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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 (30 August 2020) | Viewed by 45871

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Prof. Tadaaki Kirita

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Department of Oral and Maxillofacial Surgery, Nara Medical University, 840 Schijo-cho, Nara-Kashihara 634-8521, Japan
Interests: Oral cancer; Biomarkers; Molecular biology; Cancer genetics; Reconstructive surgery; Chemotherapy; Treatment of advanced oral cancer

Special Issue Information

Dear Colleagues,

Head and neck cancer, including oral squamous cell carcinoma (OSCC), is the sixth most common cancer worldwide. It is accepted that OSCC arises from multiple genetic alterations caused by chronic exposure to carcinogens such as alcohol, smoking, viral infections, and inflammation. These genetic alterations, which include deletions, point mutations, promoter methylation, and gene amplification of oncogenes, inactivate tumor suppressor genes. The molecular mechanisms of carcinogenesis, tumor progression, and metastasis of oral cancer have been elucidated by recent advances in molecular biology. However, many unsolved questions still remain.

This Special Issue on “Oral Squamous Cell Carcinoma” has the objective of developing an updated investigation and rationale of biological behavior of oral squamous cell carcinoma focusing on molecular biology, pathology, biomarkers, genetics, diagnostics, and therapeutics.

Prof. Tadaaki Kirita
Guest Editor

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Keywords

Oral squamous cell carcinoma
Molecular biology
Pathology
Biomarkers
Genetic mutation
Biological behavior
Diagnostics and therapeutics

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Published Papers (10 papers)

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Research

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15 pages, 3351 KiB

Open AccessArticle

Targeting mTOR-CCL20 Signaling May Improve Response to Docetaxel in Head and Neck Squamous Cell Carcinoma

by Ming-Huei Chou, Hui-Ching Chuang, Yu-Tsai Lin, Ming-Hsien Tsai, Ying-Hsien Kao, I-Chun Lin, Tai-Lin Huang, Fu-Min Fang and Chih-Yen Chien

Int. J. Mol. Sci. 2021, 22(6), 3046; https://doi.org/10.3390/ijms22063046 - 17 Mar 2021

Cited by 1 | Viewed by 3014

Abstract

Patients with advanced head and neck squamous cell carcinoma (HNSCC) usually show a dismal prognosis. It is this worthwhile to develop new, effective therapeutic regimens for these patients, such as molecular targeted therapy, which is promising as an alternative or combination treatment for HNSCC. The mammalian target of rapamycin (mTOR) pathway, which plays an important role in the carcinogenesis of HNSCC, is the most frequently activated, and is thus worthy of further investigation. In this study, two human HNSCC cell lines, FaDu and SAS, were evaluated for cell growth with trypan blue staining and tumor growth using an orthotopic xenograft model. The immunohistochemical expression of mTOR in the subcutaneous xenograft model and the inhibitory effects of docetaxel on the growth and state of activation of the PI3K/mTOR pathway were also evaluated and examined by colony formation and Western blot, respectively. Cell proliferation and migration were measured by water-soluble tetrazolium salt (WST-1) and Oris^TM cell migration assay, respectively. Furthermore, the effects of rapamycin and BEZ235, a phosphatidylinositol 3-kinases (PI3K) and mTOR inhibitor in combination with docetaxel or CCL20 were evaluated in the FaDu and SAS cells. The results showed that the expression of mTOR was significantly higher in the SAS and FaDu xenograft models than in the control. Docetaxel treatment significantly suppressed HNSCC cell proliferation and migration in vitro via the PI3K/mTOR/CCL-20 signaling pathway. Additionally, when administered in a dose-dependent fashion, mTOR inhibitors inhibited the growth and migration of the HNSCC cells. This combination was synergistic with docetaxel, resulting in almost complete cell growth and migration arrest. In conclusion, docetaxel significantly inhibited HNSCC cell proliferation and migration in vitro via the PI3K/mTOR/CCL-20 signaling pathway. The synergistic and additive activity of mTOR inhibitors combined with docetaxel shows potential as a new treatment strategy for HNSCC. Full article

(This article belongs to the Special Issue Oral Squamous Cell Carcinoma)

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17 pages, 4563 KiB

Open AccessArticle

Ginsenoside M1 Induces Apoptosis and Inhibits the Migration of Human Oral Cancer Cells

by Yu-Chieh Lee, Wei-Ting Wong, Lan-Hui Li, Lichieh Julie Chu, Mridula P. Menon, Chen-Lung Ho, Oleg V. Chernikov, Sheau-Long Lee and Kuo-Feng Hua

