不良预后指标LOX-1,诱导胰腺癌上皮间质转化转移

【作者】 张洁；

【机构】 复旦大学卫生部糖重点实验室；

【摘要】 胰腺癌是消化系统常见肿瘤之一,恶性程度高,侵袭能力强。手术是目前胰腺癌治疗的主要手段。但由于缺乏早期症状,确诊时,80%以上的患者已经失去根治性切除的机会,故胰腺癌患者预后极差,且五年生存率仅8%左右。LOX-1是由内皮细胞表达的氧化型低密度脂蛋白特异性受体(OxLDL),属Ⅱ型跨膜蛋白,C型选择素家族。正常生理条件下,LOX-1表达量很低,但在一些炎症因子,氧化应激刺激下,LOX-1的表达会显著上升,最终可能导致内皮细胞的紊乱。而胰腺瘤体血管或淋巴管中,内皮细胞的功能紊乱也是胰腺癌患者病情恶化的因素之一。已有多项研究表明,LOX-1在晚期前列腺癌、结肠直肠癌、鳞状非小细胞肺癌等多种肿瘤中发挥作用,而本项研究第一次着眼于LOX-1在胰腺癌中的相关生理调控。首先,我们收集了98名患者的病理组织样本,制作病理切片,利用免疫组织化学(IHC)的方法观测到,LOX-1蛋白在癌组织中的表达要明显高于正常组织;临床病理多因素分析(Cox regression)发现,LOX-1作为胰腺癌患者不良预后的指标之一,与胰腺癌淋巴结转移(lymph node metastasis),病例分级有显著相关性,并可以提高当前针对肿瘤患者病理分级(TNM分级法)的诊断准确度。由此,我们从细胞的角度深入研究,LOX-1与胰腺癌转移的相互关系,发现,LOX-1可明显促进胰腺癌细胞的侵袭迁移能力,而这样的促转移能力可能是通过促进EMT,即上皮间充质的转化而实现,而不论是从蛋白水平,还是数据库RNA的水平,都发现了LOX-1与EMT相关标志物(E-cadherin、β-catenin、vimentin和slug)的显著相关性。由此,我们首次发现了LOX-1对于胰腺癌转移能力的调控能力。更多还原

【Abstract】 Purpose Pancreatic cancer(PC) is an aggressive tumor with rapid progression. LOX-1 as a type Ⅱ trans-membrane glycoprotein expressed in endothelial cells involves in several cancer developments. However, the expressional profiles and functional consequences of LOX-1 in PC remain unclear. The present study was aimed to investigate the prognostic value of LOX-1 in PC patients and its function in PC metastasis.Methods LOX-1 expression was assessed by immunohistochemistory(IHC) on the tissue microarray from 98 patients with PC. The Kaplan-Meier method was used to compare survival curve. Cox regression was performed to explore the independent prognostic risks of overall survival(OS). The Harrel’s concordance index was applied to calculate the predictive accuracy of established models. The effect of LOX-1 on the migration and invasion of PC cells was tested by Transwell assay.Results We found that LOX-1 protein was highly expressed in tumor tissues and related to lymph node metastasis, TNM stage as well as poorer OS. Also, LOX-1 expression could be regarded as independent prognostic factors for PC patients. Importantly, the prognostic model by using C-index was improved remarkably when LOX-1 was added. In vitro assay also revealed that LOX-1 upregulation could promote cell migration, invasion as well as epithelial-mesenchymal transition(EMT) of PC cells.Conclusions LOX-1 is upregulated in PC tissues and predicts high lymph node metastasis,late TNM stage, as well as poor prognosis of PC patients, and in vitro assay also revealed that LOX-1 has a positive role in PC metastasis.更多还原