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Advances in Molecular Mechanism of Head and Neck Cancer
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Advances in Molecular Mechanism of Head and Neck Cancer

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 (31 October 2022) | Viewed by 51388
The Guest Editor declares that he is an employee of MSD K.K., a subsidiary of Merck & Co., Inc. and reports personal fees from MSD K.K. outside this work. Articles with potential conflicts of interest with him will be handled by Editorial Board Members.

Special Issue Editor

Dr. Nijiro Nohata

E-Mail Website
Guest Editor
MSD K.K., Tokyo, Japan
Interests: head and neck oncology; onco-genomic data analysis; non-coding RNA; angiogenesis

Special Issue Information

Dear Colleagues,

Head and neck cancer is a heterogeneous population that arises from the upper gastrointestinal tract, respiratory tract, salivary glands, thyroid glands, and nasal sinuses. Head and neck cancer is the sixth most common cancer in the world, and the risk factors that contribute to the development of head and neck squamous cell carcinoma, a major histology among head and neck cancers, are mainly heavy tobacco and alcohol consumption. Human papillomavirus infection is attracting particular attention as another risk factor for oropharyngeal cancer and its prevention. In recent years, as a result of the emergence of new treatment modalities such as immunotherapy, molecular targeted therapy and radiation therapy for head and neck cancer, the survival of patients has improved. However, organ and functional preservation, improvement of patient's Quality of Life including aesthetic aspect and social function remain as unmet medical needs. Any submission that contributes on important molecular biological findings that will help us understand the complex and diverse pathologies and leads to the development of more effective treatments for this hard-to-treat disease, are welcome for this Special Issue.

Dr. Nijiro Nohata
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. 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

  • head and neck squamous cell carcinoma (HNSCC)
  • salivary gland cancer
  • thyroid cancer
  • nasal and paranasal sinus cancer
  • immunotherapy
  • radiotherapy
  • chemotherapy
  • molecular targeted therapy
  • Human Papilloma Virus (HPV) infection
  • p53 gene alteration
  • predictive and prognostic biomarker
  • molecular mechanisms of tumor growth, metastasis and drug resistance
  • pathological analysis including tumor microenvironment

Published Papers (17 papers)

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Research

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12 pages, 1685 KiB  
Article
Use of 3D Spheroid Models for the Assessment of RT Response in Head and Neck Cancer
by Marilyn Wegge, Rüveyda Dok, Ludwig J. Dubois and Sandra Nuyts
Int. J. Mol. Sci. 2023, 24(4), 3763; https://doi.org/10.3390/ijms24043763 - 13 Feb 2023
Cited by 1 | Viewed by 1873
Abstract
Radiotherapy (RT) is a key player in the treatment of head and neck cancer (HNC). The RT response, however, is variable and influenced by multiple tumoral and tumor microenvironmental factors, such as human papillomavirus (HPV) infections and hypoxia. To investigate the biological mechanisms [...] Read more.
Radiotherapy (RT) is a key player in the treatment of head and neck cancer (HNC). The RT response, however, is variable and influenced by multiple tumoral and tumor microenvironmental factors, such as human papillomavirus (HPV) infections and hypoxia. To investigate the biological mechanisms behind these variable responses, preclinical models are crucial. Up till now, 2D clonogenic and in vivo assays have remained the gold standard, although the popularity of 3D models is rising. In this study, we investigate the use of 3D spheroid models as a preclinical tool for radiobiological research by comparing the RT response of two HPV-positive and two HPV-negative HNC spheroid models to the RT response of their corresponding 2D and in vivo models. We demonstrate that HPV-positive spheroids keep their higher intrinsic radiosensitivity when compared to HPV-negative spheroids. A good correlation is found in the RT response between HPV-positive SCC154 and HPV-negative CAL27 spheroids and their respective xenografts. In addition, 3D spheroids are able to capture the heterogeneity of RT responses within HPV-positive and HPV-negative models. Moreover, we demonstrate the potential use of 3D spheroids in the study of the mechanisms underlying these RT responses in a spatial manner by whole-mount Ki-67 and pimonidazole staining. Overall, our results show that 3D spheroids are a promising model to assess the RT response in HNC. Full article
(This article belongs to the Special Issue Advances in Molecular Mechanism of Head and Neck Cancer)
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11 pages, 2405 KiB  
Article
Tumor-Intrinsic Nuclear β-Catenin Associates with an Immune Ignorance Phenotype and a Poorer Prognosis in Head and Neck Squamous Cell Carcinomas
by Mario Sánchez-Canteli, Luis Juesas, Irati Garmendia, María Otero-Rosales, Alfonso Calvo, Monica Alvarez-Fernández, Aurora Astudillo, Luis M. Montuenga, Juana M. García-Pedrero and Juan P. Rodrigo
Int. J. Mol. Sci. 2022, 23(19), 11559; https://doi.org/10.3390/ijms231911559 - 30 Sep 2022
Cited by 1 | Viewed by 10368
Abstract
Activation of WNT/β-catenin signaling has been associated with a non-T-cell-inflamed tumor microenvironment (TME) in several cancers. The aim of this work was to investigate the relationship between β-catenin signaling and TME inflammation in head and neck squamous cell carcinomas (HNSCCs). Membrane and nuclear [...] Read more.
