EB病毒再活化進入溶裂期與在台灣高盛行率的鼻咽癌具有高度關聯。我們過去的研究顯示EB病毒的溶裂期蛋白質Zta這個轉錄活化因子會調控許多細胞基因而影響免疫細胞。值得注意的是文獻指出鼻咽癌病患體內可偵測到抗EB病毒的Zta蛋白質抗體高度增加而且鼻咽癌中Zta的表現與癌症淋巴結轉移有關。因此，我們推測Zta可能會經由調控細胞基因而影響整個腫瘤微環境，進一步促進癌細胞更加惡性。經由抗體陣列及寡核苷酸微陣列分析，我們發現Zta會調控基質金屬胜肽酶-3 (MMP-3)的表現並釋放到細胞外，已知此分解蛋白質的酵素和腫瘤轉移有高度關聯。我們以qRT-PCR及ELISA確定Zta會誘發MMP-3的mRNA及蛋白質的表現。在被EB病毒感染的鼻咽癌細胞中，刺激病毒再活化時也同樣可以看到MMP-3的上升。另外我們也證明了Zta主要經由MMP-3啟動子上-222到-89之間的三個AP-1結合位來轉活化MMP-3表現，而且Zta的DNA結合能力對於促進MMP-3表現是必需的。此外，我們使用了MMP-3 siRNA證明了Zta所誘發的MMP-3會促進鼻咽癌細胞的移行能力。有趣的是，Zta也會誘發肝素結合表皮生長因子 (HB-EGF)，一種可經由MMP-3切割變成游離態的生長因子。我們猜測Zta誘發的MMP-3會切割並釋放出細胞表面的HB-EGF，再經由自泌/旁泌作用刺激生長相關訊息傳遞。和預期不同，Zta誘發HB-EGF的釋放並不需要MMP-3，Zta促進細胞ERK1/2磷酸化也與MMP-3無關。本研究暗示Zta在鼻咽癌細胞中誘發MMP-3產生，可能促進一個讓癌症惡化的微環境。

Epstein-Barr virus (EBV) reactivation into the lytic cycle is highly associated with nasopharyngeal carcinoma (NPC), an endemic epithelial cancer in Taiwan. Our previous studies have indicated that an EBV lytic transcriptional activator Zta can induce several cellular genes to affect immune cells. Notably, antibodies against Zta are highly increased in NPC patients and Zta expression in NPC tumors is associated with lymph node metastasis. Therefore, we hypothesize that Zta may promote aggression of NPC cells by regulating other cellular genes that modulate tumor microenvironment. Using antibody array and oligonucleotide microarray, we found that Zta upregulated expression of matrix metallopeptidase (MMP)-3, an important proteolytic enzyme involved in cancer metastasis. Quantitative RT-PCR and ELISA confirmed Zta-induced MMP-3 expression at both RNA and protein levels. Upregulation of MMP-3 was also observed in EBV-infected NPC cells undergoing viral reactivation. We also identified that Zta transactivated the MMP-3 promoter through three activator protein (AP)-1 sites within -222 to -89 of the promoter, and the DNA-binding domain of Zta was required for MMP-3 induction. In addition, we used MMP-3 siRNA to demonstrate that Zta-induced MMP-3 can promote migration of NPC cells. Interestingly, Zta also upregulated heparin-binding epidermal growth factor (HB-EGF), which can be cleaved and released by MMP-3. We wondered whether Zta-induced MMP-3 cleaved and released surface HB-EGF to promote autocrine/paracrine of NPC cells and to trigger growth signaling. Unexpectedly, MMP-3 was not essential for Zta-induced HB-EGF release and ERK1/2 phosphorylation. This study implies that the EBV lytic protein Zta regulates MMP-3 production in NPC cells to promote a microenvironment that favors cancer progression.

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