Parameters used for the analysis were as follows
Parameters used for the analysis were as follows. supported by the univariate analysis (27.1 vs. 88.9 mo; = 0.0002) and multivariate model (hazard ratio = 7.09, 95%CI 1.78C28.16; = 0.005). Western Blot revealed strong induction of PD-L2 expression by interferon- (IFN) in CRC cells, and the mRNA levels of both genes were significantly correlated in CRC tissue samples. Suppression of glycosylation with tunicamycin Lavendustin A caused a shift in molecular weight and significant decrease in the expression of PD-L2 protein. In conclusion, PD-L2 overexpression in CRC cells, under the regulation by IFN and glycosylation, associates with poor survival of patients with colorectal cancer. These findings spotlight PD-L2 as a promising therapeutic target in CRC and suggest potential routes to control PD-L2 expression in CRC cells. = 0.001), but not with its positivity in inflammatory cells. Association between PD-L2 expression and clinicopathological features of CRC The CRC patients were stratified according to PD-L2 expression patterns (moderate-strong vs. negative-weak in tumor cells; poor vs. strong membrane expression patter; poor vs. strong expression in inflammatory cells) and were compared for different pathological features (Table?1). PD-L2 positive tumors displayed slight increase with the mucinous histological type (14.6% vs. 7.2%, = 0.043), although tubular and papillary histological types were not significantly lower in this subset (45.8% vs. 48.3%; 39.5% vs. 44.3%, respectively). Moreover, strong membranous expression pattern of PD-L2 associated with infiltrating ulcerative pathological type (= 0.030) and advanced tumor stage (T4 stage, = 0.011). The positivity of PD-L2 in inflammatory cells associated with mucinous histological type (0.044) and elevated pathological type (= 0.003). However, none of these PD-L2 expression patterns displayed significant association with lymph node infiltration or metastasis (Table?1). Table 1. PD-L2 expression in relation to clinicopathologic characteristics of colorectal adenocarcinomas. 0.05). PD-L2 overexpression independently associates with worse overall survival in CRC To clarify the association between PD-L2 expression and the overall survival of CRC patients, we first applied the univariate Kaplan Meier (log rank) model to compare patient survival after surgery (Fig.?3A). As a result, patients expressing higher PD-L2 in CRC tumor cells exhibited significantly shorter overall Rabbit polyclonal to PHC2 survival than those with lower PD-L2 expression (mean survival time 46.3 vs. 69.1 mo; = 0.0004). Interestingly, in both earlier CRC (AJCC stage ICII) and advanced CRC (stage IIICIV), higher PD-L2 expression associated with worse overall survival (= 0.012, and = 0.002, Fig.?3B and ?andC).C). Furthermore, we examined the prognostic effect of PD-L2 expression by multivariate COX regression model that included AJCC stage, gender, age, tumor grade (differentiation), and PD-L2 expression patters (expression in tumor cells, membranous localization, and immune cell positivity). As a result, higher PD-L2 expression in tumor cells (hazard ratio = 2.778, 95% confidence interval [CI] = 1.668C4.627; 0.0001) Lavendustin A and AJCC stage (hazard ratio = 2.901, 95% CI 1.874C4.490; 0.0001) Lavendustin A were the only factors that remained in the forward conditional model, suggesting their independent prognostic effects (Fig.?3D and ?andE).E). However, membranous localization of PD-L2 and inflammatory cell positivity did not show significant association with OS in CRC in both multivariate (Fig.?3D) and univariate (Fig.?S1A and B) models. Open in a separate window Physique 3. Validation of the association between worse overall survival and PD-L2 overexpression in tumor cells. (A) KaplanCMeier (log rank) analysis showing the survival curves of patients stratified by PD-L2 expression (value shown). (B) and (C) The multivariate COX regression model for the overall survival of CRC patients. The hazard ratios and 95% confidence interval (CI) of different factors in the COX regression model are shown in (B), with results of forward stepwise model marked in red. The detailed parameters in the model are shown in (C). To test Lavendustin A prognostic effect of PD-L2 in an impartial data set, we obtained the PD-L2 mRNA expression data (measured by microarray) in CRCs from a published study with prognostic data.22 When CRC patients were stratified according to PD-L2 expression, PD-L2 overexpression significantly associated with worse overall survival (mean survival time 27.1 vs. 88.9 mo; = 0.0002, Fig.?4A). In the multivariate COX regression model that included PD-L2 expression, age, gender, AJCC, and tumor grade (differentiation), only PD-L2 was remained in the forward conditional model (hazard ratio = 7.09, 95% CI 1.78C28.16; = 0.005), suggesting its independent and strong prognostic effect for overall survival in CRC (Fig.?4B and ?andCC). Open in a separate window Physique 4. Association between worse disease-free survival (DFS) and overexpression of PD-L2 in tumor cells. (A) Univariate analysis of DFS in patients stratified according to the PD-L2 expression level. The value is.