The Role of SOX2 and SOX9 in Radioresistance and Tumor Recurrence.

Head and neck squamous cell carcinoma (HNSCC) exhibits considerable variability in patient outcome. It has been reported that SOX2 plays a role in proliferation, tumor growth, drug resistance, and metastasis in a variety of cancer types. Additionally, SOX9 has been implicated in immune tolerance and treatment failures. SOX2 and SOX9 induce treatment failure by a molecular mechanism that has not yet been elucidated. This study explores the inverse association of SOX2/SOX9 and their distinct expression in tumors, influencing the tumor microenvironment and radiotherapy responses. Through public RNA sequencing data, human biopsy samples, and knockdown cellular models, we explored the effects of inverted SOX2 and SOX9 expression. We found that patients expressing SOX2LowSOX9High showed decreased survival compared to SOX2HighSOX9Low. A survival analysis of patients stratified by radiotherapy and human papillomavirus brings additional clinical relevance. We identified a gene set signature comprising newly discovered candidate genes resulting from inverted SOX2/SOX9 expression. Moreover, the TGF-ß pathway emerges as a significant predicted contributor to the overexpression of these candidate genes. In vitro findings reveal that silencing SOX2 enhances tumor radioresistance, while SOX9 silencing enhances radiosensitivity. These discoveries lay the groundwork for further studies on the therapeutic potential of transcription factors in optimizing HNSCC treatment.

The role of tumor acidification in aggressiveness, cell dissemination and treatment resistance of oral squamous cell carcinoma.

AIMS: To investigate the role of tumor acidification in cell behavior, migration, and treatment resistance of oral squamous cell carcinoma (OSCC). MAIN METHODS: The SCC4 and SCC25 cell lines were exposed to acidified (pH 6.8) cell culture medium for 7 days. Alternatively, a long-term acidosis was induced for 21 days. In addition, to mimic dynamic pH fluctuation of the tumor microenvironment, cells were reconditioned to neutral pH after experimental acidosis. This study assessed cell proliferation and viability by sulforhodamine B and flow cytometry. Individual and collective cell migration was analyzed by wound healing, time lapse, and transwell assays. Modifications of cell phenotype, EMT induction and stemness potential were investigated by qRT-PCR, western blot, and immunofluorescence. Finally, resistance to chemo- and radiotherapy of OSCC when exposed to acidified environmental conditions (pH 6.8) was determined. KEY FINDINGS: The exposure to an acidic microenvironment caused an initial reduction of OSCC cells viability, followed by an adaptation process. Acidic adapted cells acquired a mesenchymal-like phenotype along with increased migration and motility indexes. Moreover, tumoral extracellular acidity was capable to induce cellular stemness and to increase chemo- and radioresistance of oral cancer cells. SIGNIFICANCE: In summary, the results showed that the acidic microenvironment leads to a more aggressive and treatment resistant OSCC cell population.

Somatic mutations and promotor methylation of the ryanodine receptor 2 is a common event in the pathogenesis of head and neck cancer.

Genomic sequencing projects unraveled the mutational landscape of head and neck squamous cell carcinoma (HNSCC) and provided a comprehensive catalog of somatic mutations. However, the limited number of significant cancer-related genes obtained so far only partially explains the biological complexity of HNSCC and hampers the development of novel diagnostic biomarkers and therapeutic targets. We pursued a multiscale omics approach based on whole-exome sequencing, global DNA methylation and gene expression profiling data derived from tumor samples of the HIPO-HNC cohort (n = 87), and confirmed new findings with datasets from The Cancer Genome Atlas (TCGA). Promoter methylation was confirmed by MassARRAY analysis and protein expression was assessed by immunohistochemistry and immunofluorescence staining. We discovered a set of cancer-related genes with frequent somatic mutations and high frequency of promoter methylation. This included the ryanodine receptor 2 (RYR2), which showed variable promoter methylation and expression in both tumor samples and cell lines. Immunohistochemical staining of tissue sections unraveled a gradual loss of RYR2 expression from normal mucosa via dysplastic lesion to invasive cancer and indicated that reduced RYR2 expression in adjacent tissue and precancerous lesions might serve as risk factor for unfavorable prognosis and upcoming malignant conversion. In summary, our data indicate that impaired RYR2 function by either somatic mutation or epigenetic silencing is a common event in HNSCC pathogenesis. Detection of RYR2 expression and/or promoter methylation might enable risk assessment for malignant conversion of dysplastic lesions.

Epidemiology and Molecular Biology of Head and Neck Cancer.

Head and neck cancer is a common and aggressive malignancy with a high morbidity and mortality profile. Although the large majority of cases resemble head and neck squamous cell carcinoma (HNSCC), the current classification based on anatomic site and tumor stage fails to capture the high level of biologic heterogeneity, and appropriate clinical management remains a major challenge. Hence, a better understanding of the molecular biology of HNSCC is urgently needed to support biomarker development and personalized care for patients. This review focuses on recent findings based on integrative genomics analysis and multi-scale modeling approaches and how they are beginning to provide more sophisticated clues as to the biological and clinical diversity of HNSCC.

Loss of SOX2 expression induces cell motility via vimentin up-regulation and is an unfavorable risk factor for survival of head and neck squamous cell carcinoma.

