Authors' Affiliations: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai; and The First Teaching Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
Cancer Res. 2014 Apr 1;74(7):2026-37. doi: 10.1158/0008-5472.CAN-13-1467. Epub 2014 Feb 12.
Notch signaling has been implicated in the pathogenesis of Kaposi sarcoma. Kaposi sarcoma is an angioproliferative neoplasm that originates from Kaposi sarcoma-associated herpesvirus (KSHV) infection. Previously, we showed that the KSHV LANA protein can stabilize intracellular Notch in KSHV-infected tumor cells and promote cell proliferation. However, whether Notch signaling functions in pathologic angiogenesis of Kaposi sarcoma remains largely unknown. Hey1, an essential downstream effector of the Notch signaling pathway, has been demonstrated to play a fundamental role in vascular development. In the present study, we performed whole transcriptome, paired-end sequencing on three patient-matched clinical Kaposi sarcoma specimens and their corresponding adjacent stroma samples, with an average depth of 42 million reads per sample. Dll4, Hey1, and HeyL displayed significant upregulation in Kaposi sarcoma. Further verification based on immunohistochemistry analysis demonstrated that Hey1 was indeed highly expressed in Kaposi sarcoma lesions. Using the Matrigel plug assay, we showed that downregulation of Hey1 and γ-secretase inhibitor treatment caused dramatic reduction in the formation of new blood vessels in mice. Interestingly, LANA was responsible for the elevated level of Hey1 through inhibition of its degradation. Importantly, Hey1 stabilized by LANA promoted the neoplastic vasculature. Taken together, our data suggest that hijacking of the proangiogenic property of Hey1 by LANA is an important strategy utilized by KSHV to achieve pathologic angiogenesis and that Hey1 is a potential therapeutic target in Kaposi sarcoma.
Notch 信号通路被认为与卡波氏肉瘤的发病机制有关。卡波氏肉瘤是一种血管增生性肿瘤，起源于卡波氏肉瘤相关疱疹病毒（KSHV）感染。此前，我们表明 KSHV 的 LANA 蛋白可以稳定 KSHV 感染的肿瘤细胞内的 Notch，并促进细胞增殖。然而，Notch 信号通路是否在卡波氏肉瘤的病理性血管生成中起作用，在很大程度上仍不清楚。Hey1 是 Notch 信号通路的一个重要下游效应物，已被证明在血管发育中起着基本作用。在本研究中，我们对三个患者匹配的临床卡波氏肉瘤标本及其相应的相邻基质样本进行了全转录组、配对末端测序，每个样本的平均深度为 4200 万reads。Dll4、Hey1 和 HeyL 在卡波氏肉瘤中均显示出显著上调。基于免疫组织化学分析的进一步验证表明，Hey1 在卡波氏肉瘤病变中确实高度表达。通过 Matrigel plugs 测定，我们表明 Hey1 的下调和γ-分泌酶抑制剂处理导致新血管形成在小鼠中显著减少。有趣的是，LANA 通过抑制其降解来负责 Hey1 水平的升高。重要的是，由 LANA 稳定的 Hey1 促进了肿瘤血管的形成。总之，我们的数据表明，LANA 劫持 Hey1 的促血管生成特性是 KSHV 实现病理性血管生成的一个重要策略，并且 Hey1 是卡波氏肉瘤的一个潜在治疗靶点。
