Xiuming Ding,1 Xiuqin Wang,2 Shifen Lu,3 Xuemei Gao,4 Shumei Ju4 1Department of Intervention, Linyi Central Hospital, Linyi, People’s Republic of China; 2Department of Dermatology, The Third People’s Hospital of Linyi, Linyi, People’s Republic of China; 3Department of Gynaecology and Obstetrics, The Third People’s Hospital of Linyi, Linyi, People’s Republic of China; 4Department of Paediatrics, Linyi Central Hospital, Linyi, People’s Republic of ChinaCorrespondence: Shumei JuDepartment of Paediatrics, Linyi Central Hospital, No.17, Health Road, Yishui County, Linyi City, Shandong Province 276400, People’s Republic of ChinaEmail Jushumeimdu@126.comBackground: Colorectal cancer is the third most common malignancy worldwide and is one of the leading causes of cancer-related mortality. P120-catenin protein has been well known to exert anticancer effects in several malignant diseases. The aim of our study was to investigate the phosphorylation of p120-catenin in colon adenocarcinoma (CAC) and its association with prognosis, and its role in tumor progression.Methods: Immunohistochemical (IHC) staining was used to explore the existence of p120-catenin and its phosphorylation on tyrosine 228 (pY228-p120-catenin) in CAC samples. Overexpression and knockdown were achieved by transient transfection into SW480 cells using Lipofectamine 3000. CCK-8 and Matrigel-transwell assays were conducted to evaluate proliferation and invasion capacities, respectively. RT-qPCR and Western blotting were performed to analyze downstream signaling pathways. Chi-square test was used to analyze correlations between p120-catenin and clinicopathological characteristics. Univariate and multivariate analyses were used to identify independent prognostic factors.Results: Lower p120-catenin and pY228-p120-catenin levels were identified in CAC tissues and were both correlated with advanced tumor stage. Additionally, lower pY228-p120-catenin indicated poorer prognosis of CAC patients although p120-catenin showed little significance. Overexpression of p120-catenin suppressed SW480 cell proliferation and invasion via stabilizing E-cadherin and inhibiting RhoA activation. Phosphorylation of Y228 on p120-catenin by Src protein enhanced the anticancer effects of p120-catenin.Conclusion: P120-catenin and its phosphorylation on site Y228 play anticancer effects in colon adenocarcinoma via multiple signaling pathways. Hypophosphorylation of Y228 on p120-catenin in tumor tissues indicates poor clinical outcomes of colon adenocarcinoma patients.Keywords: colon adenocarcinoma, p120-catenin, phosphorylation, prognosis, RhoA