EB病毒之潛伏膜蛋白1上調endocan表現 及其在鼻咽癌之臨床意義

Abstract

Endocan (或稱Esm-1) 已被證實具有促進腫瘤生長的活性，它的表現也和許多種癌症的預後有關。潛伏膜蛋白1 (latent membrane protein 1, LMP1) 是EB病毒 (Epstein-Barr virus, EBV) 所表現的一種致癌蛋白，它在與EB病毒極相關的鼻咽癌致病機制中扮演非常重要的角色。 為了更進一步釐清潛伏膜蛋白1在鼻咽癌致病機制中所扮演的角色，我們使用cDNA微陣列 (cDNA microarray) 探討在人類上皮細胞中受潛伏膜蛋白1調控的基因。我們發現endocan是受潛伏膜蛋白1上調 (upregulation) 的主要細胞基因之一。Endocan基因受潛伏膜蛋白1上調的現象已在三種上皮細胞株中被證實，其中也包括一株鼻咽癌細胞株。我們發現此上調現象是透過潛伏膜蛋白1的C端活化區1和2 (carboxyl terminal activation region 1 and 2, CTAR 1 and 2) 以及NF-κB, MEK-ERK, JNK訊息傳導路徑所媒介。 為了研究endocan是否能夠在鼻咽癌組織中表現以及鼻咽癌組織中endocan的表現是否和潛伏膜蛋白1的表現有關，我們收集42例鼻咽癌組織並以組織免疫染色法進行觀察，結果顯示endocan在鼻咽癌組織中的表現率為52 % 並且endocan和潛伏膜蛋白1在鼻咽癌組織中的表現有顯著的相關 (p<0.0001)。除此之外，我們發現表現endocan的鼻咽癌病患存活期較未表現endocan的為短 (p=0.0104, log-rank test)。經由單變量與多變量統計分析，我們也初步發現endocan可能是鼻咽癌的預後因子。綜合以上所述，此研究不但發現了一個新的潛在鼻咽癌預後因子，同時也提供了一個瞭解鼻咽癌致病機制的新視野。

Endocan (or called Esm-1) has been shown to have tumorigenic activities and its expression is associated with poor prognosis in various cancers. Latent membrane protein 1 (LMP1) is an Epstein-Barr virus (EBV)-encoded oncoprotein and has been shown to play an important role in the pathogenesis of EBV-associated nasopharyngeal carcinoma (NPC). To further understand the role of LMP1 in the pathogenesis of NPC, microarray analysis of LMP1-regulated genes in epithelial cells was performed. We found that endocan was one of the major cellular genes upregulated by LMP1. This induction of endocan by LMP1 was confirmed in several epithelial cell lines including an NPC cell line. Upregulation of endocan by LMP1 was found to be mediated through the C-terminal activation region 1 and C-terminal activation region 2 (CTAR1 and CTAR2) domains of LMP1 and through the LMP1-activated NF-κB, MEK-ERK and JNK signaling pathways. To study whether endocan was expressed in NPC and whether endocan expression was associated with LMP1 expression in NPC, the expression of endocan and LMP1 in tumor tissues from 42 NPC patients was evaluated by immunohistochemistry. Expression of endocan was found in 52 % of NPC specimens. Significant correlation between LMP1 and endocan expression was observed (p<0.0001). Moreover, NPC patients with endocan expression were found to have a shorter survival than NPC patients without endocan expression (p=0.0104, log-rank test). Univariate and multivariate analyses revealed that endocan was a potential prognostic factor for NPC. Together, these studies not only identify a new molecular marker that may predict the survival of NPC patients but also provide a new insight to the pathogenesis of NPC.