Over 45,000 new cases of oral and pharyngeal cancers are diagnosed and account for over 8,000 deaths a year in the United States. An environmental chemical receptor, the aryl hydrocarbon receptor (AHR), has previously been implicated in oral squamous cell carcinoma (OSCC) initiation as well as in normal tissue-specific stem cell self-renewal. These previous studies inspired the hypothesis that the AHR plays a role in both the acquisition and progression of OSCC, as well as in the formation and maintenance of cancer stem-like cells. To test this hypothesis, AHR activity in two oral squamous cell lines was modulated with AHR prototypic, environmental and bacterial AHR ligands, AHR-specific inhibitors, and phenotypic, genomic and functional characteristics were evaluated. The data demonstrate that: 1) primary OSCC tissue expresses elevated levels of nuclear AHR as compared to normal tissue, 2) Ahr mRNA expression is up-regulated in 320 primary OSCC, 3) AHR hyper-activation with several ligands, including environmental and bacterial ligands, significantly increases AHR activity, ALDH1 activity, and accelerates cell migration, 4) AHR inhibition blocks the rapid migration of OSCC cells and reduces cell chemoresistance, 5) AHR knockdown inhibits tumorsphere formation in low adherence conditions, and 6) AHR knockdown inhibits tumor growth and increases overall survival in vivo. These data demonstrate that the AHR plays an important role in development and progression of OSCC, and specifically cancer stem-like cells. Prototypic, environmental and bacterial AHR ligands may exacerbate OSCC by enhancing expression of these properties. Implications This study, for the first time, demonstrates the ability of diverse AHR ligands to regulate AHR activity in oral squamous cell carcinoma cells, as well as regulate several important characteristics of oral cancer stem cells, in vivo and in vitro.
Head and neck cancer presents primarily as head and neck squamous cell carcinoma (HNSCC), a debilitating malignancy fraught with high morbidity, poor survival rates, and limited treatment options. Mounting evidence indicates that the Wnt/β-catenin signaling pathway plays important roles in the pathobiology of HNSCC. Wnt/β-catenin signaling affects multiple cellular processes that endow cancer cells with the ability to maintain and expand immature stem-like phenotypes, proliferate, extend survival, and acquire aggressive characteristics by adopting mesenchymal traits. A central component of canonical Wnt signaling is β-catenin, which balances its role as a structural component of E-cadherin junctions with its function as a transcriptional coactivator of numerous target genes. Recent genomic characterization of head and neck cancer revealed that while β-catenin is not frequently mutated in HNSCC, its activity is unchecked by more common mutations in genes encoding upstream regulators of β-catenin, NOTCH1, FAT1, and AJUBA. Wnt/β-catenin signaling affects a wide range epigenetic and transcriptional activities, mediated by the interaction of β-catenin with different transcription factors and transcriptional coactivators and corepressors. Furthermore, Wnt/β-catenin functions in a network with many signaling and metabolic pathways that modulate its activity. In addition to its effects on tumor epithelia, β-catenin activity regulates the tumor microenvironment by regulating extracellular matrix remodeling, fibrotic processes, and immune response. These multifunctional oncogenic effects of β-catenin make it an attractive bona fide target for HNSCC therapy.
