Inflammation and cancer: role of annexin A1 and FPR2/ALX in proliferation and metastasis in human laryngeal squamous cell carcinoma.

The anti-inflammatory protein annexin A1 (ANXA1) has been associated with cancer progression and metastasis, suggesting its role in regulating tumor cell proliferation. We investigated the mechanism of ANXA1 interaction with formylated peptide receptor 2 (FPR2/ALX) in control, peritumoral and tumor larynx tissue samples from 20 patients, to quantitate the neutrophils and mast cells, and to evaluate the protein expression and co-localization of ANXA1/FPR2 in these inflammatory cells and laryngeal squamous cells by immunocytochemistry. In addition, we performed in vitro experiments to further investigate the functional role of ANXA1/FPR2 in the proliferation and metastasis of Hep-2 cells, a cell line from larynx epidermoid carcinoma, after treatment with ANXA1(2-26) (annexin A1 N-terminal-derived peptide), Boc2 (antagonist of FPR) and/or dexamethasone. Under these treatments, the level of Hep-2 cell proliferation, pro-inflammatory cytokines, ANXA1/FPR2 co-localization, and the prostaglandin signalling were analyzed using ELISA, immunocytochemistry and real-time PCR. An influx of neutrophils and degranulated mast cells was detected in tumor samples. In these inflammatory cells of peritumoral and tumor samples, ANXA1/FPR2 expression was markedly exacerbated, however, in laryngeal carcinoma cells, this expression was down-regulated. ANXA1(2-26) treatment reduced the proliferation of the Hep-2 cells, an effect that was blocked by Boc2, and up-regulated ANXA1/FPR2 expression. ANXA1(2-26) treatment also reduced the levels of pro-inflammatory cytokines and affected the expression of metalloproteinases and EP receptors, which are involved in the prostaglandin signalling. Overall, this study identified potential roles for the molecular mechanism of the ANXA1/FPR2 interaction in laryngeal cancer, including its relationship with the prostaglandin pathway, providing promising starting points for future research. ANXA1 may contribute to the regulation of tumor growth and metastasis through paracrine mechanisms that are mediated by FPR2/ALX. These data may lead to new biological targets for therapeutic intervention in human laryngeal cancer.

Association between GSTP1, GSTM1 and GSTT1 polymorphisms involved in xenobiotic metabolism and head and neck cancer development.

Polymorphisms in the glutathione S-transferase superfamily genes that encodes enzymes involved in the phase II xenobiotic metabolism may lead head and neck cancer development. In this study we investigate the association of A313G and C341T GSTP1 polymorphisms, GSTM1 and GSTT1 null genotypes in the head and neck cancer development, interactions between these polymorphisms,the tumor histopathologic parameters and risk factors (smoking and drinking) were also evaluated in the case-control study. 775 individuals (261 patients/514 controls) were included in the study. Molecular analyzes were performed by PCR and PCR-RFLP; and statistical analyzes by Chi square and multiple logistic regression. Chi square test showed that only the genotype frequencies for GSTM1 and GSTT1 were in Hardy-Weinberg disequilibrium in both groups. Significant results with p ≤ 0.05 showed that age ≥ 48 years (OR = 11.87; 7.55-18.65), smoking (OR = 4.25; 2.70-6.69), drinking (OR = 1.59; 1.02-2.46) were possible predictors for the head and neck cancer development and the presence of A313G GSTP1 polymorphism (OR = 0.62; 0.42-0.92) decreased the risk for this disease. Individuals with the 313AG/GG GSTP1 and age ≥ 48 years (OR = 0.59; 0.38-0.91), male gender (OR = 0.54; 0.35-0.83), smokers (OR = 0.63; 0.40-0.99) and drinkers (OR = 0.57; 0.35-0.95); the GSTM1 null genotype and age < 48 years (OR = 2.46; 1.09-5.55); the GSTT1 null genotype and primary anatomical sites of pharynx (OR = 0.37; 0.17-0.79) and larynx (OR = 3.60; 1.93-6.72), can modulate the risk for the disease development. The variables age ≥ 48 years, smoking and drinking can be predictors for head and neck cancer development; moreover, A313G GSTP1 polymorphism, GSTM1 and GSTT1 null genotypes can modulate the risk for this disease.

Head and neck cancer: genetic polymorphisms and folate metabolism.

UNLABELLED: Epidemiological evidence suggests that genetic variants encoding enzymes involved in folate metabolism may modulate HNSCC risk by altering DNA methylation synthesis and genomic estability. AIM: A review of the literature on genetic polymorphisms involved in folate metabolism and risk of head and neck cancer was carried out. METHODOLOGY: An electronic search was made on the Medline database to select papers on head and neck cancer and polymorphisms involved in folate metabolism. RESULTS: The association between MTHFR C677T polymorphism and the risk of this tumor type was evaluated in nine studies; there was an association with this disease in three papers. The MTR A2756G and MTRR A66G and RFC1 A80G polymorphisms were also associated with increased risk for HNSCC. MTHFD1 G1958A polymorphism was not associated with increased risk of this disease; the evaluation results of the MTHFR A1298C polymorphism in this neoplasm were contradictory. Other polymorphisms involved in folate metabolism were not studied for this neoplasm. CONCLUSION: We conclude that polymorphisms involved in folate metabolism may modulate the risk of head and neck cancer, however, these results need to be demonstrated in different populations.

