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Biomedicines
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Oral Squamous Cell Carcinoma: Molecular Signaling Pathways and Novel Biomarkers
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Oral Squamous Cell Carcinoma: Molecular Signaling Pathways and Novel Biomarkers

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: 31 March 2025 | Viewed by 9083

Special Issue Editor

Dr. Sadhna Aggarwal

E-Mail Website
Guest Editor
University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Interests: oral squamous cell carcinoma; molecular immunology

Special Issue Information

Dear Colleagues,

Oral squamous cell carcinoma (OSCC) is the most common malignant neoplasm of the oral cavity, posing significant challenges in terms of diagnosis, treatment, and prognosis. Understanding the intricate molecular mechanisms and identifying reliable biomarkers is crucial for improved early detection, diagnosis, and targeted therapy.

The scope of this Special Issue includes the exploration of molecular signaling pathways involved in OSCC development, progression, and metastasis. It will unfold the dysregulation of key signaling pathways, including but not limited to the Notch, Wnt/β-catenin, PI3K/AKT, MAPK, and NF-κB pathways. Emphasis will be placed on elucidating the cross-talk between these pathways and their impact on tumour growth, invasion, angiogenesis, metastasis, and immune response modulation.

Additionally, this Special Issue will highlight the identification and validation of novel biomarkers in OSCC. Contributions may include studies on genetic, epigenetic, transcriptomic, proteomic, and metabolomic biomarkers, as well as their potential applications in early detection, risk assessment, prognosis prediction, and treatment response monitoring.

This Special Issue titled “Oral Squamous Cell Carcinoma: Molecular Signaling Pathways and Novel Biomarkers” welcomes original research articles, reviews, and perspectives that provide valuable insights into this field. By bringing together the latest advancements in this field, this Special Issue aims to contribute to the understanding of OSCC pathogenesis and innovative treatment strategies for improved patient outcomes.

Dr. Sadhna Aggarwal
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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 (OSCC)
  • molecular signaling pathways
  • biomarkers
  • pathogenesis
  • targeted therapy
  • tumour growth
  • tumour invasion
  • angiogenesis
  • tumour metastasis
  • immune response modulation

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Published Papers (7 papers)

