DPEP1 Inhibits Tumor Cell Invasiveness, Enhances Chemosensitivity and Predicts Clinical Outcome in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. To identify biologically relevant genes with prognostic and therapeutic significance in PDAC, we first performed the microarray gene-expression profiling in 45 matching pairs of tumor and adjacent non-tumor tissues from resected PDAC cases. We identified 36 genes that were associated with patient outcome and also differentially expressed in tumors as compared with adjacent non-tumor tissues in microarray analysis. Further evaluation in an independent validation cohort (N = 27) confirmed that DPEP1 (dipeptidase 1) expression was decreased (T: N ratio ∼0.1, PP = 0.004). Lower expression of DPEP1 in tumors was associated with poor survival (Kaplan Meier log rank) in both test cohort (P = 0.035) and validation cohort (P = 0.016). DPEP1 expression was independently associated with cancer-specific mortality when adjusted for tumor stage and resection margin status in both univariate (hazard ratio = 0.43, 95%CI = 0.24–0.76, P = 0.004) and multivariate analyses (hazard ratio = 0.51, 95%CI = 0.27–0.94, P = 0.032). We further demonstrated that overexpression of DPEP1 suppressed tumor cells invasiveness and increased sensitivity to chemotherapeutic agent Gemcitabine. Our data also showed that growth factor EGF treatment decreased DPEP1 expression and MEK1/2 inhibitor AZD6244 increased DPEP1 expression in vitro, indicating a potential mechanism for DPEP1 gene regulation. Therefore, we provide evidence that DPEP1 plays a role in pancreatic cancer aggressiveness and predicts outcome in patients with resected PDAC. In view of these findings, we propose that DPEP1 may be a candidate target in PDAC for designing improved treatments.

胰腺导管腺癌（Pancreatic ductal adenocarcinoma, PDAC）是全球致死率最高的恶性肿瘤之一。为筛选出胰腺导管腺癌中兼具预后与治疗学意义的生物学相关基因，本研究首先对45例手术切除的PDAC患者的配对肿瘤组织与邻近非肿瘤组织开展基因表达微阵列（microarray）分析。经微阵列检测，我们筛选出36个与患者预后相关，且在肿瘤组织与邻近非肿瘤组织中存在差异表达的基因。在独立验证队列（样本量N=27）中进一步验证显示，二肽酶1（dipeptidase 1, DPEP1）的表达显著下调（肿瘤与非肿瘤组织表达比值约为0.1，PP=0.004）。肿瘤组织中DPEP1低表达与患者不良生存显著相关：在发现队列（P=0.035）与验证队列（P=0.016）中，经Kaplan-Meier对数秩检验（Kaplan Meier log rank）均得到验证。在校正肿瘤分期与切缘状态后，单因素分析（风险比=0.43，95%置信区间=0.24–0.76，P=0.004）与多因素分析（风险比=0.51，95%置信区间=0.27–0.94，P=0.032）均证实，DPEP1表达与肿瘤特异性死亡率独立相关。本研究进一步证实，过表达DPEP1可抑制肿瘤细胞侵袭能力，并提高肿瘤细胞对化疗药物吉西他滨（Gemcitabine）的敏感性。体外实验数据显示，表皮生长因子（epidermal growth factor, EGF）处理可下调DPEP1表达，而MEK1/2抑制剂AZD6244可上调其表达，这提示了DPEP1基因调控的潜在分子机制。综上，本研究证实DPEP1参与胰腺癌细胞侵袭表型的调控，并可预测手术切除PDAC患者的预后。基于上述研究结果，我们提出DPEP1可作为PDAC的潜在治疗靶点，为优化临床治疗方案提供新方向。