Câncer de cabeça e pescoço: polimorfismos genéticos e metabolismo do folato / Head and neck cancer: genetic polymorphisms and folate metabolism

Evidências epidemiológicas sugerem que variantes genéticas que codificam enzimas envolvidas no metabolismo do folato podem modular o risco de câncer de cabeça e pescoço por alterar a metilação, síntese de DNA e estabilidade genômica. OBJETIVOS: Realizar uma revisão bibliográfica sobre polimorfismos genéticos envolvidos no metabolismo do folato e o risco de câncer de cabeça e pescoço. METODOLOGIA: Realizou-se uma busca eletrônica na base de dados Medline, selecionando estudos em câncer de cabeça do pescoço e polimorfismos envolvidos no metabolismo do folato. RESULTADOS: A associação do polimorfismo MTHFR C677T no risco dessa neoplasia foi avaliada em nove estudos e três deles mostraram associação com essa doença. Os polimorfismos MTR A2756G e MTRR A66G e RFC1 A80G também foram associados com aumento de risco para o câncer de cabeça e pescoço. O polimorfismo MTHFD1 G1958A não mostra associação com o risco dessa doença e os resultados da avaliação do polimorfismo MTHFR A1298C nesse tipo de neoplasia são contraditórios. Outros polimorfismos envolvidos no metabolismo do folato ainda não foram estudados nesse tipo de neoplasia. CONCLUSÃO: Concluímos que polimorfismos envolvidos no metabolismo do folato podem modular o risco desse tipo de tumor, no entanto, esses resultados precisam ser comprovados em diferentes populações.

Epidemiological evidence suggests that genetic variants encoding enzymes involved in folate metabolism may modulate HNSCC risk by altering DNA methylation synthesis and genomic estability. AIM: A review of the literature on genetic polymorphisms involved in folate metabolism and risk of head and neck cancer was carried out. METHODOLOGY: An electronic search was made on the Medline database to select papers on head and neck cancer and polymorphisms involved in folate metabolism. RESULTS: The association between MTHFR C677T polymorphism and the risk of this tumor type was evaluated in nine studies; there was an association with this disease in three papers. The MTR A2756G and MTRR A66G and RFC1 A80G polymorphisms were also associated with increased risk for HNSCC. MTHFD1 G1958A polymorphism was not associated with increased risk of this disease; the evaluation results of the MTHFR A1298C polymorphism in this neoplasm were contradictory. Other polymorphisms involved in folate metabolism were not studied for this neoplasm. CONCLUSION: We conclude that polymorphisms involved in folate metabolism may modulate the risk of head and neck cancer, however, these results need to be demonstrated in different populations.

Association between 11 genetic polymorphisms in folate-metabolising genes and head and neck cancer risk.

Genetic polymorphisms in folate metabolism may affect the risk of head and neck cancer (HNSCC) due to its involvement in DNA methylation and synthesis. We conducted a case-control study (265 HNSCC cases and 466 non-cancer controls) to investigate associations of MTHFR C677T and A1298C, MTR A2756G, MTRR A66G, RFC1 A80G, MTHFD1 G1958A, CBS 844ins68, TC2 C776G and A67G, SHMT C1420T and BHMT G742A polymorphisms with HNSCC risk. Interactions between polymorphisms and survival time, tobacco and alcohol habits, age, gender and tumour staging (TNM classification) were evaluated by multiple logistic regression analysis. We found that age ≥ 49 years (P<0.001), male gender (P=0.03), tobacco habit (P<0.001), MTHFR 1298AC/CC (P=0.028), MTR 2756AG/GG (P=0.010) and RFC1 80AG/GG (P=0.015) genotypes were associated with an increased risk of HNSCC. There were interactions between lower survival and CBS 844ins68 (P=0.005); age ≥ 49 years and MTR 2756 AG/GG (P=0.004) and RFC1 80AG/GG (P=0.006) genotypes; male gender and MTHFR 1298 AC/CC (P=0.030), MTR 2756 AG/GG (P=0.006) and RFC1 80 AG/GG (P=0.009); tobacco non-habit and MTHFD1 1958GA/AA (P=0.040); tobacco and MTHFR 1298 AC/CC (P=0.054) and MTR 2756 AG/GG (P=0.010); alcohol non-consume and RFC1 80 AG/GG (P=0.008) with HNSCC increased risk. MTHFR C677CT/TT genotypes were less frequently in advanced tumours (P=0.04). In conclusion, our data provide evidence that folate metabolism genetic polymorphisms associated with variables as advanced age, male gender, tobacco and alcohol increase HNSCC development; CBS 844ins68 and MTHFR C677T polymorphisms are associated with less survival time and advanced stage tumours, respectively.

[GSTM1 and GSTT1 genes analysis in head and neck cancer patients].