Int. J. Mol. Sci. 2020, 21(24), 9704; https://doi.org/10.3390/ijms21249704 - 19 Dec 2020

Cited by 8 | Viewed by 3043

Abstract

Oral squamous cell carcinoma (OSCC) accounts for 5.8% of all malignancies in Taiwan, and the incidence of OSCC is on the rise. OSCC is also a common malignancy worldwide, and the five-year survival rate remains poor. Therefore, new and effective treatments are needed to control OSCC. In the present study, we prepared ginsenoside M1 (20-O-beta-d-glucopyranosyl-20(S)-protopanaxadiol), a major deglycosylated metabolite of ginsenoside, through the biotransformation of Panax notoginseng leaves by the fungus SP-LSL-002. We investigated the anti-OSCC activity and associated mechanisms of ginsenoside M1 in vitro and in vivo. We demonstrated that ginsenoside M1 dose-dependently inhibited the viability of human OSCC SAS and OEC-M1 cells. To gain further insight into the mode of action of ginsenoside M1, we demonstrated that ginsenoside M1 increased the expression levels of Bak, Bad, and p53 and induced apoptotic DNA breaks, G1 phase arrest, PI/Annexin V double-positive staining, and caspase-3/9 activation. In addition, we demonstrated that ginsenoside M1 dose-dependently inhibited the colony formation and migration ability of SAS and OEC-M1 cells and reduced the expression of metastasis-related protein vimentin. Furthermore, oral administration or subcutaneous injection of ginsenoside M1 significantly reduced tumor growth in SAS xenograft mice. These results indicate that ginsenoside M1 can be translated into a potential therapeutic against OSCC. Full article

(This article belongs to the Special Issue Oral Squamous Cell Carcinoma)

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16 pages, 4361 KiB

Open AccessArticle

Platelet Induced Functional Alteration of CD4⁺ and CD8⁺ T Cells in HNSCC

by Christina Polasky, Franziska Wendt, Ralph Pries and Barbara Wollenberg

Int. J. Mol. Sci. 2020, 21(20), 7507; https://doi.org/10.3390/ijms21207507 - 12 Oct 2020

Cited by 13 | Viewed by 6723

Abstract

Platelets (PLT) are the second most abundant cell type in human blood and exert various immune-regulatory functions under both physiological and pathological conditions. In fact, immune cell regulation via platelets has been demonstrated in several studies within the past decade. However, the exact mechanisms behind T cell regulation remain poorly understood. We questioned whether the formation of aggregates of platelets and T cells has an impact on T-cell functions. In the present study, we stimulated PBMC cultures with anti-CD3 and anti-CD28 mABs and cultured them at a PLT: PBMC ratio of 1:1 or 100:1. After 24, 48, and 72 h, PD-1, PD-L1 expression, and proliferation were analyzed on T cells using flow cytometry. Cytokine production was measured in PHA stimulated CD4 cells after 6 h. We found a significant platelet-mediated decrease in PD-1 and PD-L1 expression, proliferation, as well as IFN-γ and TNF-α production. Perturbations also at least partially remained after spatial separation of PLTs from PBMCs in Transwell-assays. T cell-platelet aggregates showed similar levels of activation markers, proliferation, and secreted cytokines as their non-complexed counterparts. Results indicate a platelet mediated regulation of T cells via direct and indirect contact, but only mediocre effects of the complex formation itself. Full article

(This article belongs to the Special Issue Oral Squamous Cell Carcinoma)

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13 pages, 2571 KiB

Open AccessArticle

Malic Enzyme 1 Is Associated with Tumor Budding in Oral Squamous Cell Carcinomas

by Chie Nakashima, Tadaaki Kirita, Kazuhiko Yamamoto, Shiori Mori, Yi Luo, Takamitsu Sasaki, Kiyomu Fujii, Hitoshi Ohmori, Isao Kawahara, Takuya Mori, Kei Goto, Shingo Kishi, Rina Fujiwara-Tani and Hiroki Kuniyasu

Int. J. Mol. Sci. 2020, 21(19), 7149; https://doi.org/10.3390/ijms21197149 - 28 Sep 2020

