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1.
BMC Cancer ; 22(1): 990, 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36115941

RESUMO

BACKGROUND: A group of genetically altered cells that have not transformed into a clinical or histologically identifiable state of malignancy but contains a higher risk of transforming into one is known as the field of cancerization. Numerous molecules are being investigated for their significance in the development of this phenomenon. One such protein of this family is Kaiso also known as ZBTB33 (Zinc Finger and BTB Domain containing 33). This protein belongs to the POZ-ZF family of transcription factors and may have functional tasks similar to its other siblings such as the growth and development of vertebrates and the pathogenesis of neoplastic diseases. Nevertheless, its role in the pathogenesis, progression, epithelial mesenchyal transition and field cancerization in case of oral cancer still needs exploration. Hence, this study was designed to explore the expressional differences between the mucosa of controls and those diagnosed with oral squamous cell carcinoma (OSCC). METHODS: Soft tissue samples were obtained from the main tumor, tumor periphery and opposite buccal mucosa of 50 oral cancer patients, whereas normal mucosa was taken from 50 volunteers undergoing elective tooth removal. The acquired samples were subjected to Immunohistochemical exploration for expression of Kaiso and E-Cadherin. The expression was measured using Image-J IHC profiler and summed as Optical density. The Optical density values were then subjected to statistical analysis. RESULTS: Results revealed a significant differential expression of Kaiso between the mucosal tissues taken from oral cancer patients and controls (p-value: < 0.0001), showing almost 50% down-regulation of Kaiso in all three tissue samples taken from oral cancer patients as compared to normal mucosa. CONCLUSION: Kaiso has a significant difference of expression in the mucosa of oral cancer patients as compared to the mucosa of normal patients, making it a probable contributor to disease pathogenesis and field cancerization.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Animais , Caderinas , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/genética , Humanos , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
2.
Int J Mol Sci ; 23(17)2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36077186

RESUMO

Alcohol consumption is associated with an increased risk of several cancers, including oral/oropharyngeal squamous cell carcinoma (OSCC). Alcohol also enhances the progression and aggressiveness of existing cancers; however, its underlying molecular mechanism remains elusive. Especially, the local carcinogenic effects of alcohol on OSCC in closest contact with ingestion of alcohol are poorly understood. We demonstrated that chronic ethanol exposure to OSCC increased cancer stem cell (CSC) populations and their stemness features, including self-renewal capacity, expression of stem cell markers, ALDH activity, and migration ability. The ethanol exposure also led to a significant increase in aerobic glycolysis. Moreover, increased aerobic glycolytic activity was required to support the stemness phenotype of ethanol-exposed OSCC, suggesting a molecular coupling between cancer stemness and metabolic reprogramming. We further demonstrated that chronic ethanol exposure activated NFAT (nuclear factor of activated T cells) signaling in OSCC. Functional studies revealed that pharmacological and genetic inhibition of NFAT suppressed CSC phenotype and aerobic glycolysis in ethanol-exposed OSCC. Collectively, chronic ethanol exposure promotes cancer stemness and aerobic glycolysis via activation of NFAT signaling. Our study provides a novel insight into the roles of cancer stemness and metabolic reprogramming in the molecular mechanism of alcohol-mediated carcinogenesis.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Etanol/metabolismo , Etanol/toxicidade , Regulação Neoplásica da Expressão Gênica , Glicólise , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Bucais/patologia , Células-Tronco Neoplásicas/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
3.
BMC Oral Health ; 22(1): 378, 2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064348

