Epstein-Barr virus (EBV) 是屬於γ-皰疹病毒亞科屬的淋巴隱病毒屬，為普遍存在於人體內的病毒。EBV與許多人類已知的癌症相關，像是布凱特氏淋巴瘤 (Burkitt’s lymphoma)、何杰金淋巴瘤(Hodgkin’s lymphoma)和鼻咽癌 (Nasopharyngeal carcinoma)。EBV在鼻咽癌細胞中以type II latency的狀態存在，並且只會表現出部分的病毒蛋白質，包括EBNA1、LMP1、LMP2A、LMP2B四種蛋白。其中又以latent membrane protein 1 (LMP1)為EBV所產生的重要致癌蛋白，具有使鼻咽細胞轉型或是增加鼻咽癌細胞侵犯的能力。Integrins為不同α和β小單位組成的異型合子，用以媒介細胞與細胞之間及細胞與細胞基質之間的連結，進而提供細胞附著與移動。除此之外，integrin媒介的訊息傳遞也參與細胞的增生、分化、移動。Integrin αvβ6先前已被證明其在許多上皮相關的癌症侵犯能力中佔有重要的角色。在先前的研究中，我們發現在頭頸部腫瘤中，除了已知會表現integrin αvβ6的口腔癌外，αvβ6 integrin 也被頻繁地表現在鼻咽癌腫瘤細胞上。並且也發現EBV-LMP1可能經由NF-κB訊息傳遞途徑，使β6 integrin的表現量增加。在本研究中，我們首先證實了會在鼻咽癌腫瘤細胞表現的EBV潛伏基因中，LMP1使β6 integrin mRNA表現量上升最為顯著。並且也重新驗證了LMP1確實會經由NF-κB pathway來調控β6 integrin的表現。再者，我們也發現LMP1表現量增加，會使鼻咽癌細胞的侵犯及轉移能力上升，而此一作用可被αvβ6 integrin的阻斷抗體所抑制，顯示LMP1正向調控integrin β6的表現，可能會增強鼻咽癌細胞的侵犯及轉移能力。為了進一步了解LMP1調控integrin β6的機制，我們clone出了β6 integrin的promoter (β6p)，利用promoter assay來LMP1是否會直接透過NF-κB轉錄因子，直接調控integrin β6 promoter的活性。實驗結果顯示，LMP1可能不會直接透過NF-κB轉錄因子來調控β6 integrin promoter的活性。因此，LMP1對鼻咽癌細胞β6 integrin的調控機轉仍有待進一步探討。

Epstein Barr virus (EBV) belongs to the gamma-herpesviridae subfamily of the lymphocryptovirus genus. It is implicated in the pathogenesis of various kinds of human cancers, such as Burkitt’s lymphoma, Hodgkin’s lymphoma and nasopharyngeal carcinoma (NPC). EBV resides in NPC cells in a status called type II latency, with only a few latent genes being expressed, including EBNA1, LMP1, LMP2A and LMP2B. LMP1 is known to be the most important oncoprotein in EBV-related malignancies. Integrins are heterodimers composed by different α and β subunits. They mediate cell-to-cell or cell-to-cell extracellular matrix (ECM) contact to provide adhesion and movement. Integrin-mediated signaling pathways are also involved in cellular proliferation, differentiation and migration. Integrin αvβ6 has been demonstrated to play an important role in the invasion ability of various epithelial cancers. We have previously demonstrated that, in addition to oral cancers, αvβ6 integrin is also expressed in NPC specimens frequently. In addition, we found that EBV-LMP1 oncoprotein may upregulate β6 integrin through activation of NF-κB pathway. In this study, we first demonstrated that, among the EBV latent genes expressed in NPC, only LMP1 can significantly up-regulate cellular β6 integrin. We also reconfirmed that LMP1 up-regulates integrin β6 through activation of NF-κB pathway. Using transwell assays, we demonstrated that expression of LMP1 significantly increases migration and invasion abilities of NPC. This LMP1-mediated enhancement of migration and invasion abilities can be abolished by usingαvβ6-blocking antibody, suggesting that LMP1-mediated upregulation of integrin β6 may contribute to migration and invasion abilities of NPC cells. To further explore the mechanism of LMP1-mediated upregulation of integrin β6, we cloned β6 integrin promoter (β6p) into a reporter construct containing luciferase gene and performed promoter assay. Our results show that, in NPC cells, expression of LMP1 did not significantly activate β6 integrin promoter. The mechanism of how LMP1 upregulates integrin β6 through NF-κB activation needs further investigation.

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