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13 pages, 5097 KiB

Open AccessArticle

Calcitriol Treatment Decreases Cell Migration, Viability and β-Catenin Signaling in Oral Dysplasia

by Daniel Peña-Oyarzún, Constanza Guzmán, Catalina Kretschmar, Vicente A. Torres, Andrea Maturana-Ramirez, Juan Aitken and Montserrat Reyes

Curr. Issues Mol. Biol. 2024, 46(4), 3050-3062; https://doi.org/10.3390/cimb46040191 - 02 Apr 2024

Viewed by 453

Abstract

Nearly 90% of oral cancers are characterized as oral squamous cell carcinoma (OSCC), representing the sixth most common type of cancer. OSCC usually evolves from oral potentially malignant disorders that, in some cases, are histologically consistent with a oral dysplasia. The levels of [...] Read more.

Nearly 90% of oral cancers are characterized as oral squamous cell carcinoma (OSCC), representing the sixth most common type of cancer. OSCC usually evolves from oral potentially malignant disorders that, in some cases, are histologically consistent with a oral dysplasia. The levels of 1α,25 dihydroxyvitamin D3 (1,25-(OH)2D3; calcitriol), the active form of vitamin D3, have been shown to be decreased in patients with oral dysplasia and OSCC. Moreover, treatment with 1,25-(OH)2D3 has been proven beneficial in OSCC by inhibiting the Wnt/β-catenin pathway, a signaling route that promotes cell migration, proliferation, and viability. However, whether this inhibition mechanism occurs in oral dysplasia is unknown. To approach this question, we used dysplastic oral keratinocyte cultures and oral explants (ex vivo model of oral dysplasia) treated with 1,25-(OH)2D3 for 48 h. Following treatment with 1,25-(OH)2D3, both in vitro and ex vivo models of oral dysplasia showed decreased levels of nuclear β-catenin by immunofluorescence (IF) and immunohistochemistry (IHC). Consistently, reduced protein and mRNA levels of the Wnt/β-catenin target gene survivin were observed after treatment with 1,25-(OH)2D3. Moreover, 1,25-(OH)2D3 promoted membranous localization of E-cadherin and nuclear localization of vitamin D receptor (VDR). Functionally, DOK cells treated with 1,25-(OH)2D3 displayed diminished cell migration and viability in vitro. Full article

(This article belongs to the Special Issue Oral Cancer: Prophylaxis, Etiopathogenesis and Treatment)

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13 pages, 3298 KiB

Open AccessArticle

Investigating Cox-2 and EGFR as Biomarkers in Canine Oral Squamous Cell Carcinoma: Implications for Diagnosis and Therapy

by Rita Files, Catarina Santos, Felisbina L. Queiroga, Filipe Silva, Leonor Delgado, Isabel Pires and Justina Prada

Curr. Issues Mol. Biol. 2024, 46(1), 485-497; https://doi.org/10.3390/cimb46010031 - 04 Jan 2024

Viewed by 1187

Abstract

Oral squamous cell carcinoma (OSCC) is a common and highly aggressive dog tumor known for its local invasiveness and metastatic potential. Understanding the molecular mechanisms driving the development and progression of OSCC is crucial for improving diagnostic and therapeutic strategies. Additionally, spontaneous oral [...] Read more.

Oral squamous cell carcinoma (OSCC) is a common and highly aggressive dog tumor known for its local invasiveness and metastatic potential. Understanding the molecular mechanisms driving the development and progression of OSCC is crucial for improving diagnostic and therapeutic strategies. Additionally, spontaneous oral squamous cell carcinomas in dogs are an excellent model for studying human counterparts. In this study, we aimed to investigate the significance of two key molecular components, Cox-2 and EGFR, in canine OSCC. We examined 34 tumor sections from various dog breeds to assess the immunoexpression of Cox-2 and EGFR. Our findings revealed that Cox-2 was highly expressed in 70.6% of cases, while EGFR overexpression was observed in 44.1%. Cox-2 overexpression showed association with histological grade of malignancy (HGM) (p = 0.006) and EGFR with vascular invasion (p = 0.006). COX-2 and EGFR concurrent expression was associated with HGM (p = 0.002), as well as with the presence of vascular invasion (p = 0.002). These data suggest that Cox-2 and EGFR could be promising biomarkers and potential therapeutic targets, opening avenues for developing novel treatment strategies for dogs affected by OSCC. Further studies are warranted to delve deeper into these findings and translate them into clinical practice. Full article

