Activation of sterol regulatory element-binding protein 1 (SREBP1)-mediated lipogenesis by the Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) promotes cell proliferation and progression of nasopharyngeal carcinoma.
Activation of sterol regulatory element-binding protein 1 (SREBP1)-mediated lipogenesis by the Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) promotes cell proliferation and progression of nasopharyngeal carcinoma.
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DOI：
10.1002/path.5130
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Lo KW
中科院分区：
文献类型：
--
作者：
Lo AK;Lung RW;Dawson CW;Young LS;Ko CW;Yeung WW;Kang W;To KF;Lo KW
鼻咽癌（NPC）与eb病毒（EBV）感染密切相关。EBV编码的潜伏膜蛋白1 （LMP1）通常在鼻咽癌中表达，参与多种信号通路，促进细胞生长、转化和代谢重编程。在这里，我们报道了LMP1在促进新生脂肪生成方面的新功能。LMP1增加了甾醇调节元件结合蛋白1 （SREBP1）的表达、成熟和激活，SREBP1是脂肪生成的主要调节因子，它的下游目标脂肪酸合成酶（FASN）。LMP1还能诱导脂质合成和脂滴形成。相比之下，EBV感染的上皮细胞中LMP1的小干扰RNA （siRNA）敲低会降低SREBP1的激活和脂质生物合成。此外，通过使用mTOR抑制剂或sirna抑制哺乳动物雷帕霉素靶蛋白（mTOR）途径，可显著降低LMP1介导的SREBP1活性和脂肪生成，这表明LMP1激活mTOR途径是SREBP1介导的脂肪生成所必需的。在原发性鼻咽癌肿瘤中，FASN过表达是常见的，其高表达水平与LMP1表达显著相关。此外，FASN表达升高与NPC患者的侵袭性疾病和较差的生存率相关。木犀草素和脂肪抑制素是两种脂肪生成抑制剂，可抑制鼻咽上皮细胞的脂肪生成和增殖，其作用在表达LMP1的细胞中更为深刻。木犀草素和脂肪抑制素在体外和体内均显著抑制鼻咽癌肿瘤的生长。我们的研究结果表明，LMP1激活SREBP1介导的脂肪生成促进肿瘤细胞生长，并参与EBV驱动的鼻咽癌发病机制。我们的研究结果也揭示了利用脂肪生成抑制剂治疗局部晚期或转移性鼻咽癌的治疗潜力。©2018作者。由John Wiley & Sons Ltd代表大不列颠和爱尔兰病理学会出版的病理学杂志。
Nasopharyngeal carcinoma (NPC) is closely associated with Epstein–Barr virus (EBV) infection. The EBV‐encoded latent membrane protein 1 (LMP1), which is commonly expressed in NPC, engages multiple signaling pathways that promote cell growth, transformation, and metabolic reprogramming. Here, we report a novel function of LMP1 in promoting de novo lipogenesis. LMP1 increases the expression, maturation and activation of sterol regulatory element‐binding protein 1 (SREBP1), a master regulator of lipogenesis, and its downstream target fatty acid synthase (FASN). LMP1 also induces de novo lipid synthesis and lipid droplet formation. In contrast, small interfering RNA (siRNA) knockdown of LMP1 in EBV‐infected epithelial cells diminished SREBP1 activation and lipid biosynthesis. Furthermore, inhibition of the mammalian target of rapamycin (mTOR) pathway, through the use of either mTOR inhibitors or siRNAs, significantly reduced LMP1‐mediated SREBP1 activity and lipogenesis, indicating that LMP1 activation of the mTOR pathway is required for SREBP1‐mediated lipogenesis. In primary NPC tumors, FASN overexpression is common, with high levels correlating significantly with LMP1 expression. Moreover, elevated FASN expression was associated with aggressive disease and poor survival in NPC patients. Luteolin and fatostatin, two inhibitors of lipogenesis, suppressed lipogenesis and proliferation of nasopharyngeal epithelial cells, effects that were more profound in cells expressing LMP1. Luteolin and fatostatin also dramatically inhibited NPC tumor growth in vitro and in vivo. Our findings demonstrate that LMP1 activation of SREBP1‐mediated lipogenesis promotes tumor cell growth and is involved in EBV‐driven NPC pathogenesis. Our results also reveal the therapeutic potential of utilizing lipogenesis inhibitors in the treatment of locally advanced or metastatic NPC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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