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Head and neck squamous cell carcinoma (HNSCC) is one of the most common human cancers; however, its outcome of pharmacotherapy is always very limited. Herein, we performed a batch query in the connectivity map (cMap) based on bioinformatics, queried out 35 compounds with therapeutic potential, and screened out parbendazole as a most promising compound, which had an excellent inhibitory effect on the proliferation of HNSCC cell lines. In addition, tubulin was identified as a primary target of parbendazole, and the direct binding between them was further verified. Parbendazole was further proved as an effective tubulin polymerization inhibitor, which can block the cell cycle, cause apoptosis and prevent cell migration, and it exhibited reasonable therapeutic effect and low toxicity in the in vivo and in vitro anti-tumor evaluation. Our study repositioned an anthelmintic parbendazole to treat HNSCC, which revealed a therapeutic utility and provided a new treatment option for human cancers.
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Loco-regional recurrences and distant metastases represent the main cause of head and neck squamous cell carcinoma (HNSCC) mortality. The overexpression of chemokine receptor 4 (CXCR4) in HNSCC primary tumors associates with higher risk of developing loco-regional recurrences and distant metastases, thus making CXCR4 an ideal entry pathway for targeted drug delivery. In this context, our group has generated the self-assembling protein nanocarrier T22-GFP-H6, displaying multiple T22 peptidic ligands that specifically target CXCR4. This study aimed to validate T22-GFP-H6 as a suitable nanocarrier to selectively deliver cytotoxic agents to CXCR4+ tumors in a HNSCC model. Here we demonstrate that T22-GFP-H6 selectively internalizes in CXCR4+ HNSCC cells, achieving a high accumulation in CXCR4+ tumors in vivo, while showing negligible nanocarrier distribution in non-tumor bearing organs. Moreover, this T22-empowered nanocarrier can incorporate bacterial toxin domains to generate therapeutic nanotoxins that induce cell death in CXCR4-overexpressing tumors in the absence of histological alterations in normal organs. Altogether, these results show the potential use of this T22-empowered nanocarrier platform to incorporate polypeptidic domains of choice to selectively eliminate CXCR4+ cells in HNSCC. Remarkably, to our knowledge, this is the first study testing targeted protein-only nanoparticles in this cancer type, which may represent a novel treatment approach for HNSCC patients.
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Squamous cell carcinoma of the head and neck (HNSCC) is one of the cancers with the highest incidence rate in the world. Due to the presence of postoperative recurrence and resistance to some chemotherapeutics after the surgery, the prognosis of advanced HNSCC patients is not optimistic. Therefore, it is urgent to improve the efficiency of chemotherapeutics for HNSCC and the prognosis of HNSCC patients. Recent studies have found that ferroptosis has regulatory effect on the growth and proliferation of some types of tumor cells, reducing drug resistance in tumor treatment to a certain extent, and showing great potential in the prevention and treatment of tumors. Therefore, this article will summarize the anti-tumor mechanism of ferroptosis and the current research progress in HNSCC, providing new evidence for the treatment of HNSCC.