(This article belongs to the Special Issue Oral Cancer: Prophylaxis, Etiopathogenesis and Treatment)

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14 pages, 3435 KiB

Open AccessArticle

PRI-724 and IWP-O1 Wnt Signaling Pathway Inhibitors Modulate the Expression of Glycolytic Enzymes in Tongue Cancer Cell Lines

by Robert Kleszcz, Jarosław Paluszczak, Marta Belka and Violetta Krajka-Kuźniak

Curr. Issues Mol. Biol. 2023, 45(12), 9579-9592; https://doi.org/10.3390/cimb45120599 - 29 Nov 2023

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Abstract

The dysregulation of energetic metabolism is one of the hallmarks of cancer cells. Indeed, the growth of head and neck squamous cell carcinoma (HNSCC) cells depends heavily on glycolytic activity, which can be considered a potential therapeutic target. Wnt signaling is one of [...] Read more.

The dysregulation of energetic metabolism is one of the hallmarks of cancer cells. Indeed, the growth of head and neck squamous cell carcinoma (HNSCC) cells depends heavily on glycolytic activity, which can be considered a potential therapeutic target. Wnt signaling is one of the pathways that undergoes upregulation in HNSCC. Our previous studies have shown that Wnt signaling inhibitors—PRI-724 and IWP-O1—attenuate tongue SCC survival and reduce glucose uptake and lactate release. The aim of this research was to further evaluate the possible mechanisms of the previously observed effects. We assessed the effect of PRI-724 and IWP-O1 on the expression of selected glycolytic enzymes: phosphofructokinase M, pyruvate kinase M2, and lactate dehydrogenase. Relative transcript expression was assessed by real-time PCR, and protein levels by Western blot. Moreover, clinical data concerning mRNA and protein expression, gene promoter methylation, and HNSCC patients’ survival time were analyzed by the UALCAN tool, and protein–protein interaction was assessed using the STRING database. Experimental and bioinformatic data confirmed the relation between Wnt signaling and glycolytic enzymes in tongue cancer cells and HNSCC clinical samples. Overall, the inhibition of glucose metabolism by Wnt signaling inhibitors is a promising mode of action against tongue cancer cells. Full article

(This article belongs to the Special Issue Oral Cancer: Prophylaxis, Etiopathogenesis and Treatment)

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12 pages, 1855 KiB

Open AccessArticle

p62 Is a Potential Biomarker for Risk of Malignant Transformation of Oral Potentially Malignant Disorders (OPMDs)

by Ryo Takasaki, Fumihiko Uchida, Shohei Takaoka, Ryota Ishii, Satoshi Fukuzawa, Eiji Warabi, Naomi Ishibashi-Kanno, Kenji Yamagata, Hiroki Bukawa and Toru Yanagawa

Curr. Issues Mol. Biol. 2023, 45(9), 7630-7641; https://doi.org/10.3390/cimb45090480 - 19 Sep 2023

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Abstract

To determine the intracellular behavior of p62, a marker of selective autophagy, in oral potentially malignant disorders (OPMDs). This retrospective study includes 70 patients who underwent biopsy or surgical resection and were definitively diagnosed with OPMDs. Immunohistochemical staining for p62, XPO1, p53, and [...] Read more.

To determine the intracellular behavior of p62, a marker of selective autophagy, in oral potentially malignant disorders (OPMDs). This retrospective study includes 70 patients who underwent biopsy or surgical resection and were definitively diagnosed with OPMDs. Immunohistochemical staining for p62, XPO1, p53, and ki67 was performed on all samples and positive cell occupancy was calculated. We statistically investigated the correlation between protein expression in OPMDs and the association between malignant transformation, clinicopathological characteristics, and occupancy. ki67 expression was negatively correlated with p62 expression in the nucleus (p < 0.01) and positively correlated with p62 expression in the cytoplasm (p < 0.01). For malignant transformation, the expression of p62 in the nucleus (p = 0.03) was significantly lower in malignant transformation cases, whereas the expression of p62 in the cytoplasm (p = 0.03) and the aggregation expression (p < 0.01) were significantly higher. Our results suggest that the function of p62 is altered by its subcellular localization. In addition, defects in selective autophagy occur in cases of malignant transformation, suggesting that p62 is a potential biomarker of the risk of malignant transformation of OPMDs. Full article

(This article belongs to the Special Issue Oral Cancer: Prophylaxis, Etiopathogenesis and Treatment)