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Research

Jump to: Review

14 pages, 949 KiB  
Article
The Prognostic Value of Preoperative Total Cholesterol in Surgically Treated Oral Cavity Cancer
by Yao-Te Tsai, Ming-Hsien Tsai, Adarsh Kudva, Andrea De Vito, Chia-Hsuan Lai, Chun-Ta Liao, Chung-Jan Kang, Yuan-Hsiung Tsai, Cheng-Ming Hsu, Ethan I. Huang, Geng-He Chang, Ming-Shao Tsai and Ku-Hao Fang
Biomedicines 2024, 12(12), 2898; https://doi.org/10.3390/biomedicines12122898 - 19 Dec 2024
Viewed by 329
Abstract
Background: With growing evidence linking lipid profile changes to tumor development and cancer prognosis, we investigated the prognostic significance of preoperative serum total cholesterol (TC) levels in patients with oral cavity squamous cell carcinoma (OSCC) undergoing surgical treatment. Methods: We conducted a retrospective [...] Read more.
Background: With growing evidence linking lipid profile changes to tumor development and cancer prognosis, we investigated the prognostic significance of preoperative serum total cholesterol (TC) levels in patients with oral cavity squamous cell carcinoma (OSCC) undergoing surgical treatment. Methods: We conducted a retrospective observational study involving 310 patients with primary OSCC who received surgery at our hospital from January 2009 to December 2018. Receiver operating characteristic curve analysis was performed to determine the optimal preoperative TC cutoff value, with the Youden Index employed as the optimization criterion to maximize the sum of sensitivity and specificity. Variables with p < 0.1 in the univariable analysis were included in the multivariable Cox regression model, and stepwise selection was used to identify the optimal subset of prognostic factors for overall survival (OS) and disease-free survival (DFS). Results: An optimal TC cutoff of 157 mg/dL was established. Patients with TC < 157 mg/dL exhibited significantly lower 5-year rates of OS and DFS (p < 0.001 and p = 0.006, respectively). Multivariable analysis confirmed that TC < 157 mg/dL represented an independent prognostic factor for reduced OS and DFS rates. Subgroup analyses reinforced the consistent prognostic significance of TC. We also constructed a nomogram (concordance index: 0.74) to provide personalized OS predictions, enhancing the clinical utility of TC. Conclusions: Preoperative TC appears to be a significant prognostic factor for OS and DFS after OSCC surgery. Routine TC assessment facilitates the development of nomograms for personalized survival predictions, supports clinicians in tailoring treatment strategies, and guides nutritional or metabolic interventions to enhance patient outcomes. Further multicenter prospective studies are needed to validate our findings. Full article
(This article belongs to the Special Issue Oral Squamous Cell Carcinoma: Molecular Signaling Pathways and Novel Biomarkers)
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15 pages, 6475 KiB  
Article
Tumor Protein D53 (TPD53): Involvement in Malignant Transformation of Low-Malignant Oral Squamous Cell Carcinoma Cells
by Masataka Watanabe, Yoshiki Mukudai, Nodoka Kindaichi, Maki Nara, Konomi Yamada, Yuzo Abe, Asami Houri, Toshikazu Shimane and Tatsuo Shirota
Biomedicines 2024, 12(12), 2725; https://doi.org/10.3390/biomedicines12122725 - 28 Nov 2024
Viewed by 426
Abstract
Background/Objectives: The tumor protein D52 (TPD52) family includes TPD52, TPD53, TPD54, and TPD55. The balance between TPD52 and TPD54 expression plays an important role in high-malignant oral squamous cell carcinoma (OSCC) cells. However, the relationship between TPD53 and OSCC cells (particularly low-malignant [...] Read more.
Background/Objectives: The tumor protein D52 (TPD52) family includes TPD52, TPD53, TPD54, and TPD55. The balance between TPD52 and TPD54 expression plays an important role in high-malignant oral squamous cell carcinoma (OSCC) cells. However, the relationship between TPD53 and OSCC cells (particularly low-malignant OSCC cells) remains unclear. In the present study, we investigated the role of TPD53 in the malignant transformation of low-malignant OSCC cells. Methods: Temporal changes in the expression of TPD52 family members at the protein and mRNA levels in OSCC cells and normal human epidermal keratinocytes (NHEK) were examined. Results: The mRNA expression of TPD53 increased in HSC-3 and HSC-4 cells in a time-dependent manner. Similar results for protein expression were observed. The effects of TPD53 on anchorage-dependent and anchorage-independent proliferation, cell cycle, invasion and migration, epithelial-mesenchymal transition (EMT), and matrix metalloproteinase (MMP) activities in HSC-3 and HSC-4 cells were assayed. Finally, using the HSC-3-xenograft-nude-mice model, these effects were examined in vivo. Overexpression of TPD53 increased cell viability and the percentage of cells in the S phase. Furthermore, overexpression of TPD53 increased cell invasion, migration, and MMP activities, regardless of its effect on EMT. Notably, these effects were more pronounced in HSC-3 than in HSC-4 cells. Overexpression of TPD53 enhanced tumor formation and growth in mouse xenografts, corroborating the results of in vitro experiments. Conclusions: The present study revealed novel and important functions of TPD53 in the proliferation and invasion of low-malignant OSCC cells. Full article
(This article belongs to the Special Issue Oral Squamous Cell Carcinoma: Molecular Signaling Pathways and Novel Biomarkers)
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12 pages, 1968 KiB  
Article
ZNF671 Silencing Affects Signaling Pathways in Head and Neck Cancer via Activation of Oncogenic Non-Coding RNAs
by Kendra Smith, Rufa’i Umar Zubair, Richard V. Smith, Stelby Augustine, Nicholas F. Schlecht, Thomas J. Ow, Michael B. Prystowsky and Thomas J. Belbin
Biomedicines 2024, 12(11), 2482; https://doi.org/10.3390/biomedicines12112482 - 29 Oct 2024
Viewed by 823
Abstract