Cited by 18 | Viewed by 3652

Abstract

Budding at the tumor invasive front has been correlated with the malignant properties of many cancers. Malic enzyme 1 (ME1) promotes the Warburg effect in cancer cells and induces epithelial–mesenchymal transition (EMT) in oral squamous cell carcinoma (OSCC). Therefore, we investigated the role of ME1 in tumor budding in OSCC. Tumor budding was measured in 96 human OSCCs by immunostaining for an epithelial marker (AE1/AE3), and its expression was compared with that of ME1. A significant correlation was observed between tumor budding and ME1 expression. The correlation increased with the progression of cancer. In human OSCC cells, lactate secretion decreased when lactate fermentation was suppressed by knockdown of ME1 and lactate dehydrogenase A or inhibition of pyruvate dehydrogenase (PDH) kinase. Furthermore, the extracellular pH increased, and the EMT phenotype was suppressed. In contrast, when oxidative phosphorylation was suppressed by PDH knockdown, lactate secretion increased, extracellular pH decreased, and the EMT phenotype was promoted. Induction of chemical hypoxia in OSCC cells by CoCl₂ treatment resulted in increased ME1 expression along with HIF1α expression and promotion of the EMT phenotype. Hypoxic conditions also increased matrix metalloproteinases expression and decreased mitochondrial membrane potential, mitochondrial oxidative stress, and extracellular pH. Furthermore, the hypoxic treatment resulted in the activation of Yes-associated protein (YAP), which was abolished by ME1 knockdown. These findings suggest that cancer cells at the tumor front in hypoxic environments increase their lactate secretion by switching their energy metabolism from oxidative phosphorylation to glycolysis owing to ME1 overexpression, decrease in extracellular pH, and YAP activation. These alterations enhance EMT and the subsequent tumor budding. Tumor budding and ME1 expression are thus considered useful markers of OSCC malignancy, and ME1 is expected to be a relevant target for molecular therapy. Full article

(This article belongs to the Special Issue Oral Squamous Cell Carcinoma)

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11 pages, 962 KiB

Open AccessArticle

Paclitaxel Potentiates the Anticancer Effect of Cetuximab by Enhancing Antibody-Dependent Cellular Cytotoxicity on Oral Squamous Cell Carcinoma Cells In Vitro

by Yuta Sawatani, Yuske Komiyama, Koh-ichi Nakashiro, Daisuke Uchida, Chonji Fukumoto, Michiko Shimura, Tomonori Hasegawa, Ryouta Kamimura, Masayo Hitomi-Koide, Toshiki Hyodo and Hitoshi Kawamata

Int. J. Mol. Sci. 2020, 21(17), 6292; https://doi.org/10.3390/ijms21176292 - 31 Aug 2020

Cited by 12 | Viewed by 2749

Abstract

Administration of cetuximab (C-mab) in combination with paclitaxel (PTX) has been used for patients with head and neck squamous cell carcinoma (SCC) clinically. In this study, we attempted to clarify the molecular mechanisms of the enhancing anticancer effect of C-mab combined with PTX on oral SCC cells in vitro. We used two oral SCC cells (HSC4, OSC19) and A431 cells. PTX alone inhibited cell growth in all cells in a concentration-dependent manner. C-mab alone inhibited the growth of A431 and OSC19 cells at low concentrations, but inhibited the growth of HSC4 cells very weakly, even at high concentrations. A combined effect of the two drugs was moderate on A431 cells, but slight on HSC4 and OSC19 cells. A low concentration of PTX enhanced the antibody-dependent cellular cytotoxicity (ADCC) induced by C-mab in all of the cells tested. PTX slightly enhanced the anticancer effect of C-mab in this ADCC model on A431 and HSC4 cells, and markedly enhanced the anticancer effect of C-mab on OSC19 cells. These results indicated that PTX potentiated the anticancer effect of C-mab through enhancing the ADCC in oral SCC cells. Full article

(This article belongs to the Special Issue Oral Squamous Cell Carcinoma)

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26 pages, 24598 KiB

Open AccessArticle

Enforced C-Src Activation Causes Compartmental Dysregulation of PI3K and PTEN Molecules in Lipid Rafts of Tongue Squamous Carcinoma Cells by Attenuating Rac1-Akt-GLUT-1-Mediated Sphingolipid Synthesis

by Chien-Wei Wu, Shyang-Guang Wang, Ching-Hsiao Lee, Wen-Ling Chan, Meng-Liang Lin and Shih-Shun Chen

Int. J. Mol. Sci. 2020, 21(16), 5812; https://doi.org/10.3390/ijms21165812 - 13 Aug 2020

