Expression Of MAGE-A9 In Esophageal Squamous Cell Carcinoma And Relationship With Prognosis

Background esophageal squamous cell carcinoma is one of the most common malignant tumor,its mortality rate ranks the sixth place in the total death related to tumor,Significant regional differences in distribution and familial aggregation are prominent epidemiological characteristics of esophageal cancer,suggesting that environmental factors,dietary factors and genetic factors of family members may play a role in the development of esophageal cancer.At present,the exact meaning of the environment,diet and heredity in the course of the occurrence of esophageal cancer is not yet accurate.Esophageal cancer has the characteristics of regional aggregation,from the Mediterranean region to Japan,across the earth's subtropical high incidence of esophageal cancer,but in general,the etiology of esophageal cancer is not clear,the proposed causes are: 1.Smoking,Hot food,hot drinks,oral knot,rough esophagus,eating too fast and other factors caused by chronic inflammation may be related to the disease.2.There is a tendency to gather.3.Fungi,in some high-incidence areas of food,esophageal cancer patients on the digestive tract biopsy or sliced specimens,can isolate a variety of fungi,some of which fungi have carcinogenic effects,some fungi can promote nitrosamines and The formation of precursors,but also promote the occurrence of cancer.The lack of trace elements in the diet,molybdenum,iron,zinc,fluoride and so on in the vegetables,food and drinking water content is low;vitamin A,vitamin B and vitamin C deficiency;animal protein,fresh vegetables,fruit intake,The characteristics of patients with high incidence of esophageal cancer.5.In the high incidence of diet,drinking water,sauerkraut and even patients with saliva,nitrite content is much higher than the low to go.Esophageal mucosa long-term exposure to nitrosamines,the epithelial dysplasia,severe atypical hyperplasia,and ultimately the development of cancer.Analysis of esophageal cancer in China,esophageal cancer occurs in rural areas,several generations often live in the same area,small mobility and environmental diet similar.In the high incidence of esophageal cancer,China and other Asian countries to squamous cell carcinoma mainly in Europe and the Americas esophageal cancer to adenocarcinoma mainly squamous cell carcinoma occurred in black,smoking and drinking people.Although in recent years some domestic epidemiological studies have shown that the incidence of esophageal cancer and mortality declined,but the trend is not very clear,in the high incidence of esophageal cancer,esophageal cancer incidence and mortality rate is still domestically The forefront of the tumor.Now esophageal cancer treatment methods are mainly surgery,chemotherapy and radiotherapy.According to retrospective study found that although surgery is still the most effective means of treatment of esophageal cancer,but early symptoms of esophageal cancer is not obvious,in patients with symptoms after medical treatment,the majority of patients have entered the late,missed the best time through surgery The Studies have shown that the overall survival rate of esophageal cancer is about 20%,while the survival rate of early esophageal cancer can reach more than 90%.Therefore,the study of the occurrence of esophageal cancer,to provide early prevention and treatment is very practical significance.At present,malignant tumors are a disease caused by protein and fund levels,so targeted therapy of malignant tumors has become a hot topic in today's research.Although mechanistic studies of MAGEs are limited,there is a growing body of evidence for their interactions with other proteins,especially E3 ubiquitin ligases.The MHDs of MAGE-A2,-A3,-A6,and-C2 can bind to the coiled-coil domain of the TRIM28/KAP1 ubiquitin ligase.MAGE-C2 increases phosphorylation of TRIM28/KAP1 and improves DNA repair after double-stranded breaks,possibly by enhancing complex formation between TRIM28/KAP1 and ATM.Our lab and others have shown that MAGE binding can enhance TRIM28/KAP1's ubiquitin ligase activity against p53,resulting in its degradation in a proteasome-dependent manner.In the presence of wild-type p53,knockdown of MAGE-A genes appears to increase p53 recruitment to target promoters and increase m RNA levels of p53 transcriptional targets.Others have also suggested that MAGE-A binds to p53 DNA-binding domain directly which may prevent its transcriptional activity.Additionally,MAGE-As and-C2 may downregulate p53 activity through preventing its acetylation at promyelocytic leukemia(PML)nuclear bodies by recruiting HDAC3 and blocking p300-mediated PML acetylation.However,the relevance of MAGE-As in cancer is not limited in scope to modulating p53 function.Expression of MAGE-A3 or-A6 does not correlate with p53 mutation status in multiple tumor types.Most recently,our lab has determined the MAGE-A3-TRIM28 and MAGE-A6-TRIM28 ligase complexes can ubiquitinate the alpha catalytic subunit(PRKAA1)of the tumor suppressor AMPK that functions as the master cellular energy sensor and regulator.This event leads to AMPK degradation and reduction of overall AMPK protein levels in tumors.Furthermore,downregulation of AMPK by MAGE-A3 and-A6 led to significantly decreased autophagy levels and upregulation of m TOR signaling,which may provide the optimal environment for early tumor formation and growth.Importantly,use of AMPK agonists significantly decreased MAGE-A6-mediated anchorage-independent growth in vitro.Because AMPK agonists(e.g.metformin)and m TOR inhibitors(e.g.everolimus)are already in use in the clinic,an immediate applicable point of these results may be to utilize MAGE-A3 and-A6 as a biomarkers for effective use of these drugs.MAGE-A11 is unique among the type I MAGEs in that it is known to be involved in the regulation of hormonal signals in prostate cancer.Binding of MAGE-A11 to the N-terminal FXXLF motif of the androgen receptor(AR)facilitates SRC/p160 co-activator binding.Transcriptional activity of AR was also enhanced by epidermal growth factor(EGF)-mediated phosphorylation and ubiquitination of MAGE-A11.In addition to modulating hormone signaling,MAGE-A11 may play a role in mediating survival of tumors in stressful conditions(such as when tumors outgrow their blood supply)by stabilizing HIF-1alpha levels,possibly by binding to and inhibiting PHD2,a prolyl 4-hydroxylase which modulates HIF-1alpha stability.And in further to explore the related mechanism of MAGEs and find a new target for the treatment of esophageal squamous cell carcinoma.Objective To investigate the expression of MAGE-A9 in esophageal squamous cell carcinoma(ESCC)and normal esophageal mucosa tissues,and explore its relation clinicopathological characteristics and prognosis.Methods Reverse transcription-polymerase chain reaction(RT-PCR),one-step quantitative-PCR(q-PCR)and immunohistochemistey(IHC)analyses were performed to characterize the expression of MAGE-A9 in ESCC tissues(n=53)and normal esophageal mucosa tissues(n=30).Kaplan-Meier survival and Cox regression analyses were employed to evaluate the prognosis of 53 ESCC patients.Results he results of q PCR and IHC analysis showed that the expression of MAGE-A9 was significantly higher in ESCC than in normal tissues(p<0.05).Moreover,the expression level of MAGE-A9 protein in ESCC was significantly related to smoking(p=0.002),tumor sizes(p=0.016),lymph node metastasis(p= 0.004).Cox regression analysis revealed that MAGE-A9 expression level and lymph node metastasis were independent prognostic factors of ESCC(p=0.037,p=0.015,respectively).Conclusions The high expression of MAGE-A9 protein was detected in ESCC and most was in the cytoplasm.The 5-year survival rate of patients with MAGE-A9 positive expression was significantly lower than that with MAGE-A9 negative patients.The high expression of MAGE-A9 protein is an independent risk factor and can be used as a biomarker of poor prognosis.