCC) is the sixth most common type of cancer worldwide. Despite advancement in treatment, advanced-stage OSCC is associated with poor prognosis and high mortality. The present study aimed to investigate the anticancer activities of semilicoisoflavone B (SFB), which is a natural phenolic compound isolated from Glycyrrhiza species. The results revealed that SFB reduces OSCC cell viability by targeting cell cycle and apoptosis. The compound caused cell cycle arrest at the G2/M phase and downregulated the expressions of cell cycle regulators including cyclin A and cyclin-dependent kinase (CDK) 2, 6, and 4. Moreover, SFB induced apoptosis by activating poly-ADP-ribose polymerase (PARP) and caspases 3, 8, and 9. It increased the expressions of pro-apoptotic proteins Bax and Bak, reduced the expressions of anti-apoptotic proteins Bcl-2 and Bcl-xL, and increased the expressions of the death receptor pathway protein Fas cell surface death receptor (FAS), Fas-associated death domain protein (FADD), and TNFR1-associated death domain protein (TRADD). SFB was found to mediate oral cancer cell apoptosis by increasing reactive oxygen species (ROS) production. The treatment of the cells with N-acetyl cysteine (NAC) caused a reduction in pro-apoptotic potential of SFB. Regarding upstream signaling, SFB reduced the phosphorylation of AKT, ERK1/2, p38, and JNK1/2 and suppressed the activation of Ras, Raf, and MEK. The human apoptosis array conducted in the study identified that SFB downregulated survivin expression to induce oral cancer cell apoptosis. Taken together, the study identifies SFB as a potent anticancer agent that might be used clinically to manage human OSCC. Full article

(This article belongs to the Special Issue Oral Squamous Cell Carcinoma—Pathogenetic, Diagnostic and Therapeutic Perspectives)

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Open AccessArticle

Chemotherapeutic Drug Resistance Associated with Differential miRNA Expression of miR-375 and miR-27 among Oral Cancer Cell Lines

Kieran Caberto Huni

Jacky Cheung

Madeline Sullivan

William Taylor Robison

Katherine M. Howard

and

Karl Kingsley

Int. J. Mol. Sci. 2023, 24(2), 1244; https://doi.org/10.3390/ijms24021244 - 08 Jan 2023

Viewed by 1154

Abstract

Recent advances have suggested that non-coding miRNAs (such as miR-21, miR-27, miR-145, miR-155, miR-365, miR-375 and miR-494) may be involved in multiple aspects of oral cancer chemotherapeutic responsiveness. This study evaluated whether these specific miRNAs are correlated with oral cancer responsiveness to chemotherapies, including Paclitaxel, Cisplatin and Fluorouracil (5FU). Commercially available and well-characterized oral squamous cell carcinoma cell lines (SCC4, SCC9, SCC15, SCC25 and CAL27) revealed differing resistance and chemosensitivity to these agents—with SCC9 and SCC25 demonstrating the most resistance to all chemotherapeutic agents. SCC9 and SCC25 were also the only cell lines that expressed miR-375, and were the only cell lines that did not express miR-27. In addition, the expression of miR-375 was associated with the upregulation of Rearranged L-myc fusion (RLF) and the downregulation of Centriolar protein B (POC1), whereas lack of miR-27 expression was associated with Nucleophosmin 1 (NPM1) expression. These data have revealed important regulatory pathways and mechanisms associated with oral cancer proliferation and resistance that must be explored in future studies of potential therapeutic interventions. Full article

(This article belongs to the Special Issue Oral Squamous Cell Carcinoma—Pathogenetic, Diagnostic and Therapeutic Perspectives)

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Open AccessArticle

Role Played by Paraoxonase-2 Enzyme in Cell Viability, Proliferation and Sensitivity to Chemotherapy of Oral Squamous Cell Carcinoma Cell Lines

Valentina Notarstefano

and

Int. J. Mol. Sci. 2023, 24(1), 338; https://doi.org/10.3390/ijms24010338 - 25 Dec 2022