Cited by 6 | Viewed by 3047

Abstract

Pharmacologic intervention to affect the membrane lipid homeostasis of lipid rafts is a potent therapeutic strategy for cancer. Here we showed that gallic acid (GA) caused the complex formation of inactive Ras-related C3 botulinum toxin substrate 1 (Rac1)-phospho (p)-casein kinase 2 α (CK2α) (Tyr 255) in human tongue squamous carcinoma (TSC) cells, which disturbed the lipid raft membrane-targeting of phosphatidylinositol 3-kinase (PI3K)-Rac1-protein kinase B (Akt) signal molecules by inducing the association of p110α-free p85α with unphosphorylated phosphatase tensin homolog deleted on chromosome 10 (PTEN) in lipid rafts. The effects on induction of inactive Rac1-p-CK2α (Tyr 255) complex formation and attenuation of p-Akt (Ser 473), GTP-Rac1, glucose transporter-1 (GLUT-1) lipid raft membrane-targeting, and cell invasive activity by GA were counteracted either by CK2α short hairpin RNA or cellular-Src (c-Src) inhibitor PP1. PP1 treatment, GLUT-1 or constitutively active Rac1 ectopic-expression blocked GA-induced decreases in cellular glucose, sphingolipid and cholesterol of lipid raft membranes, p85α-p110α-GTP-Rac1 complexes, glucosylceramide synthase activity and increase in ceramide and p110α-free p85α-PTEN complex levels of lipid raft membranes, which reversed the inhibition on matrix metalloproteinase (MMP)-2/-9-mediated cell invasion induced by GA. Using transient ectopic expression of nuclear factor-kappa B (NF-κB) p65, MMP-2/-9 promoter-driven luciferase, and NF-κB-dependent luciferase reporter genes and NF-κB specific inhibitors or Rac1 specific inhibitor NSC23766, we confirmed that an attenuation of Rac1 activity by GA confers inhibition of NF-κB-mediated MMP-2/-9 expression and cell invasion. In conclusion, GA-induced c-Src activation is a key inductive event for the formation of inactive Rac1-p-CK2α (Tyr 255) complexes, which disturbed lipid raft compartment of PI3K and PTEN molecules by impairing Akt-regulated GLUT-1-mediated sphingolipid synthesis, and finally resulting in inhibition of TSC cell invasion. Full article

(This article belongs to the Special Issue Oral Squamous Cell Carcinoma)

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12 pages, 2378 KiB

Open AccessArticle

Peroxidan Plays a Tumor-Promoting Role in Oral Squamous Cell Carcinoma

by Miyako Kurihara-Shimomura, Tomonori Sasahira, Hiroyuki Shimomura and Tadaaki Kirita

Int. J. Mol. Sci. 2020, 21(15), 5416; https://doi.org/10.3390/ijms21155416 - 30 Jul 2020

Cited by 21 | Viewed by 2940

Abstract

Despite dramatic progress in cancer diagnosis and treatment, the five-year survival rate of oral squamous cell carcinoma (OSCC) is still only about 50%. Thus, the need for elucidating the molecular mechanisms underlying OSCC is urgent. We previously identified the peroxidasin gene (PXDN) as one of several novel genes associated with OSCC. Although the PXDN protein is known to act as a tumor-promoting factor associated with the Warburg effect, its function and role in OSCC are poorly understood. In this study, we investigated the expression, function, and relationship with the Warburg effect of PXDN in OSCC. In immunohistochemical analysis of OSCC specimens, we observed that elevated PXDN expression correlated with lymph node metastasis and a diffuse invasion pattern. High PXDN expression was confirmed as an independent predictor of poor prognosis by multivariate analysis. The PXDN expression level correlated positively with that of pyruvate kinase (PKM2) and heme oxygenase-1 (HMOX1) and with lactate and ATP production. No relationship between PXDN expression and mitochondrial activation was observed, and PXDN expression correlated inversely with reactive oxygen species (ROS) production. These results suggest that PXDN might be a tumor progression factor causing a Warburg-like effect in OSCC. Full article

(This article belongs to the Special Issue Oral Squamous Cell Carcinoma)

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14 pages, 2194 KiB

Open AccessArticle

Sushi Repeat Containing Protein X-linked 2 Is a Downstream Signal of LEM Domain Containing 1 and Acts as a Tumor-Promoting Factor in Oral Squamous Cell Carcinoma

by Tomonori Sasahira, Miyako Kurihara-Shimomura, Yukiko Nishiguchi, Hiroyuki Shimomura and Tadaaki Kirita

Int. J. Mol. Sci. 2020, 21(10), 3655; https://doi.org/10.3390/ijms21103655 - 22 May 2020