BackgroundHead and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy characterized by tumor heterogeneity, locoregional metastases, and resistance to existing treatments. Although a number of genomic and molecular alterations associated with HNSCC have been identified, they have had limited impact on the clinical management of this disease. To date, few targeted therapies are available for HNSCC, and only a small fraction of patients have benefited from these treatments. A frequent feature of HNSCC is the inappropriate activation of β-catenin that has been implicated in cell survival and in the maintenance and expansion of stem cell-like populations, thought to be the underlying cause of tumor recurrence and resistance to treatment. However, the therapeutic value of targeting β-catenin activity in HNSCC has not been explored.MethodsWe utilized a combination of computational and experimental profiling approaches to examine the effects of blocking the interaction between β-catenin and cAMP-responsive element binding (CREB)-binding protein (CBP) using the small molecule inhibitor ICG-001. We generated and annotated in vitro treatment gene expression signatures of HNSCC cells, derived from human oral squamous cell carcinomas (OSCCs), using microarrays. We validated the anti-tumorigenic activity of ICG-001 in vivo using SCC-derived tumor xenografts in murine models, as well as embryonic zebrafish-based screens of sorted stem cell-like subpopulations. Additionally, ICG-001-inhibition signatures were overlaid with RNA-sequencing data from The Cancer Genome Atlas (TCGA) for human OSCCs to evaluate its association with tumor progression and prognosis.ResultsICG-001 inhibited HNSCC cell proliferation and tumor growth in cellular and murine models, respectively, while promoting intercellular adhesion and loss of invasive phenotypes. Furthermore, ICG-001 preferentially targeted the ability of subpopulations of stem-like cells to establish metastatic tumors in zebrafish. Significantly, interrogation of the ICG-001 inhibition-associated gene expression signature in the TCGA OSCC human cohort indicated that the targeted β-catenin/CBP transcriptional activity tracked with tumor status, advanced tumor grade, and poor overall patient survival.ConclusionsCollectively, our results identify β-catenin/CBP interaction as a novel target for anti-HNSCC therapy and provide evidence that derivatives of ICG-001 with enhanced inhibitory activity may serve as an effective strategy to interfere with aggressive features of HNSCC.Electronic supplementary materialThe online version of this article (10.1186/s13073-018-0569-7) contains supplementary material, which is available to authorized users.
Genomic and structural analyses reveal that β-catenin/CBP signaling represses epidermal growth factor receptor (EGFR) N-glycan antennary fucosylation in oral cancer.
Artificial intelligence (AI) is a new breakthrough in technological advancements based on the concept of simulating human intelligence. These emerging technologies highly influence the diagnostic process in the field of medical sciences, with enhanced accuracy in diagnosis. This review article intends to report on the trends and application of AI models designed for diagnosis and treatment planning in orthodontics. A data search for the original research articles that were published over the last 22 years (from 1 January 2000 until 31 August 2022) was carried out in the most renowned electronic databases, which mainly included PubMed, Google Scholar, Web of Science, Scopus, and Saudi Digital Library. A total of 56 articles that met the eligibility criteria were included. The research trend shows a rapid increase in articles over the last two years. In total: 17 articles have reported on AI models designed for the automated identification of cephalometric landmarks; 12 articles on the estimation of bone age and maturity using cervical vertebra and hand-wrist radiographs; two articles on palatal shape analysis; seven articles for determining the need for orthodontic tooth extractions; two articles for automated skeletal classification; and 16 articles for the diagnosis and planning of orthognathic surgeries. AI is a significant development that has been successfully implemented in a wide range of image-based applications. These applications can facilitate clinicians in diagnosing, treatment planning, and decision-making. AI applications are beneficial as they are reliable, with enhanced speed, and have the potential to automatically complete the task with an efficiency equivalent to experienced clinicians. These models can prove as an excellent guide for less experienced orthodontists.
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy in the world with oral squamous cell carcinomas (OSCC) accounting for the majority of HNSCC cases. A major driver of OSCC is the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK) with 12 N-glycosylation sites. Fucosylated N-linked glycans on EGFR are associated with survival e.g., they suppress receptor dimerization and signaling. High levels of fucosylated glycan epitopes have been observed in OSCC, where invasive regions lose expression of linkage-specific fucosylated epitopes, suggesting that fucosylated glycans are involved in the suppression of cell growth and invasion. Previously, it was shown that inhibition of the interaction between nuclear β-catenin and CREB-binding protein (CBP) in human OSCC cells and in mouse tumor xenografts with a small molecule inhibitor ICG-001, interfered with OSCC proliferation and aggressive features in cellular, zebrafish, and murine models. E7386, a novel β-catenin/CBP modulator displays activity profile that closely overlaps with that of ICG-001 and exhibits ~50 - 100-fold lower EC50 values. Treatment with ICG-001 and E7386, increased expression of two glycosyltransferases, FUT2 and FUT3 coincident with decreased EGFR abundance that was accompanied by higher fucosylation of EGFR and upregulated expression of E-cadherin and junctional β-catenin. Further, genomic analyses showed a positive correlation between the ICG-001 and E7386 treatments and EGFR inhibition, suggesting that higher expression of antennary fucosyltransferase genes suppresses EGFR signaling. We now show using nLC-MS/MS analyses that EGFR from metastatic HSC-3 cells had low levels of fucosylated N-glycans, while EGFR from indolent CAL27 cells displayed higher levels of fucosylation at multiple EGFR N-linked glycosylation sites, and that these changes were statistically significant. In-depth characterization of multiply-fucosylated N-glycans via tandem mass spectrometry of EGFR glycopeptides revealed new insights into the identity of fucosylated glycan epitopes. Collectively, these results suggest that the β-catenin/CBP axis promotes EGFR signaling through downregulation of fucosyltransferase expression and activity. We conclude that inhibition of β-catenin/CBP signaling with a novel small molecule E7386 may serve as a therapeutic approach to downregulate EGFR pro-tumorigenic activity in HNSCC patients. Citation Format: Kevin B. Chandler, Khalid Alamoud, Bac-Cuc Nguyen, Vanessa L. Stahl, Takashi Owa, Kenichi Nomoto, Stefano Monti, Maria A. Kukuruzinska, Catherine E. Costello. Inhibition of β-catenin/CBP signaling alters EGFR fucosylation status in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5940.