RESUMO

BACKGROUND: Rapid metastasis of oral squamous cell carcinoma (OSCC) is associated with a poor prognosis and a high mortality rate. However, the molecular mechanisms underlying OSCC metastasis have not been fully elucidated. Although deregulated expression of microRNA (miRNA) has a crucial role in malignant cancer progression, the biological function of miRNA in OSCC progression remains unclear. This study aimed to investigate the function of miRNA-18a in OSCC metastatic regulation via hypoxia-inducible factor 1α (HIF-1α). METHODS: miRNA-18a-5p (miRNA-18a) expressions in patients with OSCC (n = 39) and in OSCC cell lines (e.g., YD-10B and HSC-2 cells) were analyzed using quantitative real-time polymerase chain reaction. HIF-1α protein expressions in OSCC cells treated with miRNA-18a mimics or combined with cobalt chloride were analyzed using western blotting. The miRNA-18a expression-dependent proliferation and invasion abilities of OSCC cells were analyzed using MTT assay, EdU assay, and a Transwell® insert system. RESULTS: miRNA-18a expression was significantly lower in OSCC tissue than in the adjacent normal tissue. In OSCC cell lines, HIF-1α expression was significantly decreased by miRNA-18a mimic treatment. Furthermore, the migration and invasion abilities of OSCC cells were significantly decreased by miRNA-18a mimics and significantly increased by the overexpression of HIF-1α under hypoxic conditions relative to those abilities in cells treated only with miRNA-18a mimics. CONCLUSIONS: miRNA-18a negatively affects HIF-1α expression and inhibits the metastasis of OSCC, thereby suggesting its potential as a therapeutic target for antimetastatic strategies in OSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , MicroRNAs , Neoplasias Bucais , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , MicroRNAs/metabolismo , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço
4.
Shanghai Kou Qiang Yi Xue ; 31(2): 205-210, 2022 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-36110082

RESUMO

PURPOSE: To investigate the changes of nutritional status in patients with oral squamous cell carcinoma(OSCC) and analyze the influencing factors during treatment. METHODS: Anthropometry (weight, BMI, waistline, middle circumference of left and right upper arms) and laboratory index(serum prealbumin, serum albumin, transferrins, 25-hydroxyvitamin D) were measured to represent the nutritional status of 50 patients with OSCC before operation, two days, one month and three months after operation. SPSS 24.0 software package was used for statistical analysis of the data, and influencing factors of nutrition risk in OSCC patient were analyzed with binary logistic regression model. RESULTS: Univariate and multivariate analysis showed that advanced age(OR=1.127,95%CI: 1.053-1.207), low educational level (OR=5.250, 95%CI: 1.147-21.796), smoking(OR=6.182, 95%CI: 1.631-23.433), alcohol use(OR=5.227, 95%CI: 1.336-20.450), chemoradiotherapy (OR=3.984, 95%CI: 1.199-13.242), free flap surgery (OR=8.000, 95%CI: 2.060-31.068), tracheostomy(OR=3.960, 95%CI: 1.069-14.671), cervical lymph node metastasis(OR=4.821, 95%CI: 1.418-16.399), buccal carcinoma(OR=9.000, 95%CI:1.140-71.038), tongue cancer(OR=7.200, 95%CI: 1.081-47.962), tumor stage T3-4(OR=3.542, 95%CI: 1.066-11.771) were independent influencing factors of the nutritional status of patients with OSCC. CONCLUSIONS: Aging, low educational level, smoking history and drinking history in the general demographic characteristics of patients, and chemoradiotherapy, free flap surgery, tracheostomy during treatment, as well as buccal carcinoma, tongue cancer, advanced stage and cervical lymph node metastasis are clinical characteristics, which affect the nutrition level during the treatment for OSCC patients.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Neoplasias da Língua , Carcinoma de Células Escamosas/patologia , Humanos , Metástase Linfática , Neoplasias Bucais/patologia , Neoplasias Bucais/terapia , Estado Nutricional , Pré-Albumina , Carcinoma de Células Escamosas de Cabeça e Pescoço , Transferrinas
5.
Dis Markers ; 2022: 6106503, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36118668

