Expression Of NEDD9 In Colorectal Cancer And Its Correlation With The Clinical Pathology And Prognostic Significance

Background:Colorectal cancer(CRC)is one of the most common gastrointestinal malignancies in the world.With the precipitous development of social and economic in China,Incidence and mortality rates of colorectal cancer also increased annually.The prognosis of patients with colorectal cancer has been improved with the development of diagnosis,operation,perioperative management,adjuvant chemotherapy and molecular targeted therapy.Nevertheless,the effect of comprehensive treatment of advanced patients is poor.As colorectal cancer is a complicated process which involves multiple signaling molecules.Therefore,new targets need to be developed to predict the survival and targeted therapy of patients with colorectal carcinoma.Neural precursor cell expressed,developmentally down-regulated 9(NEDD9 also known as HEF1 and Cas-L.)is Cas family protein.It has Multiple structural domains(SH2,SH3,SD,SSR,etc.)provide sites to directly bind to signaling molecules or as scaffold proteins.Nedd9 was first found in embryonic mouse brains and mediate the cell cycle,survival,migration/chemotaxis,apoptosis,differentiation and cell attachment.NEDD9 is not only activated by FAK and Src kinases by phosphorylation,but also maintains incessant activation of these kinases,involved in formation of focal adhesion.NEDD9 can also activate the AKT /PKB signaling pathway by binding to AKT inducing cell proliferation and migration.It is overexpression in gastric cancer,lung cancer,liver cancer,breast cancer and non-small cell lung cancer.And in most studies,the overexpression of NEDD9 indicates poor prognosis.Currently,there are few studies on colorectal cancer.PURPOSE:This study was designed to assess the value of diagnosis,prognosis and treatment by investigating the relationship between the expression level of NEDD9 with clinical indicators and pathological features in colorectal cancer.METHODS:A total of 56 consecutive patients with colorectal cancer who underwent surgery in China-Japan Union Hospital of Jilin University from January to July 2012 became the subjects in this retrospective study.And 30 normal colorectal pieces obtained from adjacent colorectal tissue.The histopathological diagnosis was evaluated by a reference pathologist.NEDD9 expression was detected immunohistochemically using monoclonal anti-RCAS1 antibody.In addition,4 colorectal cancer and 4 normal tissues specimens were randomly selected by Western blot.The correlation between overexpression of NEDD9 and clinicopathological features in colorectal cancer tissues was analyzed by chi-square test or Fisher's exact test.The effect of NEDD9 expression on survival rate of patients with colorectal cancer was analyzed by Kaplan-Meier method.The risk factors for prognosis of colorectal cancer were investigated by single factor and multifactor COX proportional risk model.A p value < 0.05 was considered significant.RESULTS:NEDD9 protein was positive in 56 colorectal cancer tissues,38 pieces were overexpressed(67.9%).NEDD9 was low or negative expressed in normal colorectal tissues of 30 patients,and only 3 cases showed high expression(10.0%).The high expression rate of NEDD9 was statistically significant in colorectal cancer tissues than adjacent colorectal tissues(c2= 26.214,P < 0.001).Immunoreactivity for RCAS1 was higher in stage III and IV disease(87.5%)than in stage I and II disease(47.1%).The lymph node metastasis(81.7%)were significantly higher than those without lymph node metastasis(44/0%),and the difference was statistically significant(P < 0.05).The expression level of NEDD9 was significantly higher in patients with cancer thrombosis(P < 0.05).Variables such as age,sex,BMI,pathological type and tumor size did not correlate with immunostaining for NEDD9(p > 0.05).Kaplan and Meier analysis showed 5-year survival rate of patients with NEDD9 overexpression(47.4%)was lower than patients with lower expression of NEDD9(77.8%),the Log Rank test showed that the difference in two groups of patients of curve has significant(c2= 4.172,P < 0.05).Single COX analysis indicated that the survival of patients with colorectal cancer is associated with the presence of lymph node metastasis(RR =2.910,P =0.016),expression level of NEDD9(RR = 1.186,P =0.005),pathological staging(RR = 3.413,P = 0.009).COX multivariate survival analysis: vascular tumor emboli(RR = 0.237,P < 0.05),expression level of NEDD9(RR = 1.181,P < 0.05),TNM stage(RR = 5.553,P < 0.05)were independent prognosis risk in patients with colorectal cancer.There was a similar results that NEDD9 expression in colorectal cancer(0.772±0.065)was higher than adjacent tissues(0.427±0.007)by Western blot.Conclusions:NEDD9 appears to be upregulated in colorectal cancer,and higher in patients with vascular tumor emboli,lymph node metastasis and high stages.Expression level of NEDD9,TNM stage and vascular tumor emboli are independent prognosis risk.NEDD9 expression is an independent prognostic factor for favourable prognosis in patients with colorectal cancer and is a potential therapeutic target.