Background: Novel ZNF genes, such as ZNF671, that are located on chromosome 19q13 are known to be hypermethylated at a high frequency in HNSCC as well as in other epithelial solid tumors. Their function is largely unknown. Results: Here, we show that ZNF671 [...] Read more.
Background: Novel ZNF genes, such as ZNF671, that are located on chromosome 19q13 are known to be hypermethylated at a high frequency in HNSCC as well as in other epithelial solid tumors. Their function is largely unknown. Results: Here, we show that ZNF671 is epigenetically silenced in HNSCC primary tumors compared to matched adjacent normal tissue. Moreover, low expression of ZNF671 is significantly associated with decreased survival in HNSCC patients. Over-expression of ZNF671 in UM-SCC-1 oral cancer cells resulted in a significant reduction in tumor cell mobility and invasion compared to the empty-vector control cells. Transcriptomic analysis showed that ZNF671 re-expression resulted in a significant decrease in the expression of a major oncogenic long non-coding RNA LINC00665. Conclusions: Together, these results suggest that epigenetic silencing of ZNF671 may activate multiple oncogenic signaling pathways via the resulting up-regulation of LINC00665. Full article
(This article belongs to the Special Issue Oral Squamous Cell Carcinoma: Molecular Signaling Pathways and Novel Biomarkers)
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15 pages, 3246 KiB  
Article
Stimulator of Interferon Genes Pathway Activation through the Controlled Release of STINGel Mediates Analgesia and Anti-Cancer Effects in Oral Squamous Cell Carcinoma
by Minh Phuong Dong, Neeraja Dharmaraj, Estela Kaminagakura, Jianfei Xue, David G. Leach, Jeffrey D. Hartgerink, Michael Zhang, Hana-Joy Hanks, Yi Ye, Bradley E. Aouizerat, Kyle Vining, Carissa M. Thomas, Sinisa Dovat, Simon Young and Chi T. Viet
Biomedicines 2024, 12(4), 920; https://doi.org/10.3390/biomedicines12040920 - 21 Apr 2024
Viewed by 2021
Abstract
Oral squamous cell carcinoma (OSCC) presents significant treatment challenges due to its poor survival and intense pain at the primary cancer site. Cancer pain is debilitating, contributes to diminished quality of life, and causes opioid tolerance. The stimulator of interferon genes (STING) agonism [...] Read more.
Oral squamous cell carcinoma (OSCC) presents significant treatment challenges due to its poor survival and intense pain at the primary cancer site. Cancer pain is debilitating, contributes to diminished quality of life, and causes opioid tolerance. The stimulator of interferon genes (STING) agonism has been investigated as an anti-cancer strategy. We have developed STINGel, an extended-release formulation that prolongs the availability of STING agonists, which has demonstrated an enhanced anti-tumor effect in OSCC compared to STING agonist injection. This study investigates the impact of intra-tumoral STINGel on OSCC-induced pain using two separate OSCC models and nociceptive behavioral assays. Intra-tumoral STINGel significantly reduced mechanical allodynia in the orofacial cancer model and alleviated thermal and mechanical hyperalgesia in the hind paw model. To determine the cellular signaling cascade contributing to the antinociceptive effect, we performed an in-depth analysis of immune cell populations via single-cell RNA-seq. We demonstrated an increase in M1-like macrophages and N1-like neutrophils after STINGel treatment. The identified regulatory pathways controlled immune response activation, myeloid cell differentiation, and cytoplasmic translation. Functional pathway analysis demonstrated the suppression of translation at neuron synapses and the negative regulation of neuron projection development in M2-like macrophages after STINGel treatment. Importantly, STINGel treatment upregulated TGF-β pathway signaling between various cell populations and peripheral nervous system (PNS) macrophages and enhanced TGF-β signaling within the PNS itself. Overall, this study sheds light on the mechanisms underlying STINGel-mediated antinociception and anti-tumorigenic impact. Full article
(This article belongs to the Special Issue Oral Squamous Cell Carcinoma: Molecular Signaling Pathways and Novel Biomarkers)
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16 pages, 3814 KiB  
Article
Targeting Oral Squamous Cell Carcinoma with Combined Polo-Like-Kinase-1 Inhibitors and γ-Radiation Therapy
by Subhanwita Sarkar, Ayan Chanda, Rutvij A. Khanolkar, Meghan Lambie, Laurie Ailles, Scott V. Bratman, Aru Narendran and Pinaki Bose
Biomedicines 2024, 12(3), 503; https://doi.org/10.3390/biomedicines12030503 - 23 Feb 2024
Viewed by 1622
Abstract
Polo-like-kinase-1 (PLK-1) is a serine/threonine kinase that regulates the cell cycle and acts as an oncogene in multiple cancers, including oral squamous cell carcinoma (OSCC). The loss of PLK-1 can inhibit growth and induce apoptosis, making it an attractive therapeutic target in OSCC. [...] Read more.
Polo-like-kinase-1 (PLK-1) is a serine/threonine kinase that regulates the cell cycle and acts as an oncogene in multiple cancers, including oral squamous cell carcinoma (OSCC). The loss of PLK-1 can inhibit growth and induce apoptosis, making it an attractive therapeutic target in OSCC. We evaluated the efficacy of PLK-1 inhibitors as novel, targeted therapeutics in OSCC. PLK-1 inhibition using BI6727 (volasertib) was found to affect cell death at low nanomolar concentrations in most tested OSCC cell lines, but not in normal oral keratinocytes. In cell lines resistant to volasertib alone, pre-treatment with radiotherapy followed by volasertib reduced cell viability and induced apoptosis. The combinatorial efficacy of volasertib and radiotherapy was replicated in xenograft mouse models. These findings highlight the potential of adding PLK-1 inhibitors to adjuvant therapy regimens in OSCC. Full article
(This article belongs to the Special Issue Oral Squamous Cell Carcinoma: Molecular Signaling Pathways and Novel Biomarkers)
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Review