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17 pages, 3250 KiB

Open AccessCommunication

Sequencing Analysis of MUC6 and MUC16 Gene Fragments in Patients with Oropharyngeal Squamous Cell Carcinoma Reveals Novel Mutations: A Preliminary Study

by Jadwiga Gaździcka, Krzysztof Biernacki, Silvia Salatino, Karolina Gołąbek, Dorota Hudy, Agata Świętek, Katarzyna Miśkiewicz-Orczyk, Anna Koniewska, Maciej Misiołek and Joanna Katarzyna Strzelczyk

Curr. Issues Mol. Biol. 2023, 45(7), 5645-5661; https://doi.org/10.3390/cimb45070356 - 04 Jul 2023

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Abstract

The growing incidence of oropharyngeal squamous cell carcinoma (OPSCC) calls for better understanding of the mutational landscape of such cases. Mucins (MUCs) are multifunctional glycoproteins expressed by the epithelial cells and may be associated with the epithelial tumour invasion and progression. The present [...] Read more.

The growing incidence of oropharyngeal squamous cell carcinoma (OPSCC) calls for better understanding of the mutational landscape of such cases. Mucins (MUCs) are multifunctional glycoproteins expressed by the epithelial cells and may be associated with the epithelial tumour invasion and progression. The present study aimed at the analysis of the sequence of selected MUC6 and MUC16 gene fragments in the tumour, as well as the margin, samples obtained from 18 OPSCC patients. Possible associations between the detected mutations and the clinicopathological and demographic characteristics of the study group were analysed. Sanger sequencing and bioinformatic data analysis of the selected MUC6 and MUC16 cDNA fragments were performed. Our study found 13 and 3 mutations in MUC6 and MUC16, respectively. In particular, one novelty variant found that the MUC6 gene (chr11:1018257 A>T) was the most frequent across our cohort, in both the tumour and the margin samples, and was then classified as a high impact, stop-gain mutation. The current study found novel mutations in MUC6 and MUC16 providing new insight into the genetic alternation in mucin genes among the OPSCC patients. Further studies, including larger cohorts, are recommended to recognise the pattern in which the mutations affect oropharyngeal carcinogenesis. Full article

(This article belongs to the Special Issue Oral Cancer: Prophylaxis, Etiopathogenesis and Treatment)

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15 pages, 4429 KiB

Open AccessArticle

Establishment of a Novel Anti-CD44 Variant 10 Monoclonal Antibody C₄₄Mab-18 for Immunohistochemical Analysis against Oral Squamous Cell Carcinomas

by Kenichiro Ishikawa, Hiroyuki Suzuki, Mika K. Kaneko and Yukinari Kato

Curr. Issues Mol. Biol. 2023, 45(7), 5248-5262; https://doi.org/10.3390/cimb45070333 - 21 Jun 2023

Cited by 2 | Viewed by 1298

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the most common type of head and neck cancer, and has been revealed as the second-highest expression of CD44 in cancers. CD44 has been investigated as a cancer stem cell marker of HNSCC and plays [...] Read more.

Head and neck squamous cell carcinoma (HNSCC) is the most common type of head and neck cancer, and has been revealed as the second-highest expression of CD44 in cancers. CD44 has been investigated as a cancer stem cell marker of HNSCC and plays a critical role in tumor malignant progression. Especially, splicing variant isoforms of CD44 (CD44v) are overexpressed in cancers and considered a promising target for cancer diagnosis and therapy. We developed monoclonal antibodies (mAbs) against CD44 by immunizing mice with CD44v3–10-overexpressed PANC-1 cells. Among the established clones, C₄₄Mab-18 (IgM, kappa) reacted with CHO/CD44v3–10, but not with CHO/CD44s and parental CHO-K1 using flow cytometry. The epitope mapping using peptides that cover variant exon-encoded regions revealed that C₄₄Mab-18 recognized the border sequence between variant 10 and the constant exon 16-encoded sequence. These results suggest that C₄₄Mab-18 recognizes variant 10-containing CD44v, but not CD44s. Furthermore, C₄₄Mab-18 could recognize the human oral squamous cell carcinoma (OSCC) cell line, HSC-3, in flow cytometry. The apparent dissociation constant (K_D) of C₄₄Mab-18 for CHO/CD44v3–10 and HSC-3 was 1.6 × 10⁻⁷ M and 1.7 × 10⁻⁷ M, respectively. Furthermore, C₄₄Mab-18 detected CD44v3–10 but not CHO/CD44s in Western blotting, and endogenous CD44v10 in immunohistochemistry using OSCC tissues. These results indicate that C₄₄Mab-18 is useful for detecting CD44v10 in flow cytometry and immunohistochemistry. Full article