Activation of WNT/β-catenin signaling has been associated with a non-T-cell-inflamed tumor microenvironment (TME) in several cancers. The aim of this work was to investigate the relationship between β-catenin signaling and TME inflammation in head and neck squamous cell carcinomas (HNSCCs). Membrane and nuclear β-catenin expression, PD-L1 expression, and CD8+ tumor-infiltrating lymphocyte (TIL) density were jointly evaluated by immunohistochemistry in a series of 372 HPV-negative HNSCCs. Membrane β-catenin levels decreased in carcinomas compared to the normal epithelium. Positive nuclear β-catenin was detected in 50 tumors (14.3%) and was significantly associated with a low CD8+ TIL density (168 cells/mm2 versus 293 cells/mm2 in nuclear-β-catenin-negative cases; p = 0.01) and a tendency for a lower expression of PD-L1, resulting in association with a noninflamed TME (i.e., type II, immunological ignorance). Multivariate Cox analysis further demonstrated that low infiltration by CD8+ TILs (HR = 1.6, 95% CI = 1.19–2.14, p = 0.002) and nuclear β-catenin expression (HR = 1.47, 95% CI = 1.01–2.16, p = 0.04) were both independently associated with a poorer disease-specific survival. In conclusion, tumor-intrinsic nuclear β-catenin activation is associated with a non-inflamed TME phenotype and a poorer prognosis, thereby suggesting a possible implication as an immune exclusion mechanism for a subset of HNSCC patients. Full article
(This article belongs to the Special Issue Advances in Molecular Mechanism of Head and Neck Cancer)
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18 pages, 4488 KiB  
Article
Genome-Wide Super-Enhancer-Based Analysis: Identification of Prognostic Genes in Oral Squamous Cell Carcinoma
by Tomoaki Saito, Shunichi Asai, Nozomi Tanaka, Nijiro Nohata, Chikashi Minemura, Ayaka Koma, Naoko Kikkawa, Atsushi Kasamatsu, Toyoyuki Hanazawa, Katsuhiro Uzawa and Naohiko Seki
Int. J. Mol. Sci. 2022, 23(16), 9154; https://doi.org/10.3390/ijms23169154 - 15 Aug 2022
Cited by 2 | Viewed by 2303
Abstract
Advanced-stage oral squamous cell carcinoma (OSCC) patients are treated with combination therapies, such as surgery, radiation, chemotherapy, and immunotherapy. However, OSCC cells acquire resistance to these treatments, resulting in local recurrence and distant metastasis. The identification of genes involved in drug resistance is [...] Read more.
Advanced-stage oral squamous cell carcinoma (OSCC) patients are treated with combination therapies, such as surgery, radiation, chemotherapy, and immunotherapy. However, OSCC cells acquire resistance to these treatments, resulting in local recurrence and distant metastasis. The identification of genes involved in drug resistance is essential for improving the treatment of this disease. In this study, we applied chromatin immunoprecipitation sequencing (ChIP-Seq) to profile active enhancers. For that purpose, we used OSCC cell lines that had been exposed to cetuximab for a prolonged period. In total, 64 chromosomal loci were identified as active super-enhancers (SE) according to active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) ChIP-Seq. In addition, a total of 131 genes were located in SE regions, and 34 genes were upregulated in OSCC tissues by TCGA-OSCC analysis. Moreover, high expression of four genes (C9orf89; p = 0.035, CENPA; p = 0.020, PISD; p = 0.0051, and TRAF2; p = 0.0075) closely predicted a poorer prognosis for OSCC patients according to log-rank tests. Increased expression of the four genes (mRNA Z-score ≥ 0) frequently co-occurred in TCGA-OSCC analyses. The high and low expression groups of the four genes showed significant differences in prognosis, suggesting that there are clear differences in the pathways based on the underlying gene expression profiles. These data indicate that potential stratified therapeutic strategies could be used to overcome resistance to drugs (including cetuximab) and further improve responses in drug-sensitive patients. Full article
(This article belongs to the Special Issue Advances in Molecular Mechanism of Head and Neck Cancer)
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17 pages, 2231 KiB  
Article
Diagnostic Value of MAML2 Rearrangements in Mucoepidermoid Carcinoma
by Julia C. Thierauf, Alex A. Farahani, B. Iciar Indave, Adam Z. Bard, Valerie A. White, Cameron R. Smith, Hetal Marble, Martin D. Hyrcza, John K. C. Chan, Justin Bishop, Qiuying Shi, Kim Ely, Abbas Agaimy, Maria Martinez-Lage, Vania Nose, Miguel Rivera, Valentina Nardi, Dora Dias-Santagata, Salil Garg, Peter Sadow, Long P. Le, William Faquin, Lauren L. Ritterhouse, Ian A. Cree, A. John Iafrate and Jochen K. Lennerzadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2022, 23(8), 4322; https://doi.org/10.3390/ijms23084322 - 13 Apr 2022
Cited by 7 | Viewed by 2776
Abstract
Mucoepidermoid carcinoma (MEC) is often seen in salivary glands and can harbor MAML2 translocations (MAML2+). The translocation status has diagnostic utility as an objective confirmation of the MEC diagnosis, for example, when distinction from the more aggressive adenosquamous carcinoma (ASC) is not straightforward. [...] Read more.