OBJECTIVE: To establish the clinical and demographic profile and identify risk factors among patients with head and neck cancer and relate them to the polymorphism of GSTT1 and GSTM1. METHODS: One hundred patients with head and neck cancer and 100 control group individuals without history of neoplasm were analyzed. . The molecular analysis were made by multiplex polymerase chain reaction. For statistical analysis, data were tabulated and compared by the Fisher's exact test, the Chi-square test and multiple logistic regression were also used. RESULTS: There was prevalence of smokers (OR = 5.32, CI 95% CI = 2.04-13.86 p = 0.0006), alcohol drinkers (OR = 5.04, CI 95% = 2.19-11.59 p = 0.0001) in head and neck cancer patients . The GSTT1 null genotype was found in 47% of the patient and 41% of the control group (OR = 0.67; CI 95%= 0.34-1.35; p = 0.2648). Likewise , the GSTM1 null genotype was found in 66% of the patient and 75% of the control group (OR = 2.25; CI 95%= 1.05 - 4.84; p = 0.0368). The combined GSTT1 and GSTM1 gene null genotype shown association between GSTM1 0/GSTT1 and occurrence of head and neck carcinoma (OR = 7.64; CI 95%= 1.72-34.04; p = 0.0076). Analysis of clinical-pathological features showed association between GSTT1 null genotype and larynx, the inverse relation between this genotype and pharynx. CONCLUSION: In our study it was possible to establish association between GSTM1 null genotypes and head and neck cancer.

Análise dos genes GSTM1 e GSTT1 em pacientes com câncer de cabeça e pescoço / GSTM1 and GSTT1 genes analysis in head and neck cancer patients

OBJETIVO: Estabelecer o perfil clínico e demográfico bem como identificar os fatores de risco entre os pacientes com câncer de cabeça e pescoço e relacioná-los ao polimorfismo dos genes GSTT1 e GSTM1. MÉTODOS: Foram estudados 100 pacientes com carcinoma espinocelular de cabeça e pescoço e 100 indivíduos sem história de neoplasia. A análise molecular foi realizada pela técnica de PCR multiplex. Para a análise estatística, os dados foram tabulados e comparados pelo teste exato de Fisher. Foi também utilizado o teste do Qui quadrado e de regressão logística múltipla. RESULTADOS: Há predomínio de indivíduos tabagistas (OR= 5,32; IC95 por cento= 2,04-13,86; p=0,0006), etilistas (OR= 5,04; IC95 por cento= 2,19-11,59; p= 0,0001) em pacientes com neoplasia de cabeça e pescoço. Foi identificado genótipo nulo do gene GSTT1 em 47 por cento dos pacientes e 41 por cento dos controles (OR= 0,67; IC 95 por cento= 0,34-1,35; p= 0,2648). Da mesma forma, identificou-se o genótipo nulo do gene GSTM1 em 66 por cento dos pacientes e 75 por cento dos controles (OR= 2,25; IC95 por cento= 1,05-4,84; p= 0,0368). A análise dos genótipos combinados demonstrou associação entre GSTM1*0/GSTT1 e a ocorrência de carcinoma de cabeça e pescoço (OR= 7,64; IC 95 por cento= 1,72-34,04; p= 0,0076). A análise dos parâmetros clínicos mostrou que é possível identificar associação entre genótipo GSTT1 nulo e neoplasia na laringe, o inverso ocorrendo com este genótipo e a faringe. CONCLUSÃO: Em nosso estudo foi possível estabelecer a associação entre a nulidade do genótipo GSTM1 e dos genótipos combinados GSTT1/GSTM1 *0 ([ ] / [-] a ocorrência de câncer de cabeça e pescoço.

OBJECTIVE: To establish the clinical and demographic profile and identify risk factors among patients with head and neck cancer and relate them to the polymorphism of GSTT1 and GSTM1. METHODS: One hundred patients with head and neck cancer and 100 control group individuals without history of neoplasm were analyzed. . The molecular analysis were made by multiplex polymerase chain reaction. For statistical analysis, data were tabulated and compared by the Fisher’s exact test, the Chi-square test and multiple logistic regression were also used. RESULTS: There was prevalence of smokers (OR = 5.32, CI 95 percent CI = 2.04-13.86 p = 0.0006), alcohol drinkers (OR = 5.04, CI 95 percent = 2.19-11.59 p = 0.0001) in head and neck cancer patients . The GSTT1 null genotype was found in 47 percent of the patient and 41 percent of the control group (OR = 0.67; CI 95 percent= 0.34-1.35; p = 0.2648). Likewise , the GSTM1 null genotype was found in 66 percent of the patient and 75 percent of the control group (OR = 2.25; CI 95 percent= 1.05 - 4.84; p = 0.0368). The combined GSTT1 and GSTM1 gene null genotype shown association between GSTM1*0/GSTT1 and occurrence of head and neck carcinoma (OR = 7.64; CI 95 percent= 1.72-34.04; p = 0.0076). Analysis of clinical-pathological features showed association between GSTT1 null genotype and larynx, the inverse relation between this genotype and pharynx. CONCLUSION: In our study it was possible to establish association between GSTM1 null genotypes and head and neck cancer.