Cited by 10 | Viewed by 3232

Abstract

Because oral squamous cell carcinomas (OSCCs) have a high potential for locoregional invasion and nodal metastasis, early detection and treatment are essential. A LAP2, emerin, MAN1 (LEM) domain containing 1 (LEMD1) is associated with local progression, clinical stage, nodal metastasis, poor prognosis, angiogenesis, and lymphangiogenesis in OSCC. Although LEMD is a cancer-testis antigen, the cancer-related signals related to LEMD1 remain unknown. In this study, we used a microarray analysis of OSCC cells to identify sushi repeat containing protein X-linked 2 (SRPX2) as a LEMD1-related downstream signal. LEMD1 expression was correlated with lymph node metastasis of OSCC according to the immunohistochemistry analysis. Furthermore, patients expressing SRPX2 had a significantly worse prognosis than those without SRPX2 expression. The concentration of SRPX2 in OSCC was positively correlated with the concentrations of LEMD1, urokinase plasminogen activator receptor (uPAR), and hepatocyte growth factor (HGF). In OSCC cells, SRPX2 secretion levels were elevated by interactions with uPAR and HGF. We also found that SRPX2 promotes endothelial cell proliferation and adhesion between endothelial cells and OSCC cells. These results suggest that SRPX2 might be a useful tumor marker for OSCC. Full article

(This article belongs to the Special Issue Oral Squamous Cell Carcinoma)

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Review

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21 pages, 1197 KiB

Open AccessReview

New Insights Into Oral Squamous Cell Carcinoma: From Clinical Aspects to Molecular Tumorigenesis

by Shang-Hung Chen, Sheng-Yen Hsiao, Kwang-Yu Chang and Jang-Yang Chang

Int. J. Mol. Sci. 2021, 22(5), 2252; https://doi.org/10.3390/ijms22052252 - 24 Feb 2021

Cited by 55 | Viewed by 8994

Abstract

Oral squamous cell carcinoma (SCC) is a prevalent malignant disease worldwide, especially so in Taiwan. Early- or even preclinical-stage detection is critical for reducing morbidity and mortality from oral SCC. Epidemiological and genome association studies are useful for identifying clinicopathological risk factors for preventive, diagnostic, and therapeutic approaches of oral SCC. For advanced oral SCC, effective treatments are critical to prolonging survival and enhancing quality of life. As oral SCC is characteristic of regional invasion with lymph node metastases, understanding the aggressive features of oral SCC, particularly in lymphangiogenesis, is essential for determining effective treatments. Emerging evidence has demonstrated that the tumor microenvironment (TME) plays a pivotal role in tumor growth, invasion, and metastases. Recent clinical successes in immune checkpoint inhibitors either alone or combined with chemotherapy have also supported the therapeutic value of immunotherapy in oral SCC. This review summarizes critical advances in basic knowledge of oral SCC from the perspective of clinicopathological risk factors, molecular tumorigenesis, and the TME. We also highlight our recent investigations on the microbiome, genome association studies, lymphangiogenesis, and immunomodulation in oral SCC. This review may provide new insights for oral SCC treatment by systematically interpreting emerging evidence from various preclinical and clinical studies. Full article

(This article belongs to the Special Issue Oral Squamous Cell Carcinoma)

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29 pages, 1082 KiB

Open AccessReview

The Role of the Microbiome in Oral Squamous Cell Carcinoma with Insight into the Microbiome–Treatment Axis

by Amel Sami, Imad Elimairi, Catherine Stanton, R. Paul Ross and C. Anthony Ryan

Int. J. Mol. Sci. 2020, 21(21), 8061; https://doi.org/10.3390/ijms21218061 - 29 Oct 2020

Cited by 69 | Viewed by 7319

Abstract

Oral squamous cell carcinoma (OSCC) is one of the leading presentations of head and neck cancer (HNC). The first part of this review will describe the highlights of the oral microbiome in health and normal development while demonstrating how both the oral and gut microbiome can map OSCC development, progression, treatment and the potential side effects associated with its management. We then scope the dynamics of the various microorganisms of the oral cavity, including bacteria, mycoplasma, fungi, archaea and viruses, and describe the characteristic roles they may play in OSCC development. We also highlight how the human immunodeficiency viruses (HIV) may impinge on the host microbiome and increase the burden of oral premalignant lesions and OSCC in patients with HIV. Finally, we summarise current insights into the microbiome–treatment axis pertaining to OSCC, and show how the microbiome is affected by radiotherapy, chemotherapy, immunotherapy and also how these therapies are affected by the state of the microbiome, potentially determining the success or failure of some of these treatments. Full article

(This article belongs to the Special Issue Oral Squamous Cell Carcinoma)

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