Mucoepidermoid carcinoma (MEC) is often seen in salivary glands and can harbor MAML2 translocations (MAML2+). The translocation status has diagnostic utility as an objective confirmation of the MEC diagnosis, for example, when distinction from the more aggressive adenosquamous carcinoma (ASC) is not straightforward. To assess the diagnostic relevance of MAML2, we examined our 5-year experience in prospective testing of 8106 solid tumors using RNA-seq panel testing in combinations with a two-round Delphi-based scenario survey. The prevalence of MAML2+ across all tumors was 0.28% (n = 23/8106) and the majority of MAML2+ cases were found in head and neck tumors (78.3%), where the overall prevalence was 5.9% (n = 18/307). The sensitivity of MAML2 for MEC was 60% and most cases (80%) were submitted for diagnostic confirmation; in 24% of cases, the MAML2 results changed the working diagnosis. An independent survey of 15 experts showed relative importance indexes of 0.8 and 0.65 for “confirmatory MAML2 testing” in suspected MEC and ASC, respectively. Real-world evidence confirmed that the added value of MAML2 is a composite of an imperfect confirmation test for MEC and a highly specific exclusion tool for the diagnosis of ASC. Real-world evidence can help move a rare molecular-genetic biomarker from an emerging tool to the clinic. Full article
(This article belongs to the Special Issue Advances in Molecular Mechanism of Head and Neck Cancer)
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12 pages, 3173 KiB  
Article
In Situ PD-L1 Expression in Oral Squamous Cell Carcinoma Is Induced by Heterogeneous Mechanisms among Patients
by Yutaro Kondo, Susumu Suzuki, Shoya Ono, Mitsuo Goto, Satoru Miyabe, Tetsuya Ogawa, Hiromi Tsuchida, Hideaki Ito, Taishi Takahara, Akira Satou, Toyonori Tsuzuki, Kazuhiro Yoshikawa, Ryuzo Ueda and Toru Nagao
Int. J. Mol. Sci. 2022, 23(8), 4077; https://doi.org/10.3390/ijms23084077 - 7 Apr 2022
Cited by 5 | Viewed by 3495
Abstract
The expression of programmed death ligand-1 (PD-L1) is controlled by complex mechanisms. The elucidation of the molecular mechanisms of PD-L1 expression is important for the exploration of new insights into PD-1 blockade therapy. Detailed mechanisms of the in situ expression of PD-L1 in [...] Read more.
The expression of programmed death ligand-1 (PD-L1) is controlled by complex mechanisms. The elucidation of the molecular mechanisms of PD-L1 expression is important for the exploration of new insights into PD-1 blockade therapy. Detailed mechanisms of the in situ expression of PD-L1 in tissues of oral squamous cell carcinomas (OSCCs) have not yet been clarified. We examined the mechanisms of PD-L1 expression focusing on the phosphorylation of downstream molecules of epidermal growth factor (EGF) and interferon gamma (IFN-γ) signaling in vitro and in vivo by immunoblotting and multi-fluorescence immunohistochemistry (MF-IHC), respectively. The in vitro experiments demonstrated that PD-L1 expression in OSCC cell lines is upregulated by EGF via the EGF receptor (EGFR)/PI3K/AKT pathway, the EGFR/STAT1 pathway, and the EGFR/MEK/ERK pathway, and by IFN-γ via the JAK2/STAT1 pathway. MF-IHC demonstrated that STAT1 and EGFR phosphorylation was frequently shown in PD-L1-positive cases and STAT1 phosphorylation was correlated with lymphocyte infiltration and EGFR phosphorylation. Moreover, the phosphorylation pattern of the related molecules in PD-L1-positive cells differed among the cases investigated. These findings indicate that PD-L1 expression mechanisms differ depending on the tissue environment and suggest that the examination of the tissue environment and molecular alterations of cancer cells affecting PD-L1 expression make it necessary for each patient to choose the appropriate combination drugs for PD-1 blockade cancer treatment. Full article
(This article belongs to the Special Issue Advances in Molecular Mechanism of Head and Neck Cancer)
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19 pages, 3509 KiB  
Article
Identification of Tumor-Suppressive miR-30e-3p Targets: Involvement of SERPINE1 in the Molecular Pathogenesis of Head and Neck Squamous Cell Carcinoma
by Chikashi Minemura, Shunichi Asai, Ayaka Koma, Ikuko Kase-Kato, Nozomi Tanaka, Naoko Kikkawa, Atsushi Kasamatsu, Hidetaka Yokoe, Toyoyuki Hanazawa, Katsuhiro Uzawa and Naohiko Seki
Int. J. Mol. Sci. 2022, 23(7), 3808; https://doi.org/10.3390/ijms23073808 - 30 Mar 2022
Cited by 6 | Viewed by 2032
Abstract
Recently, our studies revealed that some passenger strands of microRNAs (miRNAs) were closely involved in cancer pathogenesis. Analysis of miRNA expression signatures showed that the expression of miR-30e-3p (the passenger strand of pre-miR-30e) was significantly downregulated in cancer tissues. In this [...] Read more.
