Direct activation of emmprin and associated pathogenesis by an oncogenic herpesvirus.
Direct activation of emmprin and associated pathogenesis by an oncogenic herpesvirus.
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通过致癌疱疹病毒直接激活Emmprin和相关的发病机理。
DOI：
10.1158/0008-5472.can-09-4663
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发表时间：
2010-05-15
期刊：
影响因子：
11.2
通讯作者：
Parsons C
中科院分区：
文献类型：
--
作者：
Qin Z;Dai L;Slomiany MG;Toole BP;Parsons C
细胞外基质金属蛋白酶原是一种多功能糖蛋白，由肿瘤微环境中的癌细胞和基质细胞表达。通过肿瘤细胞内的直接作用和促进肿瘤-间质相互作用，emmprin诱导肿瘤细胞侵袭和区域血管生成。卡波西肉瘤相关疱疹病毒（KSHV）是免疫抑制背景下产生的癌症的常见病因，包括卡波西肉瘤（KS）和原发性渗出性淋巴瘤（PEL）。然而，emmprin的表达和功能是否受KSHV或其他致癌病毒在肿瘤微环境中的调节，以促进病毒性癌症发病机制仍然未知。成纤维细胞和内皮细胞支持潜伏性KSHV感染，并代表KS病变的细胞成分。因此，我们利用原代人成纤维细胞和内皮细胞来确定KSHV本身是否调节emmprin表达，以及KSHV-emmprin相互作用是否介导细胞侵袭。我们发现，KSHV促进成纤维细胞和内皮细胞的侵袭力从头感染后，通过上调emmprin，这种效果是由KSHV编码的潜伏相关核抗原（拉娜）介导的。我们进一步验证了这些发现，通过我们的观察，emmprin促进侵袭力，以及集落形成，由来自人类肿瘤的PEL细胞。总的来说，这些数据暗示KSHV激活emmprin作为癌症进展的重要机制，并支持靶向emmprin作为KSHV相关肿瘤的新治疗方法的潜在效用。
Emmprin is a multifunctional glycoprotein expressed by cancer cells and stromal cells in the tumor microenvironment. Through both direct effects within tumor cells and promotion of tumor-stroma interactions, emmprin induces tumor cell invasiveness and regional angiogenesis. The Kaposi’s sarcoma-associated herpesvirus (KSHV) is a common etiology of cancers arising in the setting of immune suppression, including Kaposi’s sarcoma (KS) and primary effusion lymphoma (PEL). However, whether emmprin expression and function are regulated by KSHV or other oncogenic viruses in the tumor microenvironment to promote viral cancer pathogenesis remains unknown. Fibroblasts and endothelial cells support latent KSHV infection and represent cellular components of KS lesions. Therefore, we utilized primary human fibroblasts and endothelial cells to determine whether KSHV itself regulates emmprin expression, and whether KSHV-emmprin interactions mediate cell invasiveness. We found that KSHV promotes fibroblast and endothelial cell invasiveness following de novo infection through the upregulation of emmprin, and that this effect is mediated by the KSHV-encoded latency-associated nuclear antigen (LANA). We further validated these findings through our observations that emmprin promotes invasiveness, as well as colony formation, by PEL cells derived from human tumors. Collectively, these data implicate KSHV activation of emmprin as an important mechanism for cancer progression and support the potential utility of targeting emmprin as a novel therapeutic approach for KSHV-associated tumors.