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@#[摘 要] 表皮生长因子受体（epidermal growth factor receptor，EGFR）在头颈部鳞状细胞癌（head and neck squamous cell carcinoma，HNSCC）的发生、发展中起着至关重要的作用。作为一种跨膜受体，EGFR参与多种信号通路，且在头颈部鳞状细胞癌组织中高表达。目前，围绕EGFR设计的HNSCC靶向治疗药物已经广泛应用于临床，但随之产生的耐药问题也日益受到关注。本文重点从信号通路、靶向药物治疗和耐药等方面综述EGFR在治疗头颈部鳞状细胞癌的最新研究进展，并探讨其发展前景。
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Head and neck squamous cell carcinoma (HNSCC) includes carcinomas in the oral cavity, pharynx and larynx. It is considered as the sixth most common form of cancer in the world. Severalstudies have confirmed that smoking and alcohol consumption are the major risk factors for HNSCC. DNA damage response genes play an important role in the maintenance of the genome. Defects in cell cycle checkpoint and DNA repair mechanisms, such asmutation or abnormalities, may lead to the wide spectrum of human diseases. The present study employs databases and computational tools to identify the genetic abnormalities associated with DNA damage related genes which might have a direct or indirect association with HNSCC. The demographic details of HNSCC patients was obtained from The Cancer Gene Atlas (TCGA, Firehose Legacy) dataset hosted by the cBioportal database. The oncoprint data analysis revealed the highest frequency of gene alteration in the ATR gene (15%), followed by ATM, BRCA2and CHEK2(5%). Other genes showed less than 5% alteration. The gene expression profile of ATRgene revealed its differential expression pattern in different grades of tumor relative to normal samples. The survival curve analysis using Kaplan-Meier method revealed that a high level expression of the ATR gene leads to poor survival rate in the female HNSCC patients when compared to males. Thus the present study has identified gross and single nucleotide variants in the ATRgene which could have a putative role in the development of tumor. Further experimental research is required to confirm this association
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The cell suicide pathway of apoptosis is a necessary event in the life of multicellular organisms. It is involved in many biological processes ranging from development to the immune response. Over expression of interleukin-1β-converting enzyme (later renamed caspase-1) was shown to be sufficient to induce apoptosis in mammalian cells. The present study aims to assess the gene alterations in the Caspase family of cytochromes so as to derive an association with HNSCC. Earlier eleven genes were found in the human genome to encode 11 human caspases, caspase-1 to caspase-10 and caspase-14, which is now populated to 13, whereas 10 genes were found in the mouse genome to encode 10 murine caspases including caspase-1, 2, 3, 6, 7, 8, 9, 11, 12 and 14 Caspases share a number of features distinguishable from other proteases. The analysis follows an observational study design, employing several computational tools to identify and predict the possible outcomes of gene alterations identified in HNSCC patients. cBioportal server was used to identify the gene alterations which was further analyzed using tools such as PROVEAN, I-Mutant and gnomAD. Several reported polymorphic variants were also identified. The pathogenicity and protein stability of gene alterations documented in the present study were identified at standard biological conditions. Further experimental studies would provide concrete evidence on the association of the observed genetic abnormalities with HNSCC especially in individuals exposed to habitual carcinogens
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Background:The 5-methyltetrahydrofolate-homocysteine methyltransferase gene (MTR) encodes the methionine synthase enzyme (OMIM 156570). Methionine synthase synthesizes methionine by re-methylation of homocysteine. A single nucleotide variation MTR-A2756G may affects the function of methionine synthase enzyme, which could lead to the development of head and neck squamous cell carcinoma (HNSCC).Methods:In current study, 292 HNSCC patients and 324 normal individuals without any history of cancer (control) were enrolled. EDTA whole blood samples of patients and control individuals were collected, and DNA was extracted. All samples were genotyped for MTR-A2756G polymorphism using polymerase chain reaction-restriction fragment length polymorphism. Frequency of polymorphism was compared between HNSCC patients and control individuals. The association of MTR-A2756G polymorphism with risk factors was statistically analysed through multivariate analysis (multiple logistic regression) whereas univariate analysis (chi square) was performed for group comparisons.Results:Univariate analysis revealed that the frequency of groups like age, smoking and MTR-A2756G genotype was different in HNC patients and controls (p value <0.05). Multivariate analysis showed that smoking (adjusted OR, 3.7; 95% CI, 2.3-6.0), age groups 41-50 years (adjusted OR, 3.6; 95% CI, .9-6.7) and >60 years (adjusted OR, 3.5; 95% CI, 1.7-7.3), MTR-A2756G genotype (adjusted OR, 2.1; 95% CI, 1.3-3.5) is associated with increased risk of HNSCC.Conclusions:Our data suggests that the MTR-A2756G polymorphism is associated with the occurrence of HNSCC in Pakistani population while the individuals between 40 to 50 years of age and tobacco smokers are at a greater risk of developing HNSCC.