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14 pages, 857 KiB  
Review
Oral Cavity Cancer Secondary to Dental Trauma: A Scoping Review
by Carlos M. Chiesa-Estomba, Miguel Mayo-Yanez, Luigi A. Vaira, Antonino Maniaci, Allen L. Feng, Maria Landa-Garmendia, Adrian Cardin-Pereda and Jerome R. Lechien
Biomedicines 2024, 12(9), 2024; https://doi.org/10.3390/biomedicines12092024 - 4 Sep 2024
Viewed by 1019
Abstract
(1) Background: Oral cavity cancer represents the most common site of origin of head and neck mucosal malignancies. A few limited studies have suggested that chronic irritation, particularly in non-healing ulcers, and fibrotic tissue from poor dentition or ill-fitting dentures had a role [...] Read more.
(1) Background: Oral cavity cancer represents the most common site of origin of head and neck mucosal malignancies. A few limited studies have suggested that chronic irritation, particularly in non-healing ulcers, and fibrotic tissue from poor dentition or ill-fitting dentures had a role in developing mouth cancer. This scoping review aims to evaluate the existing evidence concerning Oral Cavicty Cancer (OCC) in non-smokers/non-drinkers and the relationship with dental trauma. (2) Methods: A scoping review of the PubMed, Embase, and Web of Science databases was completed in adherence with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews checklist. (3) Results: Of the 33 articles that met inclusion, in 6 of them authors discussed the role of topography in dental trauma, in 11 articles authors discussed the carcinogenesis mechanism involved in chronic mucosal trauma, in 17 articles data on ill-fitting dentures was included, 4 studies dealt with the effect of broken/sharp teeth on mucosal damage, and in 7 studies the role of oral hygiene was covered. Less frequently discussed topics included gender, risk of neck nodes, and the role of potentially malignant oral disorders. (4) Conclusions: The available literature suggests a potential connection between chronic dental trauma and the development of OCC. Studies have highlighted factors such as denture use and ill-fitting dental appliances as contributors to an increased risk of oral cancer. Interestingly, we still miss data to support the hypothesis that women, particularly those without toxic habits like smoking or alcohol consumption, appear to be disproportionately affected by oral cancer related to chronic dental trauma. Full article
(This article belongs to the Special Issue Oral Squamous Cell Carcinoma: Molecular Signaling Pathways and Novel Biomarkers)
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20 pages, 2023 KiB  
Review
Unlocking the Therapeutic Potential of Oral Cancer Stem Cell-Derived Exosomes
by Prabhat Kumar, Rishabh Lakhera, Sadhna Aggarwal and Shilpi Gupta
Biomedicines 2024, 12(8), 1809; https://doi.org/10.3390/biomedicines12081809 - 9 Aug 2024
Viewed by 1883
Abstract
Oral cancer (OC) presents a significant global health burden with rising incidence rates. Despite advancements in diagnosis and treatments, the survival rate for OC patients, particularly those with advanced or recurrent disease, remains low at approximately 20%. This poor prognosis is often due [...] Read more.
Oral cancer (OC) presents a significant global health burden with rising incidence rates. Despite advancements in diagnosis and treatments, the survival rate for OC patients, particularly those with advanced or recurrent disease, remains low at approximately 20%. This poor prognosis is often due to a small population of cancer stem cells (CSCs) that are capable of self-renewal and immune evasion, playing pivotal roles in proliferation, tumor initiation, progression, metastasis, and therapy resistance. Exosomes, which are nano-sized extracellular vesicles (EVs), have emerged as crucial mediators of cell-to-cell communication within the tumor microenvironment (TME). These vesicles carry diverse molecules such as DNA, RNA, proteins, lipids, and metabolites, influencing various cellular processes. Emerging evidence suggests that CSC-derived EVs significantly promote tumor progression and metastasis and maintain the balance between CSCs and non-CSCs, which is vital for intracellular communication within the TME of oral cancer. Recent reports indicate that oral cancer stem cell-derived EVs (OCSC-EVs) influence stemness, immune evasion, metastasis, angiogenesis, tumor reoccurrence, and drug resistance. Understanding OCSC-EVs could significantly improve oral cancer diagnosis, prognosis, and therapy. In this mini-review, we explore OCSC-derived exosomes in oral cancer, examining their potential as diagnostic and prognostic biomarkers that reflect CSC characteristics, and delve into their therapeutic implications, emphasizing their roles in tumor progression and therapy resistance. However, despite their promising potential, several challenges remain, including the need to standardize isolation and characterization methods and to elucidate exosome-mediated mechanisms. Thus, a comprehensive understanding of OCSC-EVs could pave the way for innovative therapeutic strategies that have the potential to improve clinical outcomes for OC patients. Full article
(This article belongs to the Special Issue Oral Squamous Cell Carcinoma: Molecular Signaling Pathways and Novel Biomarkers)
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