Expression Of GRP78、ATF4、VEGF And CD34in Laryngeal Squamous Cell Carcinoma And The Correlation With Clinical Pathology Of Neoplasms

Laryngeal squamous cell carcinomas is one of the common malignanttumors in otolaryngology head and neck surgery. Its clinical pathologiccharacters involve insidious onset, strong invasiveness, and liability torecurrence and metastasis with poor prognosis. Insensitive to radiotherapy andchemotherapy, therapeutic resistance and recurrence are pending problems inlaryngeal squamous cell carcinoma. It is critical to explore the mechanism andeffective detection method in order to select the best therapeutic strategy. Themorbidity of malignant tumors is increasing gradually in recent years.However, the molecular mechanisms for the development of malignant tumorshave not been well characterized, which are always the study hot spots inbio-medical domain. So, it is very important to know well the mechanismunderlying and development of laryngeal squamous cell carcinoma.One of the research highlights is the activation of intracellular signaltransduction cascades such as the UPR pathway. It is known to act as anactivation factors in most malignancies and plays a critical role in regulatingcellular growth, proliferation and differentiation. It may prevent tumor celldeath, stimulate the expression of angiogenic factors and induce theexpression of intracellular matrix degradation enzymes, thus resulting inenhanced metastatic potential. It is reported that one of UPR pathway, PERK（PKR-like ER kinase；PKR:double-stranded RNA-activated protein kinase）-ATF4(activating transcription factor4), is positively correlated with VEGF.Since ATF4is induced by tumor microenvironmental factors, and regulatesprocesses relevant to cancer progression, it might serve as a potentialtherapeutic target in cancer. Since ATF4protein has shown to be present ingreater levels in cancer compared to normal tissue, and is regulated by signals of the tumor microenvironment such as hypoxia/anoxia, oxidative stress, andER stress, it could potentially serve as a special target in cancer therapy. As atarget, ATF4is attractive because it is also potentially involved inangiogenesis and adaptation of cancer cells to hypoxia/anoxia, a major causein cancer progression.The pathogenesis of laryngeal squamous cell carcinoma is not fullyunderstood. However, the expression of ATF4in laryngeal squamous cellcarcinoma and its clinical significance has not been reported. Therefore, theaim of the present study is to investigate the expression of GRP78, ATF4,VEGF and CD34in laryngeal squamous cell carcinoma, the correlationbetween the expression of GRP78, ATF4, VEGF and CD34.Objective: To investigate the expression of GRP78, ATF4, VEGF andCD34protein in laryngeal squamous cell carcinoma and their relevance toclinical pathological behaviors，and to explore the correlation between ATF4and GRP78, VEGF and CD34in UPR pathway. Our findings may set up theexperimental foundation for research on the pathogenesis and provide a newidea for clinical therapy of laryngeal squamous cell carcinoma.Methods:36surgically resected laryngeal carcinoma specimens weretaken. All patients had received neither chemotherapy nor radiation therapybefore tumor resection.7cases of para-cancerous normal laryngeal tissueswere used.Immunohistochemical staining(S-P methods) for the paraffin sectionswere used to exam the expression of GRP78, ATF4, VEGF and CD34in36laryngeal squamous cell carcinoma tissues and7para-cancerous laryngealtissues. Using statistical analysis，we analysed the expression of GRP78, ATF4,VEGF and CD34with reference to clinical pathological factors of laryngealsquamous cell carcinoma.Results:1Comparison of expressions of GRP78, ATF4, VEGF and CD34inlaryngeal squamous cell carcinoma and para-cancerous laryngeal tissues werecarried out. The results demonstrated that all of the factors above showed higher expression in laryngeal carcinoma than in para-cancerous normallaryngeal tissues. The differences were statistically significant (all P<0.01).2The expression of GRP78, ATF4, VEGF and CD34was positivelyrelated to tumor grade, clinical stage, pathological differentiation and cervicallymph node metastasis (all P<0.05)，but was not statistically correlated withage, gender and primary site.(all P>0.05).3The expression of GRP78was positively correlated to the expression ofATF4and VEGF in laryngeal squamous cell carcinoma tissues (r<1). Theexpression of ATF4was positively correlated to the expression ofVEGF(r<1).The expression of VEGF was positively correlated to theexpression of ATF4and VEGF in laryngeal squamous cell carcinoma tissuesCD34(r<1; r<1).Conclusion:1cancer cell activated ERS and UPR，when it was absence of nutritivematerial in the development of laryngeal squamous cell carcinom.2Activation of GRP78and ATF4in laryngeal squamous cell carcinoma，so they express correlation with clinical pathological behaviors of laryngealsquamous cell carcinoma.3UPR could regulate VEGF by ATF4，which promotes tumor angiogen-esis. So ATF4is correlation with invasion and metastasis of the laryngealcarcinoma.