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@#[Abstract] Objective: To explore the expression and regulation mechanism of Dickkopf-1 (DKK1) in head and neck squamous cell carcinoma (HNSCC) tissues. Methods: Based on the TCGA database, the relationship of DKK1 expression in HNSCC tissues and its methylation site with patients’prognosis was analyzed. GO and KEGG gene enrichment method were used to analyze the signaling pathways of DKK1 enrichment. STRING was used to analyze the interaction between DKK1 protein and other proteins. TargetScan was used to analyze the miRNAs that regulate the expression of DKK1, and the transcription factors of DKK1 were analyzed with the TRRUST website. Results: DKK1 gene was highly expressed in HNSCC tissues (P<0.01), and its expression level was significantly correlated with the HPV status, age, pathological grade, and clinical stage of patients (all P<0.05); the prognosis of HNSCC patients with high DKK1 expression was poorer than those with low DKK1 expression (P<0.01). There were 19 methylation sites in DKK1, 12 of which were significantly different between cancer tissues and normal tissues (P<0.05), and 11 sites were significantly related to the prognosis of HNSCC (P<0.05). In addition, miRNA, circRNA, lincRNA and transcription factors, etc. also participated in the regulation of DKK1. A total of 5 DKK1-related PPI networks that may involve in the occurrence, development, invasion and metastasis of HNSCC were obtained. Conclusion: DKK1 is highly expressed in HNSCC tissues and is a risk factor for poor prognosis of HNSCC patients. DKK1 plays an important role in the pathogenesis of HNSCC and is expected to become a potential target for HNSCC treatment.
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@#[Abstract] Objective: To detect the expression of CD39 in head and neck squamous cell carcinoma (HNSCC) tisseus, and to analyze its correlation with patients’clinicopathological features and its prognostic significance. Methods: Tissue specimens and case data of 85 patients with HNSCC underwent surgery at Cancer Hospital of Tianjin from May 2012 to December 2013 were collected for this study. Gene chips were obtained from Oncomine database, and HNSCC cell lines SCC15, UM1, and Cal25 were selected for this study. Online analysis was performed to compare the differential expression of CD39 in buccal mucosa (BM) tissues and HNSCC tissues, Western blotting and Immunohistochemistry (IHC) were used to detect the protein expression of CD39 in HNSCC tissues. Spearman’ s correlation analysis was used to study the correlation between the expressions of CD39 and clinicopathological features of HNSCC patients. Both Kaplan-Meier curve analysis and Log rank test were used to analyze the association between the expression of CD39 in HNSCC tissues and the survival of patients, and Cox risk proportional regression model was used to evaluate the relationship between CD39 expression and the risk of relapse. Results: The transcription level of CD39 was obviously up-regulated in HNSCC tissues than in BM tissues (P<0.01), and CD39 expression was detected in HNSCC cell lines SCC15, UM1 and Cal25. Dexamethasone (DXM) could enhance the expression of CD39 in UM1 cells in dose-dependent manner. CD39 was highly expressed in 53 (62.4%) HNSCC patients, which was positively correlated with preoperative chemotherapy (r=0.234, P<0.05). The recurrence-free survival (RFS) of patients with high CD39 expression was significantly shortened (P<0.05), and high CD39 expression was an independent relapse risk factor (HR=2.328, 95%CI=1.091-4.967; P<0.05) for patients with HNSCC. Conclusion: CD39 is DXM-inducively and constitutively expressed in HNSCC. And over-expression of CD39 is an independent predictor of poor prognosis in HNSCC patients, indicating its important role in the progression of HNSCC.
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Head and neck squamous cell carcinoma (HNSCC) is a kind of malignant tumor characterized by metastasis and local invasion. Its recurrence rate is high after surgery and radiotherapy, and the prognosis and quality of life are poor. In recent years, programmed death-1 (PD-1) inhibitors have been recommended in National Comprehensive Cancer Network (NCCN) guidelines for the treatment of recurrent, unresectable, and metastatic HNSCC, and their efficacy has been remarkable. PD-1 inhibitors constitute a new treatment for the patients with advanced HNSCC who are refractory to platinum-based chemotherapy and can increase the probability of surgical resection, reduce the risk of postoperative dysfunction, and improve the survival and quality of life. This article reviews the structure and mechanism of the PD-1/PD-L1 immunocheckpoint, as well as research progress on its inhibitors in the treatment of HNSCC.