RESUMO

Objective: To investigate the multiomics immune-related lncRNA analysis of oral squamous cell carcinoma and its correlation with prognosis. Methods: Through the bioinformatics database, a total of 346 oral squamous cell carcinoma (OSCC) related samples were retrieved. Bioinformatics analysis screened out the difference lncRNAs in the sample tissue and normal tissue, combined with literature research to clarify the target. The biological functions of differentially expressed lncRNAs were predicted. The differential expression network of differentially expressed lncRNAs and mRNAs was established. The correlation analysis software was used to analyze the correlation between oral squamous cell carcinoma multiomics immune-related lncRNA and prognosis. Results: 3054 lncRNAs in OSCC tissues are highly correlated with immune genes. 76 immune-related lncRNAs were different in tumor and adjacent tissues. Cancer Hallmark, Phenotype, and Subcellular Location analysis were completed. The results showed that lncRNAs can participate in tumor cell invasion, metastasis, proliferation, and apoptosis. Select the 15 most important lncRNAs above, draw Kaplan-Meier curve to complete the survival curve analysis, and complete the analysis and arrangement of the relevant data. LINC00460, CASC9, and HCG22 were screened for subsequent analysis. Complete the GO and KEGG enrichment analysis. LINC00460, CASC9, and macrophages M0 are positively correlated; CASC9 is negatively correlated with macrophages M1; LINC00460 is positively correlated with macrophages M1; HCG22 is associated with mast cells resting positive correlation; LINC00460 was negatively correlated with mast cell resting. CASC9 and HCG22 were significantly correlated with the age and stage of OSCC patients; 2 key lncRNA and 79 miRNAs were extracted from the database, to complete 86 pairs of interactions; the target mRNAs were predicted based on the above miRNAs. A total of 631 pairs of interactions were predicted (including 21 miRNAs and 562 mRNAs), and the regulatory mechanism of key gene ceRNA network was constructed. Conclusion: The differential expression of multiple lncRNAs and mRNAs was screened, and the downregulated lncRNAs were more than the upregulated lncRNAs. The lncRNA LINC00460, CASC9, and HCG22 had a strong correlation with prognosis.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , MicroRNAs , Neoplasias Bucais , RNA Longo não Codificante , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Humanos , MicroRNAs/genética , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Prognóstico , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética
6.
Front Immunol ; 13: 954567, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119104

RESUMO

Oral potentially malignant disorders (OPMD) are precursors of oral squamous cell carcinoma (OSCC), and the presence of oral epithelial dysplasia (OED) in OPMD confers an increased risk of malignant transformation. Emerging evidence has indicated a role for the immune system in OPMD disease progression; however, the underlying immune mechanisms remain elusive. In this study, we used immune signatures established from cancer to delineate the immune profiles of moderate and severe OED, which are considered high-risk OPMD. We demonstrated that moderate and severe OEDs exhibit high lymphocyte infiltration and upregulation of genes involved in both immune surveillance (major histocompatibility complex-I, T cells, B cells and cytolytic activity) and immune suppression (immune checkpoints, T regulatory cells, and tumor-associated macrophages). Notably, we identified three distinct subtypes of moderate and severe OED: immune cytotoxic, non-cytotoxic and non-immune reactive. Active immune surveillance is present in the immune cytotoxic subtype, whereas the non-cytotoxic subtype lacks CD8 immune cytotoxic response. The non-immune reactive subtype showed upregulation of genes involved in the stromal microenvironment and cell cycle. The lack of T cell infiltration and activation in the non-immune reactive subtype is due to the dysregulation of CTNNB1, PTEN and JAK2. This work suggests that moderate and severe OED that harbor the non-cytotoxic or non-immune reactive subtype are likely to progress to cancer. Overall, we showed that distinct immune responses are present in high-risk OPMD, and revealed targetable pathways that could lead to potential new approaches for non-surgical management of OED.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , Lesões Pré-Cancerosas , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Transformação Celular Neoplásica/genética , Humanos , Hiperplasia , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Lesões Pré-Cancerosas/genética , Microambiente Tumoral/genética
7.
Oncol Rep ; 48(4)2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36082807

