Different Expression Of Asef2 In Right And Left Colon Cancer And Its Relationship With Clinicopathologic Characteristics And Prognosis

Background and Purpose Asef2 is a newly found guanine-nucleotide exchange factor recent years, which can be enhanced by adenomatous polyposis coli (APC) and specific for Racl and Cdc42 and involved in cell skeleton construction. Asef2 is reported to regulate cell morphology, adhesion and migration and is associated with tumour angiogenesis.There were only few research about Asef2 before, and all about it were limited to experiment in cells or animal model. At present no study is reported about the expression of Asef2 in human colon tissue and its relationship with clinicopathologic characteristics and prognosis is still unknown. In the meanwhile, as the progression in the research of biological behaviour in colon cancer, a few oncogenes、tumor suppressor genes and genetic phenotypes have been found differentially expressed in right- and left-sided colon cancer, and one molecular marker may have different prognostic significance in right- and left-sided colon cancer. Therefore someone has doubted that one colon lumen but maybe two organs and colon cancer should be regarded as two different entities.For the first part of the present study, we aimed to explore the expression of Asef2 in right-and left-sided colon cancer and its relationship with clinicopathologic characteristics and prognosis. For the second part, our purpose is to clarify the differences of epidemiological, clinicopathologic and survival parameters between right- and left-sided colon cancer.Materials and Methods For the first part, the expression of Asef2 was detected in paired normal and tumor tissues from 38 patients with colon cancer by IHC, western blot and RT-PCR. GEO database was used to study the expression difference in normal and tumor tissues by the high-throughput microarray technology to validate our results.We then detect the expression of Asef2 in 143 paraffin sections by IHC and explore its expression of Asef2 in right- and left- sided colon cancer and its relationship with clinicopathologic characteristics and prognosis, and then use GEO database to validate our results. For the second part. We retrospectively analyzed the medical records of 1088 consecutive colon cancer patients who received surgery at our hospital. Right- and left-sided colon cancers were compared regarding the clinical and histological parameters.The survival analysis was performed by the Kaplan-Meier method, and the log-rank test was used to determine the statistical significance of differences. Cox proportional hazards regression models were used for the multivariate survival analyses. The recurrence pattern of patients with Ⅰ-Ⅲ disease after surgery was compared between right- and left- sided colon cancer.Results We identified a higher expression of Asef2 protein (by western blot 84.2%,32/38; by IHC 72.9%,132/181) in colon cancer tissue. Typically, we identified increased Asef2 mRNA levels (71.4%%,15/21) in colon cancer compared to its paired normal epithelium.Nineteen cases of colon cancer tissues showed an increased level of Asef2 mRNA(79.2%,19/24) by gene chip in GSE 10950. There was a strong correlation of Asef2-positive expression with lymph node involvement (χ2=8.504, P=0.004).The proportion of AsefZ-positive expression was higher in the left-side colon cancer than in the right-sided colon cancer (χ2=5.065, P=0.024).The results were confirmed in GSE40967, which found a significant correlation of increased Asef2 mRNA expression with lymph node involvement and left-side colon cancer. In right-sided colon cancer, patients with Asef2-positive expression tumors had significantly reduced overall survival and progression free survival compared to those with Asef2-negative tumors, but in left colon cancer this difference could not be seen.Futhermore, our retrospective study showed that right-and left-sided colon cancers are significantly different regarding epidemiological, clinical, and histological parameters.Firstly, patients with right-sided colon cancer were significantly older, higher proportin of women, and predominantly more advanced disease.Secondly,a higher percentage of poorly differentiated adenocarcinoma(25.2%vs13.2%), mucinous adenocarcinoma (33.5%vs17.3%) and vascular invasion (9.9%vs3.9%) were found in right-sided colon cancer, all theses differences were significant(P=0.000).Thirdly, the survial was different, The five-years overall survival of right-and left-sided colon cancer was Ⅰ/Ⅱ stage,91.4% vs 88.6%(P =0.819); Ⅲ stage,66.1% vs 75.4%(P=0.010); and Ⅳ stage,27.8% vs 38.5%(P=0.020) respectively. COX multivariate analysis showed that the site of colon cancer are independent prognostic factors (OR=1.426,95%CI:1.100-1.848).Lastly, the recurrence pattern was different, anastomotic recurrence was more frequently found in the left-sided colon cancer,while peritoneal metastasis was more frequently found in the right-sided colon cancer.Conclusions The expression of Asef2 was significantly increased in cancer and lymph node involvement tumor.There was a significantly different Asef2 expression in the right- and left-sided colon cancer.Asef2 might be regarded as molecular markers for recurrence and survival in right-sided colon cancer but not in left-sided colon cancer. Asef2 may play a different role in the pathogenesis of colon cancer in different subsites.The pathogenesis of right- and left-sided colon cancer should be different, and epidemiological, clinicopathologic parameters,survival,and recurrence pattern were all significantly different between right- and left-sided colon cancer. In the field of colon cancer research, especially in advanced disease, carcinomas of the right and left colon should be considered as different tumor entities.