Pathway signature and cellular differentiation in clear cell renal cell carcinoma.
Pathway signature and cellular differentiation in clear cell renal cell carcinoma.
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DOI：
10.1371/journal.pone.0010696
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发表时间：
2010-05-18
期刊：
影响因子：
3.7
通讯作者：
Copland JA
中科院分区：
文献类型：
--
作者：
Tun HW;Marlow LA;von Roemeling CA;Cooper SJ;Kreinest P;Wu K;Luxon BA;Sinha M;Anastasiadis PZ;Copland JA
肾透明细胞癌(CcRCC)是最常见的肾癌。本研究的目的是明确肾小管细胞癌的生物学途径特征和细胞分化程序。我们使用Affymetrix HG-U133a和HG-U133b GeneChips结合全面的生物信息学分析，包括通路分析，对早期肾细胞癌和患者匹配的正常肾组织进行了基因表达谱分析。在两个独立的样本集上进行了实时荧光聚合酶链式反应和免疫组织化学的验证。在分化培养液中对ccRCC细胞系及其匹配的正常肾上皮细胞进行细胞分化实验，以确定其间充质分化潜能。我们发现了一个独特的途径信号，具有三个主要的生物学变化--正常肾功能丧失、代谢下调和免疫激活--这揭示了一个成脂基因表达信号与ccRCC标志性的富含脂质的透明细胞形态有关。在分化培养液中培养正常肾和肾小管上皮细胞发现，只有肾小管上皮细胞被诱导成脂，而且令人惊讶的是，成骨分化。CcRCC的基因表达特征与上皮间充质转化(EMT)一致。我们发现对正常肾脏发育至关重要的四个发育转录因子(GATA3、Tfcp2L1、TFAP2B、DMRT2)显著下调。肾小管上皮细胞癌在体外缺乏上皮分化、间充质/成脂转分化和多潜能间充质干细胞样分化能力。我们认为，发育中转录因子的下调可能参与了肾细胞癌的异常分化。我们提出了一个模型，在这个模型中，正常的肾上皮细胞经历了去分化、EMT和成脂转分化，导致了ccRCC。由于ccRCC细胞在成脂培养液中生长恢复了ccRCC特有的表型，我们已经鉴定出一种新的体外ccRCC细胞模型，该模型更接近于ccRCC肿瘤的形态。
Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer. The purpose of this study is to define a biological pathway signature and a cellular differentiation program in ccRCC. We performed gene expression profiling of early-stage ccRCC and patient-matched normal renal tissue using Affymetrix HG-U133a and HG-U133b GeneChips combined with a comprehensive bioinformatic analyses, including pathway analysis. The results were validated by real time PCR and IHC on two independent sample sets. Cellular differentiation experiments were performed on ccRCC cell lines and their matched normal renal epithelial cells, in differentiation media, to determine their mesenchymal differentiation potential. We identified a unique pathway signature with three major biological alterations—loss of normal renal function, down-regulated metabolism, and immune activation–which revealed an adipogenic gene expression signature linked to the hallmark lipid-laden clear cell morphology of ccRCC. Culturing normal renal and ccRCC cells in differentiation media showed that only ccRCC cells were induced to undergo adipogenic and, surprisingly, osteogenic differentiation. A gene expression signature consistent with epithelial mesenchymal transition (EMT) was identified for ccRCC. We revealed significant down-regulation of four developmental transcription factors (GATA3, TFCP2L1, TFAP2B, DMRT2) that are important for normal renal development. ccRCC is characterized by a lack of epithelial differentiation, mesenchymal/adipogenic transdifferentiation, and pluripotent mesenchymal stem cell-like differentiation capacity in vitro. We suggest that down-regulation of developmental transcription factors may mediate the aberrant differentiation in ccRCC. We propose a model in which normal renal epithelial cells undergo dedifferentiation, EMT, and adipogenic transdifferentiation, resulting in ccRCC. Because ccRCC cells grown in adipogenic media regain the characteristic ccRCC phenotype, we have indentified a new in vitro ccRCC cell model more resembling ccRCC tumor morphology.
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