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一种研究肝癌上皮-间充质转化的非典型系统。

An Atypical System for Studying Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma.

机构信息

CSIR-Centre for Cellular and Molecular Biology, Hyderabad, 500007 India.

出版信息

Sci Rep. 2016 May 20;6:26282. doi: 10.1038/srep26282.

DOI:10.1038/srep26282
PMID:27197891
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4873837/
Abstract

Intrahepatic and extrahepatic metastases are frequently detected in hepatocellular carcinoma (HCC). Epithelial-mesenchymal transition (EMT) is believed to drive metastasis. There are not many well-established model systems to study EMT in HCC. Here we identified an atypical EMT while characterizing a population of mesenchymal cells in Huh7.5 hepatoma cell cultures. Cells with distinct morphology appeared during geneticin treatment of Huh7.5 cultures. Molecular characterization of geneticin resistant Huh7.5M cells confirmed EMT. Huh7.5M cells expressed cancer stem cell markers. p38MAPK and ERK1/2 were substantially activated in Huh7.5M cells. Their Inhibition elevated E-Cadherin expression with concerted suppression of Vimentin and anchorage independent growth in Huh7.5M cells. TGFβ could not induce EMT in Huh7.5 cultures, but enriched mesenchymal populations, similar to geneticin. Huh7.5M cells formed more aggressive solid tumors, primarily comprising cells with epithelial morphology, in nude mice. Canonical EMT-TFs did not participate in this atypical EMT, indicating that the established canonical EMT-TFs do not drive every EMT and there is a dire need to identify additional factors. The system that we characterized is a unique model to study EMT, MET and biphasic TGFβ signaling in HCC and offers considerable potential to facilitate more insightful studies on deeper questions in tumor metastasis.

摘要

肝癌（HCC）中常可检测到肝内和肝外转移。上皮-间充质转化（EMT）被认为是转移的驱动因素。目前，用于研究 HCC 中 EMT 的成熟模型系统并不多。在这里，我们在对 Huh7.5 肝癌细胞培养物中的间质细胞进行特征分析时，发现了一种非典型的 EMT。在对 Huh7.5 细胞培养物进行遗传霉素处理时，出现了具有独特形态的细胞。对遗传霉素抗性 Huh7.5M 细胞的分子特征分析证实了 EMT 的发生。Huh7.5M 细胞表达了癌症干细胞标志物。p38MAPK 和 ERK1/2 在 Huh7.5M 细胞中被大量激活。抑制它们会协同上调 E-钙黏蛋白的表达，同时抑制 Huh7.5M 细胞的非锚定依赖性生长。TGFβ不能诱导 Huh7.5 培养物发生 EMT，但类似于遗传霉素，它可富集间充质细胞群。在裸鼠中，Huh7.5M 细胞形成侵袭性更强的实体瘤，主要由具有上皮形态的细胞组成。经典 EMT-TFs 并未参与这种非典型 EMT，表明已建立的经典 EMT-TFs 并未驱动所有 EMT，迫切需要鉴定其他因子。我们所描述的系统是研究 HCC 中 EMT、MET 和双相 TGFβ 信号的独特模型，为深入研究肿瘤转移中的更深刻问题提供了巨大潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08c1/4873837/4df3d667eff5/srep26282-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08c1/4873837/a84f36d48543/srep26282-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08c1/4873837/01b8815b92e5/srep26282-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08c1/4873837/84475cf11bf2/srep26282-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08c1/4873837/7f6851eaa41a/srep26282-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08c1/4873837/9aa4418dfd69/srep26282-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08c1/4873837/a190568723d6/srep26282-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08c1/4873837/4df3d667eff5/srep26282-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08c1/4873837/a84f36d48543/srep26282-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08c1/4873837/01b8815b92e5/srep26282-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08c1/4873837/84475cf11bf2/srep26282-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08c1/4873837/7f6851eaa41a/srep26282-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08c1/4873837/9aa4418dfd69/srep26282-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08c1/4873837/a190568723d6/srep26282-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08c1/4873837/4df3d667eff5/srep26282-f7.jpg

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