Recently, our studies revealed that some passenger strands of microRNAs (miRNAs) were closely involved in cancer pathogenesis. Analysis of miRNA expression signatures showed that the expression of miR-30e-3p (the passenger strand of pre-miR-30e) was significantly downregulated in cancer tissues. In this study, we focused on miR-30e-3p (the passenger strand of pre-miR-30e). We addressed target genes controlled by miR-30e-3p that were closely associated with the molecular pathogenesis of head and neck squamous cell carcinoma (HNSCC). Ectopic expression assays demonstrated that the expression of miR-30e-3p attenuated cancer cell malignant phenotypes (e.g., cell proliferation, migration, and invasive abilities). Our analysis of miR-30e-3p targets revealed that 11 genes (ADA, CPNE8, C14orf126, ERGIC2, HMGA2, PLS3, PSMD10, RALB, SERPINE1, SFXN1, and TMEM87B) were expressed at high levels in HNSCC patients. Moreover, they significantly predicted the short survival of HNSCC patients based on 5-year overall survival rates (p < 0.05) in The Cancer Genome Atlas (TCGA). Among these targets, SERPINE1 was found to be an independent prognostic factor for patient survival (multivariate Cox regression; hazard ratio = 1.6078, p < 0.05). Aberrant expression of SERPINE1 was observed in HNSCC clinical samples by immunohistochemical analysis. Functional assays by targeting SERPINE1 expression revealed that the malignant phenotypes (e.g., proliferation, migration, and invasion abilities) of HNSCC cells were suppressed by the silencing of SERPINE1 expression. Our miRNA-based approach will accelerate our understanding of the molecular pathogenesis of HNSCC. Full article
(This article belongs to the Special Issue Advances in Molecular Mechanism of Head and Neck Cancer)
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15 pages, 2067 KiB  
Article
PKM2 Modulation in Head and Neck Squamous Cell Carcinoma
by Verena Boschert, Jonas Teusch, Urs D. A. Müller-Richter, Roman C. Brands and Stefan Hartmann
Int. J. Mol. Sci. 2022, 23(2), 775; https://doi.org/10.3390/ijms23020775 - 11 Jan 2022
Cited by 8 | Viewed by 2426
Abstract
The enzyme pyruvate kinase M2 (PKM2) plays a major role in the switch of tumor cells from oxidative phosphorylation to aerobic glycolysis, one of the hallmarks of cancer. Different allosteric inhibitors or activators and several posttranslational modifications regulate its activity. Head and neck [...] Read more.
The enzyme pyruvate kinase M2 (PKM2) plays a major role in the switch of tumor cells from oxidative phosphorylation to aerobic glycolysis, one of the hallmarks of cancer. Different allosteric inhibitors or activators and several posttranslational modifications regulate its activity. Head and neck squamous cell carcinoma (HNSCC) is a common disease with a high rate of recurrence. To find out more about PKM2 and its modulation in HNSCC, we examined a panel of HNSCC cells using real-time cell metabolic analysis and Western blotting with an emphasis on phosphorylation variant Tyr105 and two reagents known to impair PKM2 activity. Our results show that in HNSCC, PKM2 is commonly phosphorylated at Tyrosine 105. Its levels depended on tyrosine kinase activity, emphasizing the importance of growth factors such as EGF (epidermal growth factor) on HNSCC metabolism. Furthermore, its correlation with the expression of CD44 indicates a role in cancer stemness. Cells generally reacted with higher glycolysis to PKM2 activator DASA-58 and lower glycolysis to PKM2 inhibitor Compound 3k, but some were more susceptible to activation and others to inhibition. Our findings emphasize the need to further investigate the role of PKM2 in HNSCC, as it could aid understanding and treatment of the disease. Full article
(This article belongs to the Special Issue Advances in Molecular Mechanism of Head and Neck Cancer)
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17 pages, 38939 KiB  
Article
Molecular Pathogenesis of the Coronin Family: CORO2A Facilitates Migration and Invasion Abilities in Oral Squamous Cell Carcinoma
by Ikuko Kase-Kato, Shunichi Asai, Chikashi Minemura, Kenta Tsuneizumi, Sachi Oshima, Ayaka Koma, Atsushi Kasamatsu, Toyoyuki Hanazawa, Katsuhiro Uzawa and Naohiko Seki
Int. J. Mol. Sci. 2021, 22(23), 12684; https://doi.org/10.3390/ijms222312684 - 24 Nov 2021
Cited by 4 | Viewed by 1884
Abstract
In humans, the coronin family is composed of seven proteins containing WD-repeat domains that regulate actin-based cellular processes. Some members of the coronin family are closely associated with cancer cell migration and invasion. The Cancer Genome Atlas (TCGA) analysis revealed that CORO1C, [...] Read more.