RESUMO

The present study aimed to investigate the clinical and biological significance of Src­associated in mitosis 68 kDa (Sam68) in oral squamous cell carcinoma (OSCC). Immunohistochemical analysis was performed on tissue samples obtained from 77 patients with OSCC. Univariate analysis revealed that the high expression of Sam68 was significantly correlated with advanced pathological T stage (P=0.01), positive lymphovascular invasion (P=0.01), and pathological cervical lymph node metastasis (P<0.01). Moreover, multivariate analysis demonstrated that the high expression of Sam68 was an independent predictive factor for cervical lymph node metastasis (odds ratio, 4.39; 95% confidence interval, 1.49­14.23; P<0.01). These results indicated that high Sam68 expression contributed to tumor progression, especially cervical lymph node metastasis, in OSCC. mRNA sequencing was also performed to assess the changes in the transcriptome between OSCC cells with Sam68 knockdown and control cells with the aim of elucidating the biological roles of Sam68. Gene Ontology enrichment analysis revealed that downregulated differentially expressed genes (DEGs) were concentrated in some biological processes related to epithelial­mesenchymal transition. Among these DEGs, it was established that vimentin was particularly downregulated in these cells. It was also confirmed that Sam68 knockdown reduced the motility of OSCC cells. Furthermore, the immunohistochemical study of vimentin identified the association between vimentin expression and Sam68 expression as well as cervical lymph node metastasis. In conclusion, the present study suggested that the high expression of Sam68 may contribute to metastasis by regulating vimentin expression and a motile mesenchymal phenotype in OSCC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Ligação a DNA , Neoplasias Bucais , Proteínas de Ligação a RNA , Carcinoma de Células Escamosas de Cabeça e Pescoço , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Ligação a DNA/genética , Humanos , Metástase Linfática , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Fenótipo , Proteínas de Ligação a RNA/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Vimentina/genética
8.
Biomed Pharmacother ; 154: 113632, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36063646

RESUMO

Local recurrence of colorectal cancer (CRC) can occur in patients after curative resection, and additional surgical resection may therefore be required; however, this is a significant burden for patients, because additional surgical resection may necessitate the resection of other organs such as the bladder, prostate, uterus, or sacral bone. Therefore, there is a need for alternative therapeutic strategies. We focused on boron neutron capture therapy (BNCT) as a treatment modality that can selectively target tumor cells without excessive damage to normal tissues. The usefulness of BNCT to pelvic CRC remains unknown. This study investigated the anti-cancer effect of boronophenylalanine (BPA)-mediated BNCT in a previously established mouse model of pelvic recurrence of CRC. Uptake of BPA in CRC was observed both in vitro and in vivo, and the concentrations were sufficient for BNCT. Our results are the first to show that BPA-mediated BNCT prolonged the survival of experimental mice with pelvic tumors; moreover, it did not cause any obvious severe side effects in the treated animals. In conclusion, BPA-mediated BNCT could contribute to treating local recurrence of pelvic CRC.


Assuntos
Terapia por Captura de Nêutron de Boro , Neoplasias Colorretais , Neoplasias Bucais , Neoplasias Pélvicas , Animais , Compostos de Boro/uso terapêutico , Terapia por Captura de Nêutron de Boro/efeitos adversos , Terapia por Captura de Nêutron de Boro/métodos , Neoplasias Colorretais/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Neoplasias Bucais/patologia , Neoplasias Pélvicas/tratamento farmacológico , Neoplasias Pélvicas/etiologia
9.
Molecules ; 27(17)2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-36080226

RESUMO

Different aspects of intra-tumor heterogeneity (ITH), which are associated with the development of cancer and its response to treatment, have postulated prognostic value. Here we searched for potential association between phenotypic ITH analyzed by mass spectrometry imaging (MSI) and prognosis of head and neck cancer. The study involved tissue specimens resected from 77 patients with locally advanced oral squamous cell carcinoma, including 37 patients where matched samples of primary tumor and synchronous lymph node metastases were analyzed. A 3-year follow-up was available for all patients which enabled their separation into two groups: with no evidence of disease (NED, n = 41) and with progressive disease (PD, n = 36). After on-tissue trypsin digestion, peptide maps of all cancer regions were segmented using an unsupervised approach to reveal their intrinsic heterogeneity. We found that intra-tumor similarity of spectra was higher in the PD group and diversity of clusters identified during image segmentation was higher in the NED group, which indicated a higher level of ITH in patients with more favorable outcomes. Signature of molecular components that correlated with long-term outcomes could be associated with proteins involved in the immune functions. Furthermore, a positive correlation between ITH and histopathological lymphocytic host response was observed. Hence, we proposed that a higher level of ITH revealed by MSI in cancers with a better prognosis could reflect the presence of heterotypic components of tumor microenvironment such as infiltrating immune cells enhancing the response to the treatment.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Carcinoma de Células Escamosas/patologia , Humanos , Metástase Linfática , Espectrometria de Massas , Neoplasias Bucais/diagnóstico por imagem , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Prognóstico , Microambiente Tumoral
10.
Medicina (Kaunas) ; 58(8)2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-36013570

