Chang Ye Rim, Park Taesung, Park Sung Hyo, Kim Yong Kang, Lee Kyoung Bun, Kim Sun-Whe, Jang Jin-Young
Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Department of Surgery, Dankook University College of Medicine, Cheonan, Korea.
Oncotarget. 2017 Dec 7;9(1):306-320. doi: 10.18632/oncotarget.23012. eCollection 2018 Jan 2.
There is an urgent need to investigate the genetic changes that occur in intraductal papillary mucinous neoplasm (IPMN), which is a well-known precursor of pancreatic cancer. In this study, gene expression profiling was performed by removing unwanted variation to determine the differentially expressed genes (DEGs) associated with malignant progression of IPMN. Among the identified DEGs, zinc finger E-box binding homeobox 1 (ZEB1) and E-cadherin, a crucial regulator of epithelial-to-mesenchymal transition (EMT), was validated among identified DEGs. A total of 76 fresh-frozen tissues were used for gene expression profiling and formalin-fixed, paraffin-embedded blocks from 87 patients were obtained for immunohistochemical analysis. Loss of E-cadherin expression ( = 0.023, odd ratio [OR] = 4.923) and expression of ZEB1 in stromal cells (stromal ZEB1, < 0.001, OR = 26.800) were significantly correlated with degree of dysplasia. The hazard of death was significantly increased in patients with loss of E-cadherin expression (hazard ratio [HR] = 13.718, = 0.004), expression of epithelial ZEB1 (HR = 19.117, = 0.001), and stromal ZEB1 (HR = 6.373, = 0.043). Based on the results of this study, loss of E-cadherin and expression of stromal ZEB1 are associated with increased risk of malignant progression. Epithelial and stromal ZEB1, as well as E-cadherin may be strong predictors of survival in patients with IPMN. Our finding suggests that these EMT markers may be utilized as potential prognosticators and may be used to improve and personalize treatment of IPMN.
迫切需要研究导管内乳头状黏液性肿瘤（IPMN）中发生的基因变化，IPMN是一种众所周知的胰腺癌前体。在本研究中，通过去除不必要的变异进行基因表达谱分析，以确定与IPMN恶性进展相关的差异表达基因（DEG）。在鉴定出的DEG中，锌指E盒结合同源框1（ZEB1）和上皮-间质转化（EMT）的关键调节因子E-钙黏蛋白在鉴定出的DEG中得到验证。共使用76个新鲜冷冻组织进行基因表达谱分析，并获得87例患者的福尔马林固定、石蜡包埋块用于免疫组织化学分析。E-钙黏蛋白表达缺失（P = 0.023，比值比[OR] = 4.923）和基质细胞中ZEB1的表达（基质ZEB1，P < 0.001，OR = 26.800）与发育异常程度显著相关。E-钙黏蛋白表达缺失的患者死亡风险显著增加（风险比[HR] = 13.718，P = 0.004），上皮ZEB1表达（HR = 19.117，P = 0.001）和基质ZEB1表达（HR = 6.373，P = 0.043）。基于本研究结果,E-钙黏蛋白缺失和基质ZEBl表达与恶性进展风险增加有关。上皮和基质ZEB1以及E-钙黏蛋白可能是IPMN患者生存的有力预测指标。我们的发现表明，这些EMT标志物可作为潜在的预后指标，并可用于改善IPMN的治疗并使其个性化。