In humans, the coronin family is composed of seven proteins containing WD-repeat domains that regulate actin-based cellular processes. Some members of the coronin family are closely associated with cancer cell migration and invasion. The Cancer Genome Atlas (TCGA) analysis revealed that CORO1C, CORO2A, and CORO7 were significantly upregulated in oral squamous cell carcinoma (OSCC) tissues (p < 0.05). Moreover, the high expression of CORO2A was significantly predictive of the 5-year survival rate of patients with OSCC (p = 0.0203). Overexpression of CORO2A was detected in OSCC clinical specimens by immunostaining. siRNA-mediated knockdown of CORO2A suppressed cancer cell migration and invasion abilities. Furthermore, we investigated the involvement of microRNAs (miRNAs) in the molecular mechanism underlying CORO2A overexpression in OSCC cells. TCGA analysis confirmed that tumor-suppressive miR-125b-5p and miR-140-5p were significantly downregulated in OSCC tissues. Notably, these miRNAs bound directly to the 3′-UTR of CORO2A and controlled CORO2A expression in OSCC cells. In summary, we found that aberrant expression of CORO2A facilitates the malignant transformation of OSCC cells, and that downregulation of tumor-suppressive miRNAs is involved in CORO2A overexpression. Elucidation of the interaction between genes and miRNAs will help reveal the molecular pathogenesis of OSCC. Full article
(This article belongs to the Special Issue Advances in Molecular Mechanism of Head and Neck Cancer)
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12 pages, 1452 KiB  
Article
Effect of EGFR on SQSTM1 Expression in Malignancy and Tumor Progression of Oral Squamous Cell Carcinoma
by Yu-Kai Tseng, Chun-Feng Chen, Chih-Wen Shu, Cheng-Hsin Lee, Yan-Ting Chou, Yi-Jing Li, Huei-Han Liou, Jiin-Tsuey Cheng, Chun-Lin Chen, Luo-Ping Ger and Pei-Feng Liu
Int. J. Mol. Sci. 2021, 22(22), 12226; https://doi.org/10.3390/ijms222212226 - 12 Nov 2021
Cited by 6 | Viewed by 1742
Abstract
Oral squamous cell carcinoma (OSCC) is one of the most common types of malignant tumor. Sequestosome 1 (SQSTM1) serves as an adaptor of autophagy for degrading protein aggregates. The regulation of autophagy by EGFR and its clinical impacts are indicated in various types [...] Read more.
Oral squamous cell carcinoma (OSCC) is one of the most common types of malignant tumor. Sequestosome 1 (SQSTM1) serves as an adaptor of autophagy for degrading protein aggregates. The regulation of autophagy by EGFR and its clinical impacts are indicated in various types of cancer. However, the association of EGFR and SQSTM1 in OSCC is still unknown. Our results show that the expression levels of SQSTM1 and EGFR proteins are higher in tumor tissues than in the corresponding tumor-adjacent (CTAN) tissues of OSCC patients. The expression levels of SQSTM1 were positively associated with the EGFR expression level. High co-expression of SQSTM1 and EGFR is associated with poor prognosis in OSCC patients. Moreover, SQSTM1 expression is decreased in EGFR-knockdown cells. Cell growth and invasion/migration are also decreased in cells with single/combined knockdowns of EGFR and SQSTM1 or in SQSTM1-knockdown cells without EGFR kinase inhibitor Lapatinib treatment compared to that in scrambled cells. However, cell growth and invasion/metastasis were not significantly different between the scrambled cells and SQSTM1-knockdown cells in the presence of Lapatinib. This study is the first to indicate the biological roles and clinical significance of SQSTM1 regulation by EGFR in OSCC. Full article
(This article belongs to the Special Issue Advances in Molecular Mechanism of Head and Neck Cancer)
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13 pages, 1646 KiB  
Article
SOD2 Enhancement by Long-Term Inhibition of the PI3K Pathway Confers Multi-Drug Resistance and Enhanced Tumor-Initiating Features in Head and Neck Cancer
by Wei-Ting Hsueh, Shang-Hung Chen, Chia-Hung Chien, Shao-Wen Chou, Pei-I Chi, Jui-Mei Chu and Kwang-Yu Chang
Int. J. Mol. Sci. 2021, 22(20), 11260; https://doi.org/10.3390/ijms222011260 - 19 Oct 2021
Cited by 5 | Viewed by 2045
Abstract
The phosphoinositide-3-kinase (PI3K) pathway has widely been considered as a potential therapeutic target for head and neck cancer (HNC); however, the application of PI3K inhibitors is often overshadowed by the induction of drug resistance with unknown mechanisms. In this study, PII3K inhibitor resistant [...] Read more.