RESUMO

Oral papilloma lesions may appear as a result of HPV infection, or not, and only special molecular methods could differentiate them. Low-risk and high-risk HPV types could induce oral HPV papillomatosis with different natural evolution, clearance and persistence mechanisms. The pathogenic mechanisms are based on the crosstalk between the oral epithelial and immune cells and this very efficient virus. HPV acts as a direct inducer in the process of transforming a benign lesion into a malignant one, the cancerization process being also debated in this paper. According to the degree of malignity, three types of papillomatous lesions can be described in the oral cavity: benign lesions, potential malign disorders and malignant lesions. The precise molecular diagnostic is important to identify the presence of various virus types and also the virus products responsible for its oncogenicity. An accurate diagnostic of oral papilloma can be established through a good knowledge of etiological and epidemiological factors, clinical examination and laboratory tests. This review intends to update the pathogenic mechanisms driving the macroscopic and histological features of oral papillomatosis having HPV infection as the main etiological factor, focusing on its interreference in the local immunity. In the absence of an accurate molecular diagnostic and knowledge of local immunological conditions, the therapeutic strategy could be difficult to decide.


Assuntos
Neoplasias Bucais , Papiloma , Infecções por Papillomavirus , Humanos , Neoplasias Bucais/etiologia , Neoplasias Bucais/patologia , Papiloma/diagnóstico , Papiloma/patologia , Papillomaviridae , Infecções por Papillomavirus/complicações
11.
Molecules ; 27(16)2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-36014389

RESUMO

Oral squamous cell carcinoma (OSCC) is a global public health problem with high incidence and mortality. The chemotherapeutic agents used in the clinic, alone or in combination, usually lead to important side effects. Thus, the discovery and development of new antineoplastic drugs are essential to improve disease prognosis and reduce toxicity. In the present study, acridine-core naphthoquinone compounds were synthesized and evaluated for their antitumor activity in OSCC cells. The mechanism of action, pharmacokinetics, and toxicity parameters of the most promising compound was further analyzed using in silico, in vitro, and in vivo methods. Among the derivatives, compound 4e was highly cytotoxic (29.99 µM) and selective (SI 2.9) at levels comparable and generally superior to chemotherapeutic controls. Besides, compound 4e proved to be non-hemolytic, stable, and well tolerated in animals at all doses tested. Mechanistically, compound 4e promoted cell death by apoptosis in the OSCC cell, and molecular docking studies suggested this compound possibly targets enzymes important for tumor progression, such as RSK2, PKM2, and topoisomerase IIα. Importantly, compound 4e presented a pharmacological profile within desirable parameters for drug development, showing promise for future preclinical trials.


Assuntos
Antineoplásicos , Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Naftoquinonas , Acridinas/farmacologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Simulação de Acoplamento Molecular , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/patologia , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico
12.
BMC Genomics ; 23(1): 611, 2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-35999496

RESUMO

BACKGROUND: Emerging transcriptome-wide high-throughput screenings reveal the landscape and functions of RNAs, such as circular RNAs (circRNAs), in human cancer. In addition, the post-transcriptional RNA internal modifications, especially N6-methyladenosine (m6A), greatly enrich the variety of RNAs metabolism. However, the m6A modification on circRNAs has yet to be addressed. RESULTS: Here, we report an epitranscriptome-wide mapping of m6A-modified circRNAs (m6A-circRNA) in oral squamous cell carcinoma (OSCC). Utilizing the data of m6A methylated RNA immunoprecipitation sequencing (MeRIP-seq) and m6A-circRNAs microarray, we found that m6A-circRNAs exhibited particular modification styles in OSCC, which was independent of m6A-mRNA. Besides, m6A modification on circRNAs frequently occurred on the long exons in the front part of the coding sequence (CDS), which was distinct from m6A-mRNA that in 3'-UTR or stop codon. CONCLUSION: In conclusion, our work preliminarily demonstrates the traits of m6A-circRNAs, which may bring enlighten for the roles of m6A-circRNAs in OSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Carcinoma de Células Escamosas/patologia , Humanos , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , RNA/metabolismo , RNA Circular , RNA Mensageiro/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço
13.
Front Immunol ; 13: 941667, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35990685