Recurrent gain on chromosome 3q26 encompassing the gene locus for the transcription factor SOX2 is a frequent event in human squamous cell carcinoma, including head and neck squamous cell carcinoma (HNSCC). Numerous studies demonstrated that SOX2 expression and function is related to distinct aspects of tumor cell pathophysiology. However, the underlying molecular mechanisms are not well understood, and the correlation between SOX2 expression and clinical outcome revealed conflicting data. Transcriptional profiling after silencing of SOX2 expression in a HNSCC cell line identified a set of up-regulated genes related to cell motility (e.g. VIM, FN1, CDH2). The inverse regulation of SOX2 and aforementioned genes was validated in 18 independent HNSCC cell lines from different anatomical sites. The inhibition of cell migration and invasion by SOX2 was confirmed by constant or conditional gene silencing and accelerated motility of HNSCC cells after SOX2 silencing was partially reverted by down-regulation of vimentin. In a retrospective study, SOX2 expression was determined by immunohistochemical staining on tissue microarrays containing primary tumor specimens of two independent HNSCC patient cohorts. Low SOX2 expression was found in 19.3% and 44.9% of primary tumor specimens, respectively. Univariate analysis demonstrated a statistically significant correlation between low SOX2 protein levels and reduced progression-free survival (Cohort I 51 vs. 16 months; Cohort II 33 vs. 12 months) and overall survival (Cohort I 150 vs. 37 months; Cohort II 33 vs. 16 months). Multivariate Cox proportional hazard model analysis confirmed that low SOX2 expression serves as an independent prognostic marker for HNSCC patients. We conclude that SOX2 inhibits tumor cell motility in HNSCC cells and that low SOX2 expression serves as a prognosticator to identify HNSCC patients at high risk for treatment failure.

Oral desmoplastic melanoma mimicking inflammatory hyperplasia.

INTRODUCTION: Desmoplastic melanoma (DM) arising in the oral cavity is a rare neoplasm that may be confused with a variety of non-melanocytic benign or malignant lesions. OBJECTIVES: To present a case of DM in the oral mucosa mimicking fibrous inflammatory hyperplasia, discusses the difficulties involved in the diagnosis and offers a literature review on the clinicopathologic and immunohistochemincal aspects of this neoplasm. CASE REPORT: A 62-year-old white male, smoker, was referred with a chief complaint of pain and swelling in the palate. The oral examination revealed multiple brown-to-black patches and a non-pigmented sessile nodule located on the mucosa of the hard palate. The clinical diagnosis of the pigmented lesions was either oral melanosis or melanoma. The nodular lesion was clinically diagnosed as fibrous inflammatory hyperplasia. Incisional biopsy was performed on the pigmented lesion and the microscopic sections revealed a melanotic macule. The nodular lesions histologically revealed an amelanotic desmoplastic melanoma. CONCLUSIONS: Reactive lesions close to a pigmented area should be investigated with great care.

Reporte de una posible correlación entre la gingivitis ulceronecrotizante y la mononucleosis / Report a possible correlation between necrotizing ulcerative gingivitis and mononucleosis

Necrotizing ulcerative gingivitis is a relatively uncommon periodontal disease, characterized by ulceration, necrosis, pain and gingival bleeding. Factors often related to its occurrence include stress and systemic viral infections, such as those caused by cytomegalovirus and Epstein-Barr virus type 1, the latter being also considered the causative agent of infectious mononucleosis. This article aims to describe a clinical case of a female patient who presented with necrotizing ulcerative gingivitis associated with a clinical picture of infectious mononucleosis, as well as to review the literature concerning a possible correlation between these pathologies. This patient presented to our health care facility with necrotizing ulcerative gingivitis accompanied by lymphadenopathy, fever and prostration, after laboratory tests, Epstein-Barr virus type 1 infection was confirmed, as well as the co-occurrence of pathologies: necrotizing ulcerative gingivitis and infectious mononucleosis. Symptom remission in both disorders also occurred concomitantly, after instruction in plaque control measures and palliative medication for control of systemic symptoms. Therefore, although there is no scientific validation of an association between these two pathologies, it is imperative that all diagnostic alternatives be considered and investigated, in order to establish the therapeutic approach most appropriate to the patient(AU

La gingivitis ulcerativa necrótica es una enfermedad periodontal no común caracterizada por ulceración, necrosis, dolor y sangrado gingival. Los factores a menudo relacionados con su ocurrencia incluyen el estrés y las infecciones virales sistémicas como aquellas causadas por Cytomegalovirus y el virus Epstein-Barr tipo 1, donde este último es el agente causal de la mononuclerosis infecciosa. El objetivo de este trabajo fue describir el caso clínico de una mujer con gingivitis ulcerativa necrótica asociada a un cuadro clínico de mononucleosis infecciosa, así como hacer una revisión de la literatura concerniente a una posible correlación entre estas enfermedades. Esta paciente se presentó con una gingivitis ulcerativa necrótica acompañada de linfadenopatía, fiebre y postración después de las pruebas de laboratorio, donde se confirmó una infección por Epstein-Barr tipo 1 así como la ocurrencia conjunta de gingivitis ulcerativa necrótica y mononucleosis infecciosa. También se produjo una remisión concomitante de los síntomas en ambos trastornos después de la instrucción en medidas para el control de placas y una medicación paliativa para el control de los síntomas sistémicos. Por lo tanto, aunque no existió una validación científica de una asociación entre estas dos entidades, es imperativo que se consideren e investiguen todas las alternativas diagnósticas para establecer el enfoque terapéutico más apropiado para el paciente(AU)