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Background:Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive and invasive cancer types. Squamous cell carcinomas of the oral cavity are among the ten most common cancers in the world, and accounts for almost 3-5% of all malignancies. The invasive edges of head and neck squamous cell carcinomas often display different morphological and molecular characteristics than more superficial parts of the same tumor. Methods:In our 2 year retrospective study, carried at a tertiary care centre of north India, main aim was to evaluate the prognostic significance of several parameters of the modified Bryne’s grading system along with probability of survival in OSCC patients.Results:Out of 60 cases 40 were males and 20 were females. Tumor differentiation was assessed which showed that 90% of the tumors were well differentiated, 6.6% of the tumors were moderately differentiated and 3.4% of the tumors were poorly differentiated. The predominant POI in the primary OSCC was pattern 2 (63.4% in 38 cases) followed by pattern 3, pattern 1and pattern 4 (28.4% in17 cases, 6.6% in 4 cases and 1.6% in 1 case) respectively.Conclusions:Distributing all the cases according to the Bryne’s prognostic groups we found that 13 (21.7%) cases belonged to group with a score of <9, and 47 cases (78.3%) had a score of >9.The 5-year tumour-specificsurvival in OSCC patients with invasive front score of <9 was 95% compared to 46.25% in patients with high invasive front score >9.
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Head and neck Squamous cell carcinoma (HNSCC) is highly prevalent in Northeast India. The widespread use of tobacco exposure is a known risk factor, makingmitochondrial DNA (mtDNA) more susceptible to damage by oxidative stress incomparison to nuclear DNA. Mitochondrial dysfunction being a hallmark of cancer, thestudy aims to evaluate liquid biopsy involving circulating cell-free mitochondrial DNA(cfmtDNA) as an early diagnostic marker by reducing the dependability over tumor tissuebiopsy specimen. A total of 50 HNSCC cases reported at Cancer Hospital, Guwahati MedicalCollege from January 2018 to August 2018 were included in this study. Cell-free DNA wasisolated using QIAamp Circulating Nucleic Acid Kit. PCR based amplification ofmitochondrial D-loop, followed by direct sequencing. Our result indicated the presence ofsomatic mutations (73(A/G), 93(G/A), 146(T/C) and 207 (G/A)). Polymorphism was alsoobserved in the sequences (263A>G, 275G>A, 318T>C, 16034T>C, 16257C>A and16519T>C) upon comparison with reference sequence. Analysis of c-tract region showedthe presence of an additional cytosine nucleotide at position 309.Identifying somaticmutations in cfmtDNA using liquid biopsy approach will certainly minimize thedependency of clinicians and molecular biologist over the availability of tumor tissuespecimens. The identified somatic variations from our study will help in theimplementation of preventive measure. Therefore, our study provides an early mtDNAdiagnostic marker using liquid biopsy approach.