Head and neck cancer is a debilitating malignancy, with the majority of cases arising in the oral cavity as oral squamous cell carcinoma (OSCC). A major driver of OSCC is the epidermal growth factor receptor (EGFR), whose activity is aberrantly upregulated in >80% of tumors. EGFR is highly modified with N-linked glycans; fucosylation of N-glycans interferes with EGFR dimerization and activation. Thus, post-transcriptional changes may govern EGFR activity. In OSCC, EGFR signaling converges on Wnt/β-catenin activity, known to play pivotal roles in the pathobiology of this malignancy through the interaction of nuclear β-catenin with the histone acetyltransferase CREB-binding protein (CBP). We have shown that a small molecule inhibitor of β-catenin-CBP interaction, ICG-001, interferes with OSCC proliferation and aggressive features in cellular, zebrafish and murine models. Also, OSCC-cell line derived mouse tumor xenografts exhibit reduced EGFR abundance, and genomic analyses show a positive correlation between ICG-001 and EGFR inhibition. Given that modification of EGFR with N-glycans impacts its cell-surface localization and signaling, we hypothesized that ICG-001 affects EGFR N-glycosylation. To determine the effect of inhibition of β-catenin/CBP activity on cellular N-glycosylation programs, N-glycans from CAL27 and HSC3 cells treated with ICG-001 or vehicle control were released, permethylated, and analyzed via MALDI-TOF MS. Next, EGFR glycopeptides from CAL27 and HSC3 cells treated with ICG-001 or vehicle control, were analyzed with an Orbitrap Fusion™ Lumos™ Tribrid™ mass spectrometer (Thermo Scientific) using EThcD. In CAL27 cells, we observed higher levels of high mannose (less processed) N-glycans and complex fucosylated N-glycans, whereas in HSC3 cells we observed complex, afucosylated N-glycans. After ICG-001 treatment, HSC3 cells displayed higher levels of fucosylated N-glycans, suggesting that ICG-001, via inhibition of β-catenin/CBP signaling, promotes a more indolent-like glycan profile. Similarly, EGFR from CAL27 cells had highly fucosylated N-glycans, while EGFR from HSC3 cells displayed N-glycans with a paucity of fucose. Treatment of HSC3 cells with ICG-001 led to higher fucosylation, potentially inhibiting EGFR signaling. Parallel analyses of gene expression signatures in response to ICG-001 treatment in HSC-3 cells showed increased transcriptional expression of fucosyltransferases, FUT2 and FUT3. Our studies suggest that the β-catenin/CBP axis promotes EGFR signaling through downregulation of FUT2 and FUT3 expression and activity. Thus, inhibition of β-catenin/CBP signaling with ICG-001 may serve as a therapeutic approach to downregulate EGFR pro-tumorigenic activity in OSCC. Supported by NIH grants P41 GM104603 (CEC), F32 CA196157 (KBC), and by the Evans Center for Interdisciplinary Biomedical Research ARC #9950000118 (MAK). Citation Format: Kevin B. Chandler, Vanessa L. Stahl, Khalid Alamoud, Bach-Cuc Nguyen, Vinay Kartha, Khikmet Sadykov, Stefano Monti, Maria A. Kukuruzinska, Catherine E. Costello. Deciphering the role of protein glycosylation in oral cancer: insights into tumor biology and treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2633.
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