The phosphoinositide-3-kinase (PI3K) pathway has widely been considered as a potential therapeutic target for head and neck cancer (HNC); however, the application of PI3K inhibitors is often overshadowed by the induction of drug resistance with unknown mechanisms. In this study, PII3K inhibitor resistant cancer cells were developed by prolonged culturing of cell lines with BEZ235, a dual PI3K and mammalian target of rapamycin (mTOR) inhibitor. The drug resistant HNC cells showed higher IC50 of the proliferation to inhibitors specifically targeting PI3K and/or mTOR, as compared to their parental cells. These cells also showed profound resistance to drugs of other classes. Molecular analysis revealed persistent activation of phosphorylated AKT at threonine 308 in the drug resistant cells and increased expression of markers for tumor-initiating cells. Interestingly, increased intra-cellular ROS levels were observed in the drug resistant cells. Among anti-oxidant molecules, the expression of SOD2 was increased and was associated with the ALDH-positive tumor-initiating cell features. Co-incubation of SOD inhibitors and BEZ235 decreased the stemness feature of the cells in vitro, as shown by results of the spheroid formation assay. In conclusion, dysregulation of SOD2 might contribute to the profound resistance to PI3K inhibitors and the other drugs in HNC cells. Full article
(This article belongs to the Special Issue Advances in Molecular Mechanism of Head and Neck Cancer)
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16 pages, 4457 KiB  
Article
Identification of Tumor Suppressive Genes Regulated by miR-31-5p and miR-31-3p in Head and Neck Squamous Cell Carcinoma
by Sachi Oshima, Shunichi Asai, Naohiko Seki, Chikashi Minemura, Takashi Kinoshita, Yusuke Goto, Naoko Kikkawa, Shogo Moriya, Atsushi Kasamatsu, Toyoyuki Hanazawa and Katsuhiro Uzawa
Int. J. Mol. Sci. 2021, 22(12), 6199; https://doi.org/10.3390/ijms22126199 - 8 Jun 2021
Cited by 16 | Viewed by 2901
Abstract
We identified the microRNA (miRNA) expression signature of head and neck squamous cell carcinoma (HNSCC) tissues by RNA sequencing, in which 168 miRNAs were significantly upregulated, including both strands of the miR-31 duplex (miR-31-5p and miR-31-3p). The aims of this study [...] Read more.
We identified the microRNA (miRNA) expression signature of head and neck squamous cell carcinoma (HNSCC) tissues by RNA sequencing, in which 168 miRNAs were significantly upregulated, including both strands of the miR-31 duplex (miR-31-5p and miR-31-3p). The aims of this study were to identify networks of tumor suppressor genes regulated by miR-31-5p and miR-31-3p in HNSCC cells. Our functional assays showed that inhibition of miR-31-5p and miR-31-3p attenuated cancer cell malignant phenotypes (cell proliferation, migration, and invasion), suggesting that they had oncogenic potential in HNSCC cells. Our in silico analysis revealed 146 genes regulated by miR-31 in HNSCC cells. Among these targets, the low expression of seven genes (miR-31-5p targets: CACNB2 and IL34; miR-31-3p targets: CGNL1, CNTN3, GAS7, HOPX, and PBX1) was closely associated with poor prognosis in HNSCC. According to multivariate Cox regression analyses, the expression levels of five of those genes (CACNB2: p = 0.0189; IL34: p = 0.0425; CGNL1: p = 0.0014; CNTN3: p = 0.0304; and GAS7: p = 0.0412) were independent prognostic factors in patients with HNSCC. Our miRNA signature and miRNA-based approach will provide new insights into the molecular pathogenesis of HNSCC. Full article
(This article belongs to the Special Issue Advances in Molecular Mechanism of Head and Neck Cancer)
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Review

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29 pages, 1059 KiB  
Review
DNA Damage Response Mechanisms in Head and Neck Cancer: Significant Implications for Therapy and Survival
by Chara Papalouka, Maria Adamaki, Panagiota Batsaki, Panagiotis Zoumpourlis, Antonis Tsintarakis, Maria Goulielmaki, Sotirios P. Fortis, Constantin N. Baxevanis and Vassilis Zoumpourlis
Int. J. Mol. Sci. 2023, 24(3), 2760; https://doi.org/10.3390/ijms24032760 - 1 Feb 2023
Cited by 8 | Viewed by 3239
Abstract
Head and neck cancer (HNC) is a term collectively used to describe a heterogeneous group of tumors that arise in the oral cavity, larynx, nasopharynx, oropharynx, and hypopharynx, and represents the sixth most common type of malignancy worldwide. Despite advances in multimodality treatment, [...] Read more.
Head and neck cancer (HNC) is a term collectively used to describe a heterogeneous group of tumors that arise in the oral cavity, larynx, nasopharynx, oropharynx, and hypopharynx, and represents the sixth most common type of malignancy worldwide. Despite advances in multimodality treatment, the disease has a recurrence rate of around 50%, and the prognosis of metastatic patients remains poor. HNCs are characterized by a high degree of genomic instability, which involves a vicious circle of accumulating DNA damage, defective DNA damage repair (DDR), and replication stress. Nonetheless, the damage that is induced on tumor cells by chemo and radiotherapy relies on defective DDR processes for a successful response to treatment, and may play an important role in the development of novel and more effective therapies. This review summarizes the current knowledge on the genes and proteins that appear to be deregulated in DDR pathways, their implication in HNC pathogenesis, and the rationale behind targeting these genes and pathways for the development of new therapies. We give particular emphasis on the therapeutic targets that have shown promising results at the pre-clinical stage and on those that have so far been associated with a therapeutic advantage in the clinical setting. Full article
(This article belongs to the Special Issue Advances in Molecular Mechanism of Head and Neck Cancer)
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30 pages, 1087 KiB  
Review
The Therapeutic Landscape of Salivary Gland Malignancies—Where Are We Now?
by Robbert Cleymaet, Tijl Vermassen, Renaat Coopman, Hubert Vermeersch, Stijn De Keukeleire and Sylvie Rottey
Int. J. Mol. Sci. 2022, 23(23), 14891; https://doi.org/10.3390/ijms232314891 - 28 Nov 2022
Cited by 5 | Viewed by 1593
Abstract
Salivary gland malignancies (SGMs) account for less than 5% of new diagnoses in head and neck tumors. If feasible, surgery is the preferred treatment modality. Nevertheless, some malignancies have a tendency of recurrence, with possible distant metastasis. Alternative treatment strategies, such as primary [...] Read more.