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Objective:This study aims to explore the anticancer effects and potential mechanisms of HJC0152, a novel STAT3 inhibitor, on the invasion and migration capacities of human head and neck squamous cell carcinoma (HNSCC) cell lines in vitro. Methods:Cells were divided into two groups, the dimethyl sulfoxide (DMSO) group and the HJC0152 group in which HNSCC cell lines UM-1 and SCC-15 were treated with DMSO or HJC0152 for 24 h. The total expression levels of STAT3, p-STAT3 (Tyr705/Ser727), MMP-2/9, N/E-cadherin, TWIST1, and vimentin;and the cytoplasm and nuclear expression levels of STAT3 and p-STAT3 (Tyr705/Ser727) were detected by Western blot assay. Wound healing and Transwell assays were employed to detect the invasion and migration abilities of the UM-1 and SCC-15 cells. The expression and location of N/E-cadherin were visualized by immunofluorescence staining. Results:Western blot indicated that the total expression of p-STAT3 (Tyr705), MMP-2/9, N-cadherin, TWIST1, and vimentin were significantly declined and that E-cadherin was remarkably elevated in the HJC0152 group cells compared with that of the DMSO group, with no difference in STAT3 or p-STAT3 (Ser727). Cytoplasm and nuclear STAT3 (Tyr705) were also inhibited by HJC0152. Wound healing and Transwel assays indicated that tumor invasion and migration capacities were impressively attenuated in the HJC0152 group cells compared to that of the DMSO group. Conclusion:HJC0152 suppresses the phosphorylation of STAT3 at Tyr705 in the HNSCC cell lines, leading to impair transcription activity, deplete expression levels of target genes, and subsequently inhibit migration and invasion capabilities of HNSCC.
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Head and neck squamous cell carcinoma(HNSCC) is the sixth most common malignancies of human beings. The prognosis of advanced HNSCC is poor despite improvements in traditional treatment strategies including surgery, chemotherapy, and radiotherapy. Cancer immunotherapy is the use of the immune system to treat cancer, which provides a sustained antitumor reaction but an absense of chemoresistance. Cancer immunotherapy is becoming the forth treatment strategy towards cancer. Therefore, we reviewed the current state of immunotherapy for HNSCC.
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Objective To observe the efficacy of nedaplatin(NDP),Asha Leigh Per(L-OHP)and cisplatin(DDP)combined with radiotherapy and chemotherapy in the treatment of locally advanced head and neck squamous cell carcinoma.Methods The clinical data of ninety-seven cases of locally advanced squamous cell carcinoma of head and neck treated in Guigang City People′s Hospital from May 2012 to May 2017 were retrospectively analyzed.33 cases were treated with NDP+5-Fu(5- fluorouracil,5-Fu)(group NDP),32 cases were treated with L-OHP+5-Fu(group L-OHP),32 cases were treated with DDP+5-Fu(group DDD).The three groups were treated with radiotherapy.Curative effect and adverse reaction of the three groups were compared.Results The results showed that the effective rate of the NDP group was 78.8%,slightly higher than that in the group L-OHP(75.0%)and group DDP(62.5%),the difference among the 3 groups was statistically significant(χ2=2.365,P=0.031).In the course of treatment,there were various degrees of adverse reactions in the three groups,no grade IV adverse reactions occurred.The incidence rate of adverse reactions in group NDP was(49.78±3.22)%,lower than that of group L-OHP(50.89±3.47)%,and that of group L-OHP was lower than that of group DDP(53.26 ± 4.19)%.But the difference among the three groups was not statistically significant(P=0.099).Conclusion NDP and L-OHP have good curative effect on head and neck squamous cell carcinoma,and NDP performs better than L-OHP.
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Objective:This study aims to explore the anticancer effects and potential mechanisms of HJC0152, a novel STAT3 inhibitor, on the invasion and migration capacities of human head and neck squamous cell carcinoma (HNSCC) cell lines in vitro. Methods:Cells were divided into two groups, the dimethyl sulfoxide (DMSO) group and the HJC0152 group in which HNSCC cell lines UM-1 and SCC-15 were treated with DMSO or HJC0152 for 24 h. The total expression levels of STAT3, p-STAT3 (Tyr705/Ser727), MMP-2/9, N/E-cadherin, TWIST1, and vimentin;and the cytoplasm and nuclear expression levels of STAT3 and p-STAT3 (Tyr705/Ser727) were detected by Western blot assay. Wound healing and Transwell assays were employed to detect the invasion and migration abilities of the UM-1 and SCC-15 cells. The expression and location of N/E-cadherin were visualized by immunofluorescence staining. Results:Western blot indicated that the total expression of p-STAT3 (Tyr705), MMP-2/9, N-cadherin, TWIST1, and vimentin were significantly declined and that E-cadherin was remarkably elevated in the HJC0152 group cells compared with that of the DMSO group, with no difference in STAT3 or p-STAT3 (Ser727). Cytoplasm and nuclear STAT3 (Tyr705) were also inhibited by HJC0152. Wound healing and Transwel assays indicated that tumor invasion and migration capacities were impressively attenuated in the HJC0152 group cells compared to that of the DMSO group. Conclusion:HJC0152 suppresses the phosphorylation of STAT3 at Tyr705 in the HNSCC cell lines, leading to impair transcription activity, deplete expression levels of target genes, and subsequently inhibit migration and invasion capabilities of HNSCC.