RESUMO

Oral squamous cell carcinoma (OSCC) is one of the most frequent types of oral cancer in developing countries and its burden correlates with exposure to tobacco and excessive alcohol consumption. Toll like receptors (TLRs) are major sensors of inflammatory stimuli, from both microbial and sterile causes and as such, they have been related to tumor progression and metastasis. Here, we evaluated the expression of TLR2, 4 and 9 as well as CD3+, CD8+ and Granzyme B+ cell infiltration by immunohistochemistry in oral samples of 30 patients with OSCC, classified according to their consumption of alcohol. Our findings indicate that there is a significant association between heavy alcohol consumption and tumors with higher expression levels of TLR9. Moreover, patients with TLR9high tumors, as well as those who indicated high consumption of alcohol exhibited a diminished overall survival. TCGA data analysis indicated that TLR9high tumors express a significant increase in some genes related with the oral cavity itself, inflammation and tumor promotion. Our analysis of tumor infiltrating leukocytes demonstrated that the major differences perceived in heavy alcohol consumers was the location of CD8+ T cells infiltrating the tumor, which showed lower numbers intratumorally. Our data suggest the existence of a pathogenic loop that involves alcohol consumption, high TLR9 expression and the immunophenotype, which might have a profound impact on the progression of the disease.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Carcinoma de Células Escamosas/metabolismo , Humanos , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Receptor Toll-Like 9
14.
Sci Rep ; 12(1): 14283, 2022 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-35995987

RESUMO

Early detection of oral cancer in low-resource settings necessitates a Point-of-Care screening tool that empowers Frontline-Health-Workers (FHW). This study was conducted to validate the accuracy of Convolutional-Neural-Network (CNN) enabled m(mobile)-Health device deployed with FHWs for delineation of suspicious oral lesions (malignant/potentially-malignant disorders). The effectiveness of the device was tested in tertiary-care hospitals and low-resource settings in India. The subjects were screened independently, either by FHWs alone or along with specialists. All the subjects were also remotely evaluated by oral cancer specialist/s. The program screened 5025 subjects (Images: 32,128) with 95% (n = 4728) having telediagnosis. Among the 16% (n = 752) assessed by onsite specialists, 20% (n = 102) underwent biopsy. Simple and complex CNN were integrated into the mobile phone and cloud respectively. The onsite specialist diagnosis showed a high sensitivity (94%), when compared to histology, while telediagnosis showed high accuracy in comparison with onsite specialists (sensitivity: 95%; specificity: 84%). FHWs, however, when compared with telediagnosis, identified suspicious lesions with less sensitivity (60%). Phone integrated, CNN (MobileNet) accurately delineated lesions (n = 1416; sensitivity: 82%) and Cloud-based CNN (VGG19) had higher accuracy (sensitivity: 87%) with tele-diagnosis as reference standard. The results of the study suggest that an automated mHealth-enabled, dual-image system is a useful triaging tool and empowers FHWs for oral cancer screening in low-resource settings.


Assuntos
Telefone Celular , Aprendizado Profundo , Neoplasias Bucais , Telemedicina , Detecção Precoce de Câncer/métodos , Humanos , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/patologia , Sistemas Automatizados de Assistência Junto ao Leito , Telemedicina/métodos
15.
Int J Mol Sci ; 23(16)2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-36012205

RESUMO

Oral potentially malignant disorders (OPMDs) are a group of diseases involving the oral mucosa and that have a risk of carcinogenesis. The microenvironment is closely related to carcinogenesis and cancer progression by regulating the immune response, cell metabolic activities, and mechanical characteristics. Meanwhile, there are extensive interactions between the microenvironments that remodel and provide favorable conditions for cancer initiation. However, the changes, exact roles, and interactions of microenvironments during the carcinogenesis of OPMDs have not been fully elucidated. Here, we present an updated landscape of the microenvironments in OPMDs, emphasizing the changes in the immune microenvironment, metabolic microenvironment, mechanical microenvironment, and neural microenvironment during carcinogenesis and their carcinogenic mechanisms. We then propose an immuno-metabolic-mechanical-neural interaction network to describe their close relationships. Lastly, we summarize the therapeutic strategies for targeting microenvironments, and provide an outlook on future research directions and clinical applications. This review depicts a vivid microenvironment landscape and sheds light on new strategies to prevent the carcinogenesis of OPMDs.