Salivary gland malignancies (SGMs) account for less than 5% of new diagnoses in head and neck tumors. If feasible, surgery is the preferred treatment modality. Nevertheless, some malignancies have a tendency of recurrence, with possible distant metastasis. Alternative treatment strategies, such as primary radiation or chemotherapeutics, often present low response rates. As a result, there is an unmet need for novel therapeutic approaches. Nowadays, target-based therapies (e.g., small inhibitors and immunotherapy) are used by the medical oncologist for possible treatment of advanced SGMs. Based on recent published trials, some novel treatments may provide additional disease control for some patients. However, sample sizes are small, the general findings are unsatisfactory, and a lot of uncertainties remain to be elucidated. Nevertheless, research shows that patients do not benefit from blind administration of systemic treatments and therefore a more personalized approach is highly needed. The aim of this review paper is to summarize the most recent advances in the biological understanding and molecular pathways of salivary gland cancers, the association of these pathways with the current treatments used and their implications for more personalized targeted-based therapies. Full article
(This article belongs to the Special Issue Advances in Molecular Mechanism of Head and Neck Cancer)
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10 pages, 706 KiB  
Review
The Hypothalamic–Pituitary–Thyroid Axis Equivalent in Normal and Cancerous Oral Tissues: A Scoping Review
by Lisa Wu, Stephen Xu, Brian Yang, Jenny Yang, Claire Yee and Nicola Cirillo
Int. J. Mol. Sci. 2022, 23(22), 14096; https://doi.org/10.3390/ijms232214096 - 15 Nov 2022
Cited by 1 | Viewed by 1527
Abstract
The hypothalamic–pituitary–thyroid (HPT) axis is crucial in regulating thyroid hormone levels that contribute to the development and homeostasis of the human body. Current literature supports the presence of a local HPT axis equivalent within keratinocytes of the skin, with thyroid hormones playing a [...] Read more.
The hypothalamic–pituitary–thyroid (HPT) axis is crucial in regulating thyroid hormone levels that contribute to the development and homeostasis of the human body. Current literature supports the presence of a local HPT axis equivalent within keratinocytes of the skin, with thyroid hormones playing a potential role in cancer progression. However, this remains to be seen within oral tissue cells. An electronic search of Scopus and PubMed/Medline databases was conducted to identify all original publications that reported data on the production or effects of HPT axis components in normal or malignant cells of the oral cavity. The search identified 221 studies, of which 14 were eligible. Eight studies were retrospective analyses of clinical samples, one study involved both in vivo and in vitro experiments, and the remaining five studies were conducted in vitro using cell lines. The search identified evidence of effects of HPT components on oral cancer cells. However, there were limited data for the production of HPT axis components by oral tissues. We conclude that a possible role of the local HPT axis equivalent in the oral mucosa may not be established at present. The gaps in knowledge identified in this scoping review, particularly regarding the production of HPT components by oral tissues, warrant further investigation. Full article
(This article belongs to the Special Issue Advances in Molecular Mechanism of Head and Neck Cancer)
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27 pages, 623 KiB  
Review
Novel Systemic Treatment Modalities Including Immunotherapy and Molecular Targeted Therapy for Recurrent and Metastatic Head and Neck Squamous Cell Carcinoma
by Soma Ghosh, Pooja A. Shah and Faye M. Johnson
Int. J. Mol. Sci. 2022, 23(14), 7889; https://doi.org/10.3390/ijms23147889 - 17 Jul 2022
Cited by 22 | Viewed by 4760
Abstract
Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common cancers worldwide. More than half of patients with HNSCC eventually experience disease recurrence and/or metastasis, which can threaten their long-term survival. HNSCCs located in the oral cavity and larynx are usually [...] Read more.
Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common cancers worldwide. More than half of patients with HNSCC eventually experience disease recurrence and/or metastasis, which can threaten their long-term survival. HNSCCs located in the oral cavity and larynx are usually associated with tobacco and/or alcohol use, whereas human papillomavirus (HPV) infection, particularly HPV16 infection, is increasingly recognized as a cause of oropharyngeal HNSCC. Despite clinical, histologic, and molecular differences between HPV-positive and HPV-negative HNSCCs, current treatment approaches are the same. For recurrent disease, these strategies include chemotherapy, immunotherapy with PD-1-inhibitors, or a monoclonal antibody, cetuximab, that targets epidermal growth factor; these therapies can be administered either as single agents or in combination. However, these treatment strategies carry a high risk of toxic side effects; therefore, more effective and less toxic treatments are needed. The landscape of HNSCC therapy is changing significantly; numerous clinical trials are underway to test novel therapeutic options like adaptive cellular therapy, antibody-drug conjugates, new targeted therapy agents, novel immunotherapy combinations, and therapeutic vaccines. This review helps in understanding the various developments in HNSCC therapy and sheds light on the path ahead in terms of further research in this field. Full article
(This article belongs to the Special Issue Advances in Molecular Mechanism of Head and Neck Cancer)
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13 pages, 961 KiB  
Review
Tracking the Molecular Fingerprint of Head and Neck Cancer for Recurrence Detection in Liquid Biopsies
by Araceli Diez-Fraile, Joke De Ceulaer, Charlotte Derpoorter, Christophe Spaas, Tom De Backer, Philippe Lamoral, Johan Abeloos and Tim Lammens
Int. J. Mol. Sci. 2022, 23(5), 2403; https://doi.org/10.3390/ijms23052403 - 22 Feb 2022
Cited by 8 | Viewed by 2762
Abstract
The 5-year relative survival for patients with head and neck cancer, the seventh most common form of cancer worldwide, was reported as 67% in developed countries in the second decade of the new millennium. Although surgery, radiotherapy, chemotherapy, or combined treatment often elicits [...] Read more.
The 5-year relative survival for patients with head and neck cancer, the seventh most common form of cancer worldwide, was reported as 67% in developed countries in the second decade of the new millennium. Although surgery, radiotherapy, chemotherapy, or combined treatment often elicits an initial satisfactory response, relapses are frequently observed within two years. Current surveillance methods, including clinical exams and imaging evaluations, have not unambiguously demonstrated a survival benefit, most probably due to a lack of sensitivity in detecting very early recurrence. Recently, liquid biopsy monitoring of the molecular fingerprint of head and neck squamous cell carcinoma has been proposed and investigated as a strategy for longitudinal patient care. These innovative methods offer rapid, safe, and highly informative genetic analysis that can identify small tumors not yet visible by advanced imaging techniques, thus potentially shortening the time to treatment and improving survival outcomes. In this review, we provide insights into the available evidence that the molecular tumor fingerprint can be used in the surveillance of head and neck squamous cell carcinoma. Challenges to overcome, prior to clinical implementation, are also discussed. Full article
(This article belongs to the Special Issue Advances in Molecular Mechanism of Head and Neck Cancer)
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12 pages, 1879 KiB  
Brief Report
An ErbB Lineage Co-Regulon Harbors Potentially Co-Druggable Targets for Multimodal Precision Therapy in Head and Neck Squamous Cell Carcinoma
by Markus Bredel, Hyunsoo Kim and James A. Bonner
Int. J. Mol. Sci. 2022, 23(21), 13497; https://doi.org/10.3390/ijms232113497 - 4 Nov 2022
Cited by 1 | Viewed by 1411
Abstract
The ErbB lineage of oncogenic receptor tyrosine kinases is frequently overexpressed in head and neck squamous cell carcinomas. A common co-regulon triggered by the ErbB proteins; involving shared signaling circuitries; may harbor co-druggable targets or response biomarkers for potential future multimodal precision therapy [...] Read more.
The ErbB lineage of oncogenic receptor tyrosine kinases is frequently overexpressed in head and neck squamous cell carcinomas. A common co-regulon triggered by the ErbB proteins; involving shared signaling circuitries; may harbor co-druggable targets or response biomarkers for potential future multimodal precision therapy in ErbB-driven head and neck squamous cell carcinoma. We here present a cohort-based; genome-wide analysis of 488 head and neck squamous cell carcinomas curated as part of The Cancer Genome Atlas Project to characterize genes that are significantly positively co-regulated with the four ErbB proteins and those that are shared among all ErbBs denoting a common ErbB co-regulon. Significant positive gene correlations involved hundreds of genes that were co-expressed with the four ErbB family members (q < 0.05). A common; overlapping co-regulon consisted of a core set of 268 genes that were uniformly co-regulated with all four ErbB genes and highly enriched for functions in chromatin organization and histone modifications. This high-priority set of genes contained ten putative antineoplastic drug-gene interactions. The nature and directionality of these ten drug-gene associations was an inhibiting interaction for seven (PIK3CB; PIK3C2B; HDAC4; FRK; PRKCE; EPHA4; and DYRK1A) of them in which the drug decreases the biological activity or expression of the gene target. For three (CHD4; ARID1A; and PBRM1) of the associations; the directionality of the interaction was such that the gene predicted sensitivit y to the drug suggesting utility as potential response biomarkers. Drug-gene interactions that predicted the gene product to be reduced by the drug included a variety of potential targeted molecular agent classes. This unbiased genome-wide analysis identified a target-rich environment for multimodal therapeutic approaches in tumors that are putatively ErbB-driven. The results of this study require preclinical validation before ultimately devising lines of combinatorial treatment strategies for ErbB-dependent head and neck squamous cell carcinomas that incorporate these findings. Full article
(This article belongs to the Special Issue Advances in Molecular Mechanism of Head and Neck Cancer)
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