PPARγ is dispensable for clear cell renal cell carcinoma progression.
PPARγ is dispensable for clear cell renal cell carcinoma progression.
复制标题
DOI：
10.1016/j.molmet.2018.05.013
复制
发表时间：
2018-08
影响因子：
8.1
通讯作者：
Simon MC
中科院分区：
文献类型：
--
作者：
Sanchez DJ;Steger DJ;Skuli N;Bansal A;Simon MC
肾透明细胞癌(CcRCC)是肾癌的一种亚型，主要表现为强烈的脂质积聚，已有研究表明其在肿瘤进展中起着重要作用。我们假设，在肾细胞癌肿瘤和细胞系中都检测到的过氧化物酶体增殖物激活受体γ(PPARγ)促进了肾细胞癌中的脂质储存，并在这种情况下促进了肿瘤的发生。PPARγ在转录水平上调节脂肪细胞中与脂肪和葡萄糖代谢有关的一些基因，但其在肾癌中的作用尚未被描述。本研究的目的是阐明肾癌细胞内源性PPARγ的功能。利用染色质免疫沉淀和深度测序(ChIP-SEQ)，我们发现PPARγ及其异源二聚体RXR在整个基因组中大约1000个位置占据了典型的DR1PPAR结合基序，这些结合基序可以细分为脂肪共享的和ccRCC特异的位点。CRISPR-Cas9介导的功能丧失研究表明，PPARγ对于体外和体内肾细胞癌细胞的存活、增殖和迁移是必不可少的。此外，令人惊讶的是，PPARγ缺失对肾癌典型的“透明细胞”表型的强健脂肪堆积几乎没有影响。我们的结果表明，在晚期肾细胞癌中，PPARγ既没有肿瘤抑制作用，也没有致癌作用，因此针对PPARγ的单药治疗不太可能对这种疾病有效。肾细胞癌细胞中PPARγ独特的表达谱说明了细胞类型在决定PPARγ功能中的重要性。PPARγ在肾细胞癌患者标本和细胞系中的表达相对肾上皮细胞升高。肾细胞癌和脂肪细胞的PPAR、γ-RXR信号转运体是不同的。PPARγ对于体外和体内肾细胞癌细胞的存活、增殖和迁移都是必不可少的。肾细胞癌中脂质的储存和甘油三酯的合成不依赖于PPARγ。
Clear cell renal cell carcinoma (ccRCC) is a subtype of kidney cancer defined by robust lipid accumulation, which prior studies have indicated plays an important role in tumor progression. We hypothesized that the peroxisome proliferator-activated receptor gamma (PPARγ), detected in both ccRCC tumors and cell lines, promotes lipid storage in ccRCC and contributes to tumorigenesis in this setting. PPARγ transcriptionally regulates a number of genes involved in lipid and glucose metabolism in adipocytes, yet its role in ccRCC has not been described. The objective of this study was to elucidate endogenous PPARγ function in ccRCC cells. Using chromatin immunoprecipitation followed by deep sequencing (ChIP-seq), we found that PPARγ and its heterodimer RXR occupy the canonical DR1 PPAR binding motif at approximately 1000 locations throughout the genome that can be subdivided into adipose-shared and ccRCC-specific sites. CRISPR-Cas9 mediated, loss-of-function studies determined that PPARγ is dispensable for viability, proliferation, and migration of ccRCC cells in vitro and in vivo. Also, surprisingly, PPARγ deletion had little effect on the robust lipid accumulation that typifies the “clear cell” phenotype of kidney cancer. Our results suggest that PPARγ plays neither a tumor suppressive nor oncogenic role in advanced ccRCC, and thus single-agent therapeutics targeting PPARγ are unlikely to be effective for the treatment of this disease. The unique cistrome of PPARγ in ccRCC cells demonstrates the importance of cell type in determining the functions of PPARγ. PPARγ expression is elevated in ccRCC patient samples and cell lines relative to renal epithelium. The PPARγ-RXR cistrome is distinct between ccRCC and adipocytes. PPARγ is dispensable for viability, proliferation, and migration of ccRCC cells in vitro and in vivo. Lipid storage and triglyceride synthesis occur independently of PPARγ in ccRCC.
登录
查看更多内容
影响因子：
7.7
作者：
Halstead AM;Kapadia CD;Bolzenius J;Chu CE;Schriefer A;Wartman LD;Bowman GR;Arora VK
通讯作者：
Arora VK
影响因子：
3.7
作者：
Ivanov DP;Parker TL;Walker DA;Alexander C;Ashford MB;Gellert PR;Garnett MC
通讯作者：
Garnett MC
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
9.7
作者：
Fujita, Megumi;Yagami, Tatsurou;Okamura, Noboru
通讯作者：
Okamura, Noboru
DOI：
10.1073/pnas.1307237110
发表时间：
2013-05-28
影响因子：
11.1
作者：
Kamphorst, Jurre J.;Cross, Justin R.;Rabinowitz, Joshua D.
通讯作者：
Rabinowitz, Joshua D.