Assuntos
Doenças da Boca , Neoplasias Bucais , Lesões Pré-Cancerosas , Carcinogênese , Humanos , Mucosa Bucal/metabolismo , Neoplasias Bucais/patologia , Lesões Pré-Cancerosas/terapia , Microambiente Tumoral
16.
Int J Mol Sci ; 23(16)2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-36012461

RESUMO

The most prevalent oral cancer globally is oral squamous cell carcinoma (OSCC). The invasion of adjacent bones and the metastasis to regional lymph nodes often lead to poor prognoses and shortened survival times in patients with OSCC. Encouraging immunotherapeutic responses have been seen with immune checkpoint inhibitors (ICIs); however, these positive responses to monotherapy have been limited to a small subset of patients. Therefore, it is urgent that further investigations into optimizing immunotherapies are conducted. Areas of research include identifying novel immune checkpoints and targets and tailoring treatment programs to meet the needs of individual patients. Furthermore, the advancement of combination therapies against OSCC is also critical. Thus, additional studies are needed to ensure clinical trials are successful. Mice models are advantageous in immunotherapy research with several advantages, such as relatively low costs and high tumor growth success rate. This review paper divided methods for establishing OSCC mouse models into four categories: syngeneic tumor models, chemical carcinogen induction, genetically engineered mouse, and humanized mouse. Each method has advantages and disadvantages that influence its application in OSCC research. This review comprehensively surveys the literature and summarizes the current mouse models used in immunotherapy, their advantages and disadvantages, and details relating to the cell lines for oral cancer growth. This review aims to present evidence and considerations for choosing a suitable model establishment method to investigate the early diagnosis, clinical treatment, and related pathogenesis of OSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Modelos Animais de Doenças , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Camundongos , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Experimentação Humana Terapêutica
17.
J Contemp Dent Pract ; 23(5): 479-481, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35986453

RESUMO

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity with pathognomonic histopathologic features of invading nests, islands, or chords of malignant epithelial cells. Although the histological features are quite uniform across a majority of the cases, they can drastically change in different variants of OSCC, such as clear cell, spindle cell/sarcomatoid, adenoid/acantholytic/pseudoglandular, basaloid, papillary and adenosquamous, etc.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Humanos , Linfonodos/patologia , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço
18.
Cell Death Dis ; 13(8): 701, 2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-35961969

RESUMO

Oral submucous fibrosis (OSF) is a chronic and insidious oral potentially malignant disorder associated with a 4-17% risk of oral squamous cell carcinoma (OSCC). Our previous study found that proteasomal activator 28 gamma (PA28γ) is frequently overexpressed in oral squamous cell carcinoma and negatively correlated with poor patient prognosis. However, the role of PA28γ in the occurrence and development of OSF remains unclear. Here, we screened PA28γ-related genes and investigated their function in OSF. We demonstrated that the expression of PA28γ was positively associated with MEK1 and gradually elevated from normal to progressive stages of OSF tissue. Arecoline, a pathogenic component of OSF, could upregulate the protein levels of PA28γ and phosphorylated MEK1 and contribute to epithelial to mesenchymal transition (EMT) in epithelial cells. Notably, PA28γ could interact with MEK1 and upregulate its phosphorylation level. Furthermore, arecoline upregulated BRAF, which can interact with PA28γ and upregulate its protein level. Additionally, BRAF, PA28γ, and MEK1 could form protein complexes and then enhance the MEK1/ERK signaling pathways. The concrete mechanism of the protein stability of PA28γ is that BRAF mediates its degradation by inhibiting its ubiquitination. These findings underscore the instrumental role of PA28γ in the BRAF/MEK1 pathway and enhanced EMT through MEK1/ERK activation in OSF.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Fibrose Oral Submucosa , Arecolina/farmacologia , Autoantígenos , Carcinoma de Células Escamosas/patologia , Transição Epitelial-Mesenquimal/genética , Humanos , MAP Quinase Quinase 1/metabolismo , Neoplasias Bucais/patologia , Fibrose Oral Submucosa/genética , Complexo de Endopeptidases do Proteassoma , Proteínas Proto-Oncogênicas B-raf , Carcinoma de Células Escamosas de Cabeça e Pescoço
19.
Cell Death Dis ; 13(8): 703, 2022 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-35963855

