• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文会议>Conference on biochemical and molecular engineering XX >ROLE OF CD36 AND FREE FATTY ACID UPTAKE IN EPITHELIAL-MESENCHYMAL TRANSITION OF HEPATOCELLULAR CARCINOMA CELLS
【24h】

ROLE OF CD36 AND FREE FATTY ACID UPTAKE IN EPITHELIAL-MESENCHYMAL TRANSITION OF HEPATOCELLULAR CARCINOMA CELLS

机译：CD36的作用和游离脂肪酸摄取在肝细胞癌细胞上皮 - 间充质转变中的作用

获取原文
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related death worldwide. The liver is the main site of free fatty acid (FFA) metabolism; epidemiological studies link HCC tumorigenesis and elevated mortality rates to obesity, which manifests as increased FFA. Previous studies investigated the cytotoxic and pro-inflammatory effects of FFA, but did not focus on its influence on HCC progression. In this study, we hypothesized that elevated FFAs induce the epithelial-mesenchymal transition (EMT) program, facilitating a metastatic, invasive HCC phenotype. We investigated the association between obesity, EMT progression and alterations in FFA-uptake proteins in TCGA HCC gene expression data and validated the results in protein samples from human HCC tumors. In order to scrutinize the phenotypic effects of elevated FFA, we assessed the migratory and invasive ability of HCC cell lines treated with various FFAs, and further verified the expression of EMT markers using qPCR, confocal microscopy and flow cytometry. Bioinformatic analysis of TCGA data revealed that obese patients have higher levels of CD36, a trans-membrane protein that facilitates FFA transport into the cell. CD36 expression levels were strongly correlated with an EMT gene signature. However, the degree of EMT itself was not associated with the body mass index (BMI) of the patients. These results were corroborated in protein measurements from human HCC tumor samples. Additionally, we observed that saturated and monounsaturated FFA-treated HCC cell lines exhibited increased migration, invasion, dissociation, and development of the characteristic EMT morphology. Next, we confirmed the expression of EMT markers using qPCR and confocal imaging, demonstrating that chemical inhibition of CD36 reversed the FFA-induced EMT phenotype. Given the known cytotoxic effects of elevated FFAs on hepatocytes, we tested a population-distribution hypothesis using flow cytometry. We found that although some cells succumbed to the cytotoxic effects of high FFA, a distinct population not only evaded cell death, but also acquired EMT. We further utilized PCR arrays to determine that Wnt and TGF-beta signaling pathways, potential drivers of the EMT program, were activated upon FFA treatment and showed that repression of these pathways prevented migration and invasion in FFA treated cells. Our research demonstrates the role of CD36 and FFAs in activating the EMT program via induction of Wnt and TGF-beta signaling, and provides the first direct evidence that elevated FFA uptake promotes progression of HCC through EMT. Further elucidation of this program may provide insights for management of advanced HCC.
机译：肝细胞癌（HCC）是全世界癌症相关死亡的第三个主要原因。肝脏是游离脂肪酸（FFA）代谢的主要部位;流行病学研究将HCC肿瘤引发和肥胖的死亡率提高，表现为FFA增加。之前的研究研究了FFA的细胞毒性和促炎作用，但并未关注其对HCC进展的影响。在这项研究中，我们假设升高的FFA诱导上皮 - 间充质转换（EMT）程序，促进转移性，侵入性HCC表型。我们调查了肥胖症，EMT进展和改变在TCGA HCC基因表达数据中的FFA吸收蛋白质之间的关联，并验证了来自人HCC肿瘤的蛋白质样品的结果。为了仔细检查升高FFA的表型效果，我们评估了用各种FFA治疗的HCC细胞系的迁移和侵袭能力，并使用QPCR，共聚焦显微镜和流式细胞术进一步验证EMT标记的表达。 TCGA数据的生物信息分析显示，肥胖患者具有较高水平的CD36，促进FFA输送到细胞中的跨膜蛋白。 CD36表达水平与EMT基因签名强烈相关。然而，EMT本身的程度与患者的体重指数（BMI）无关。这些结果在人HCC肿瘤样品中的蛋白质测量中得到了证实。此外，我们观察到饱和和单不饱和的FFA处理的HCC细胞系表现出迁移，侵袭，解离以及发展特征EMT形态的发展。接下来，我们证实了使用QPCR和共聚焦成像的EMT标记的表达，证明CD36的化学抑制逆转了FFA诱导的EMT表型。鉴于肝细胞上升高的FFA的已知细胞毒性作用，我们使用流式细胞术测试了人群分布假设。我们发现，虽然一些细胞屈服于高FFA的细胞毒性效应，但是一个不同的人口不仅逃避细胞死亡，而且还获得了EMT。我们进一步利用了PCR阵列以确定WNT和TGF-Beta信号传导途径，EMT程序的潜在司机在FFA治疗时被激活，并显示出这些途径的抑制阻止了FFA处理细胞中的迁移和侵袭。我们的研究展示了CD36和FFA通过诱导WNT和TGF-Beta信号传导激活EMT程序的作用，并提供了升高的FFA摄取升高通过EMT的进展的直接证据。本计划的进一步阐明可能提供对高级HCC管理的见解。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号