Cited by 5 | Viewed by 1304

Abstract

Oral squamous cell carcinoma represents the most aggressive and frequent form of head and neck cancer. Due to drug resistance, the 5-year survival rate of patients with advanced disease is less than 50%. In order to identify molecular targets for effective oral cancer treatment, we focused on paraoxonase-2 enzyme. Indeed, based on data previously obtained from preliminary immunohistochemistry and Western blot analyses performed on tissue specimens, the enzyme was found to be upregulated in tumor compared with normal oral mucosa. Therefore, paraoxonase-2 gene silencing was achieved in HSC-3 and HOC621 oral cancer cell lines, and the effect on cell proliferation, viability, apoptosis induction and sensitivity to cisplatin and 5-fluorouracil treatment was evaluated. Fourier Transform InfraRed Microspectroscopy analyzed alterations of cellular macromolecules upon treatment. Enzyme level and cell proliferation were also determined in cisplatin-resistant clones obtained from HOC621 cell line, as well as in parental cells. Reported data showed that paraoxonase-2 knockdown led to a reduction of cell proliferation and viability, as well as to an enhancement of sensitivity to cisplatin, together with the activation of apoptosis pathway. Spectroscopical data demonstrated that, under treatment with cisplatin, oxidative damage exerted on lipids and proteins was markedly more evident in cells down-regulating paraoxonase-2 compared to controls. Interestingly, enzyme expression, as well as cell proliferation were significantly higher in cisplatin-resistant compared with control HOC621 cells. Taken together these results seem to candidate the enzyme as a promising target for molecular treatment of this neoplasm. Full article

(This article belongs to the Special Issue Oral Squamous Cell Carcinoma—Pathogenetic, Diagnostic and Therapeutic Perspectives)

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Review

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Open AccessReview

Comparison of Immunohistochemical Markers in Oral Submucous Fibrosis and Oral Submucous Fibrosis Transformed to Oral Squamous Cell Carcinoma—A Systematic Review and Meta-Analysis

and

Int. J. Mol. Sci. 2023, 24(14), 11771; https://doi.org/10.3390/ijms241411771 - 21 Jul 2023

Viewed by 605

Abstract

The objective of the study was to compare the expression of immunohistochemical (IHC) markers of oral submucous fibrosis (OSMF) (non-transformed group) to those of oral squamous cell carcinoma (OSCC) transformed from OSMF (transformed group). The search for comparative cross-sectional studies was carried out in PubMed and Scopus abiding to the PICO criteria, where expression of IHC markers in OSMF were compared with that of OSCC transformed from OSMF. The cellular distribution, number of positive cases, staining intensity, and mean immunoreactive score (IRS) of each IHC marker were evaluated in both groups. A total of 14 studies were included in the systematic review, in which immunoexpression of 15 epithelial and 4 connective tissue biomarkers were evaluated. Expression of β1-integrin, OCT-3, CD1a, CD207, survivin, Dickkopf-1, COX-2, hTERT, CTGF, MDM2, Ki-67, and α-SMA were increased during transformation of OSMF to OSCC. Conversely, expression of PTEN and lysyl oxidase decreased during transformation of OSMF to OSCC. Expression of a group of epithelial markers, such as COX2, hTERT, CTGF, survivin, MDM2, and p53, was 38 times lower in the non-transformed group cases compared to transformed group cases (95% CI: 58% to 10%; p = 0.01; and I² = 90%). Meta-analysis of all markers involved in cell metabolism/apoptosis, which included β1-integrin along with the above markers also suggested 42 times lower expression in the non-transformed group as compared to the transformed group (95% CI: 58% to 10%; p = 0.01; and I² = 90%). Sub-group analyses on cytoplasmic and nuclear epithelial markers were inconclusive. Meta-analysis of connective tissue markers was also inconclusive. No publication bias was found. Instead of delving into numerous markers without a strong basis for their use, it is advisable to further study the markers identified in this study to explore their clinical utility. Full article

(This article belongs to the Special Issue Oral Squamous Cell Carcinoma—Pathogenetic, Diagnostic and Therapeutic Perspectives)

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