RESUMO

Oral squamous cell carcinoma (OSCC), the most common malignancy of the oral and maxillofacial region, severely affects human health. However, current treatments for OSCC commonly show only a ~60% 5-year survival rate of patients with distant metastases, indicating an urgent need for targeted treatments for patients with advanced metastases. Here, we report a survival-related long non-coding RNA, CYTOR, which is highly expressed in the lesions of oral cancer patients. We found that CYTOR can promote both migration and invasion in oral cancer cells as well as the epithelial-mesenchymal transition (EMT). RNA-sequencing of CYTOR-knockdown oral cancer cells revealed that CYTOR can regulate mitochondrial respiration and RNA splicing. Mechanistically, we found that nuclear-localized CYTOR interacts with HNRNPC, resulting in stabilization of ZEB1 mRNAs by inhibiting the nondegradative ubiquitination of HNRNPC. By synthesizing CYTOR-targeting small interfering RNAs (siRNAs) encapsulated in Nanoscale Metal Organic Frameworks (NMOFs), we demonstrate the targeted suppression of CYTOR to inhibit invasion and metastasis of oral cancer cells in a nude mouse model. Cumulatively, this study reveals the potential role of the CYTOR-HNRNPC-ZEB1 axis in regulating mitochondrial metabolism and glycolysis of oral cancer cells, and illustrates the effective use of lncRNA targeting in anti-metastatic cancer therapies.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , RNA Longo não Codificante , Animais , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Glicólise/genética , Neoplasias de Cabeça e Pescoço/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/genética , Humanos , Camundongos , Neoplasias Bucais/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/metabolismo , Respiração , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
20.
Biomed Res Int ; 2022: 3543948, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35983249

RESUMO

Background: The survival rate of oral squamous cell carcinoma (OSCC) is only 50% due to a high incidence of metastasis. Long noncoding RNAs (lncRNAs) play a crucial role in OSCC genesis and progression, although their potential role in the metastasis of OSCC remains unclear. Methods: The transcriptome of 5 metastatic and 5 nonmetastatic OSCC samples were assessed by RNA sequencing. The biological functions and regulatory mechanisms of LEMD1-AS1 in OSCC were explored by in vitro and in vivo assays. Results: We identified 487 differentially expressed mRNAs (DEmRNAs) and 1507 differentially expressed lncRNAs (DElncRNAs) in OSCC with cervical lymph node (LN) metastasis relative to the nonmetastatic samples. In addition, both LEMD1-AS1 and its cognate LEMD1 were up-regulated in metastatic OSCC compared to nonmetastatic OSCC. Gain-of-function, loss-of-function, and rescue experiments indicated that LEMD1-AS1 upregulated LEMD1 to increase OSCC migration and invasion in vitro and in vivo. Mechanistically, LEMD1-AS1 stabilized LEMD1 and increased its mRNA and protein levels, and consequently activated the PI3K-AKT signaling pathway to facilitate OSCC metastasis. Conclusions: We established the lncRNA-mRNA landscape of metastatic OSCC, which indicated that LEMD1-AS1 enhanced OSCC metastasis by stabilizing its antisense transcript LEMD1. Thus, LEMD1-AS1 is a potential biomarker for predicting metastasis, as well as a therapeutic target of OSCC.


Assuntos
Neoplasias Bucais , Proteínas de Neoplasias , RNA Longo não Codificante , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática/genética , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Proteínas de Neoplasias/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
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