(This article belongs to the Special Issue Oral Cancer: Prophylaxis, Etiopathogenesis and Treatment)

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12 pages, 6837 KiB

Open AccessArticle

M2 Macrophages-Derived Exosomal miRNA-23a-3p Promotes the Progression of Oral Squamous Cell Carcinoma by Targeting PTEN

by Jun Li, Yongjie Bao, Sisi Peng, Chao Jiang, Luying Zhu, Sihai Zou, Jie Xu and Yong Li

Curr. Issues Mol. Biol. 2023, 45(6), 4936-4947; https://doi.org/10.3390/cimb45060314 - 07 Jun 2023

Cited by 1 | Viewed by 1416

Abstract

Exosomes from tumor cells and immune cells regulate the tumor microenvironment through the biomolecules or microRNAs (miRNAs) they carry. This research aims to investigate the role of miRNA in exosomes derived from tumor-associated macrophages (TAMs) in the progression of oral squamous cell carcinoma [...] Read more.

Exosomes from tumor cells and immune cells regulate the tumor microenvironment through the biomolecules or microRNAs (miRNAs) they carry. This research aims to investigate the role of miRNA in exosomes derived from tumor-associated macrophages (TAMs) in the progression of oral squamous cell carcinoma (OSCC). RT-qPCR and Western blotting assays were used to determine the expression of genes and proteins in OSCC cells. CCK-8, Scratch assay and invasion-related proteins were utilized to detect the malignant progression of tumor cells. High-throughput sequencing predicted differentially expressed miRNAs in exosomes secreted by M0 and M2 macrophages. Compared with exosomes from M0 macrophages, exosomes from M2 macrophages led to enhanced proliferation and invasion of OSCC cells and inhibited their apoptosis. High-throughput sequencing results show that miR-23a-3p is differentially expressed in exosomes from M0 and M2 macrophages. MiRNA target gene database predicts that phosphatase and tensin homolog (PTEN) are target genes of miR-23a-3p. Further studies revealed that transfection of miR-23a-3p mimics inhibited PTEN expression in vivo and in vitro and promoted the malignant progression of OSCC cells, which was reversed by miR-23a-3p inhibitors. MiR-23a-3p in exosomes derived from M2 macrophages promotes malignant progression of OSCC. PTEN is a potential intracellular target of miR-23a-3p. MiR-23a-3p, an M2 macrophage-associated exosome, is a promising target for the future treatment of OSCC. Full article

(This article belongs to the Special Issue Oral Cancer: Prophylaxis, Etiopathogenesis and Treatment)

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Review

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19 pages, 1575 KiB

Open AccessReview

Head and Neck Squamous Cell Carcinoma Vaccine: Current Landscape and Perspectives

by Piero Giuseppe Meliante, Carla Petrella, Marco Fiore, Antonio Minni and Christian Barbato

Curr. Issues Mol. Biol. 2023, 45(11), 9215-9233; https://doi.org/10.3390/cimb45110577 - 16 Nov 2023

Cited by 1 | Viewed by 1552

Abstract

The treatment of unresectable or metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) has traditionally relied on chemotherapy or radiotherapy, yielding suboptimal outcomes. The introduction of immunotherapy has significantly improved HNSCC treatment, even if the long-term results cannot be defined as satisfactory. Its [...] Read more.

The treatment of unresectable or metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) has traditionally relied on chemotherapy or radiotherapy, yielding suboptimal outcomes. The introduction of immunotherapy has significantly improved HNSCC treatment, even if the long-term results cannot be defined as satisfactory. Its mechanism of action aims to counteract the blockade of tumor immune escape. This result can also be obtained by stimulating the immune system with vaccines. This review scope is to comprehensively gather existing evidence and summarize ongoing clinical trials focused on therapeutic vaccines for HNSCC treatment. The current landscape reveals numerous promising drugs in the early stages of experimentation, along with a multitude of trials that have been suspended or abandoned for years. Nonetheless, there are encouraging results and ongoing experiments that instill hope for potential paradigm shifts in HNSCC therapy. Full article

(This article belongs to the Special Issue Oral Cancer: Prophylaxis, Etiopathogenesis and Treatment)

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