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Background: Deficiency of micro nutrients and trace elements has been associated with Head and Neck Squamous cell carcinomas (HNSCC). There is however a paucity of studies demonstrating this association in the West African sub-region. Aim: To determine the serum level of zinc, vitamin A and nutritional status of HNSCC patients at the University College Hospital, Ibadan. Methods: This was a case-control study of 65 consecutive patients with histological diagnosis of HNSCC. The controls were 65 healthy volunteers similar in age, sex and socioeconomic status. The participants’ height, weight, mid upper arm and waist circumference were measured and, serum Zinc and Vitamin A (Retinol) levels were assayed. The data from cases were analysed and compared with the controls using statistical package for social sciences version 15 software. Significance was set at p < 0.05. Results: The mean ages of cases and controls were 50.9±15.2 years and 49.49±16.35 years respectively. The commonest sites of HNSCC were the Nasopharynx and Sinonasal regions. Fifty five (84.6%) HNSCC patients presented with advanced form of the disease (stage III and IV). The mean body mass index of cases and controls was 22.66±4.70 and 23.14±3.8 respectively (p=0.524). The mean serum zinc level of the controls (113.63±6.04) was significantly higher than the cases (89.84±14.27) (p=0.000). The mean serum vitamin A (retinol) level of the controls (77.74 µg/dl±2.82) was significantly higher than the cases (61.34±5.89) (p=0.000). Conclusion: There are more Head and Neck Squamous cell carcinoma patients with malnutrition than the healthy population. Although no abnormality of serum zinc and retinol was found in both groups, there is a trend of lower levels of these nutrients in the patients than healthy individuals.
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Objective:To explore the role of CXCR2 in the invasion and metastasis of head and neck squamous cell carcinoma (HNSCC).Methods:The expression of CXCR2 in HNSCC tissues of 105 cases was detected by immunohistochemical staining,the correlation between CXCR2 expression and cervical lymph node metastases of HNSCC was analysed.Then,3 stable HNSCC cell lines with CXCR2 interference were established,the effects of CXCR2 silencing on cell migration and invasion were observed by in vitro tests.Results:CXCR2 was positively expressed in 51.43% of HNSCC specimens and was statistically associated with the cervical lymph node metastases of HNSCC.CXCR2 silencing markedly inhibited the migration and invasion of HNSCC cells in vitro.Conclu-sion:CXCR2 may play a key role in the invasion and metastases of HNSCC.
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Background & objectives: Prodrug activation strategy as well as immunotherapy have been widely used for cancer gene therapy. In the present study, using a head and neck squamous cell carcinoma (HNSCC) xenograft nude mouse model, we have investigated whether the two therapies in combination could improve tumour cell kill. We also investigated induction of immune effector cells viz., NK (DX5+) and DC (CD11c+) in vivo, post-combination gene therapy. Methods: A retroviral vector producing cell line (PLTK47.1 VPC) carrying Herpes simplex virus thymidine kinase gene (HSVtk) was used for intratumoural injection into NT8e xenograft tumours followed by the prodrug ganciclovir (GCV). IL-2 plasmid DNA was injected intramuscularly. Immune cells were analyzed by flow-cytometry. Non parametric ANOVA was performed with Kruskal Wallis test. Results: IL-2 could induce proliferation of both NK cells (DX5+) and dendritic cells (CD11c+) in vivo. Apoptosis was higher in combination therapy group as compared to HSVtk/GCV alone or IL-2 alone and was mediated through caspase-3 dependent pathway. Significant reduction in tumour volume was seen in all 3 treatment arms as compared to controls. Interpretation & conclusions: Combination of suicide gene therapy and immunotherapy leads to successful tumour regression in a HNSCC xenograft mouse model. Immunotherapy could help in a systemic long lived anti-tumour immune response which would prove powerful for the treatment of metastatic cancers, and also for minimal residual disease. The results of this study may form the basis for Phase 1 clinical trials.
