HIF2α-Dependent Lipid Storage Promotes Endoplasmic Reticulum Homeostasis in Clear-Cell Renal Cell Carcinoma.
HIF2α-Dependent Lipid Storage Promotes Endoplasmic Reticulum Homeostasis in Clear-Cell Renal Cell Carcinoma.
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DOI：
10.1158/2159-8290.cd-14-1507
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发表时间：
2015-06
期刊：
影响因子：
28.2
通讯作者：
Simon MC
中科院分区：
文献类型：
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作者：
Qiu B;Ackerman D;Sanchez DJ;Li B;Ochocki JD;Grazioli A;Bobrovnikova-Marjon E;Diehl JA;Keith B;Simon MC
透明细胞肾细胞癌（ccRCC）的两个标志是组成性缺氧诱导因子（HIF）信号传导和丰富的细胞内脂滴（LD）。然而，脂质储存的调节及其在ccRCC中的作用尚不完全清楚。原发性ccRCC样本的转录谱显示，LD外壳蛋白基因PLIN 2的表达在肿瘤中升高，并与HIF-2α激活相关，但与HIF-1α激活无关。HIF-2α依赖性PLIN 2表达促进异种移植肿瘤中的脂质储存、增殖和活力。从机制上讲，脂质储存维持了内质网（ER）的完整性，这在功能上和物理上与LD相关。具体地，PLIN 2依赖性脂质储存抑制细胞毒性ER应激反应，否则所述细胞毒性ER应激反应是由ccRCC细胞特有的升高的蛋白质合成活性引起的。因此，除了促进ccRCC增殖和合成代谢外，HIF-2α还调节脂质储存以维持ER稳态，特别是在营养和氧气限制的条件下，从而促进肿瘤细胞存活。
Two hallmarks of clear cell renal cell carcinoma (ccRCC) are constitutive hypoxia inducible factor (HIF) signaling and abundant intracellular lipid droplets (LDs). However, regulation of lipid storage and its role in ccRCC are incompletely understood. Transcriptional profiling of primary ccRCC samples revealed that expression of the LD coat protein gene PLIN2 was elevated in tumors and correlated with HIF-2α, but not HIF-1α, activation. HIF-2α dependent PLIN2 expression promoted lipid storage, proliferation, and viability in xenograft tumors. Mechanistically, lipid storage maintained integrity of the endoplasmic reticulum (ER), which is functionally and physically associated with LDs. Specifically, PLIN2 dependent lipid storage suppressed cytotoxic ER stress responses that otherwise result from elevated protein synthetic activity characteristic of ccRCC cells. Thus, in addition to promoting ccRCC proliferation and anabolic metabolism, HIF-2α modulates lipid storage to sustain ER homeostasis, particularly under conditions of nutrient and oxygen limitation, thereby promoting tumor cell survival.