Subject(s)
Analysis of Variance , Animals , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/immunology , Carcinoma, Squamous Cell/therapy , Cell Line , Cell Proliferation/drug effects , Dendritic Cells/drug effects , Flow Cytometry , Genes, Transgenic, Suicide/genetics , Genetic Therapy/methods , Genetic Vectors , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/immunology , Head and Neck Neoplasms/therapy , Humans , Immunotherapy/methods , In Situ Nick-End Labeling , Interleukin-2/administration & dosage , Interleukin-2/pharmacology , Killer Cells, Natural/drug effects , Mice , Retroviridae , Statistics, Nonparametric , Xenograft Model Antitumor AssaysABSTRACT
O carcinoma epidermóide de cabeça e pescoço é responsável por 90% das neoplasias malignas, nesta região. Molecularmente, inúmeras vias de sinalização, ainda não muito bem compreendidas, são responsáveis pelo seu crescimento e invasão para tecidos vizinhos, além de metástases para órgãos distantes. Este trabalho destinou-se a avaliar o crosstalk entre as vias de sinalização do PTEN, Akt, Mdm2 e p53 em quatro linhagens de células de carcinoma epidermóide (HN6, HN19, HN30 e HN31) e queratinócitos imortalizados (HaCat), estimulados com EGF (fator de crescimento epitelial) e 17-AAG. Para observar a localização e os níveis de PTEN, Akt, Mdm2 e p53 nos diferentes compartimentos celulares estas proteínas foram localizadas e quantificadas no interior celular através das técnicas de imunofluorescência e western blot, respectivamente. Os resultados mostraram que a ativação da via do PI3K/Akt, pelo EGF, promoveu a proliferação celular, sendo HN31 a linhagem celular de melhor resposta proliferativa. Quando as células foram tratadas com 17-AAG a linhagem HN31 foi a que melhor traçou um perfil apoptótico com diminuição dos níveis de Akt, ausência de Mdm2 e aumento dos níveis de PTEN e p53. As linhagens celulares HN6 e HN19 continuaram apresentando níveis significativos de Akt e Mdm2, o que sugere um potencialmais agressivo devido a manutenção do comportamento proliferativo e anti-apoptótico destas linhagens.
Head and neck squamous cell carcinoma (HNSCC) represents 90% of all head and neck malignancies. Cancer growth, invasion and metastasis are due to several signaling pathways that, unfortunately, are not completely understood. The aim of this study was the crosstalk evaluation among PTEN, Akt, Mdm2 and p53 signaling pathways in four different HNSCC cell lines (HN6, HN19, HN30 and HN31) and HaCat cell line (immortalized keratinocytes), all of than treated with 10ng/ml EGF (epidermal growth factor) and 2ìM 17-AAG. Western blot and imunofluorescence were performed in order to analyze PI3K/Akt signaling key target proteins: PTEN, Akt, Mdm2 and p53. Treatment of HNSCC cell lines with EGF resulted in activation of the PI3K/Akt pathway and enhanced cell proliferation. The results showed higher proliferative activity in HN31 cell line. The treatment of HNSCC cell lines with 17-AAG inhibited the proliferation in various levels. HN31 cell lines expressed PTEN and p53 in high levels and low expression for Akt and Mdm2 proteins. These findings suggest that 17-AAG can induce p53-dependent apoptosis in HN31 cell lines. On the contrary, HN6 and HN19 cell lines displayed high levels of Akt and Mdm2 proteins, resulting in decreased apoptosis and increased aggressive potential.