Activation of pluripotent genes in hepatic progenitor cells in the transition of nonalcoholic steatohepatitis to pre-malignant lesions
Activation of pluripotent genes in hepatic progenitor cells in the transition of nonalcoholic steatohepatitis to pre-malignant lesions
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非酒精性脂肪性肝炎向癌前病变转变过程中多能基因的激活
DOI：
10.1038/labinvest.2017.84
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发表时间：
2017-09
影响因子：
5
通讯作者：
Wu Jian
中科院分区：
文献类型：
--
作者：
Xu Gang;Ye Juan;Liu Xue Jing;Zhang Ning Ping;Zhao Yi Ming;Fan Jia;Liu Xiu Ping;Wu Jian
非酒精性脂肪性肝炎被认为是一种癌前状态。然而，对NASH的肝癌发生机制知之甚少。本研究旨在研究患者标本和动物模型中肝祖细胞中多能基因（c-Myc，Oct-4，KLF-4和Nanog）和形态发生基因（Gli-1）的激活，以确定正常干/祖细胞成为NASH-HCC起源的可能性。在这项研究中，与邻近的非肿瘤肝组织相比，多能和形态发生基因在人NASH-HCC组织中的表达显著上调。在喂食高脂肪/卡路里饮食加饮用水中的高果糖/葡萄糖（HFC饮食加HF/G）长达12个月后，小鼠发生肥胖、胰岛素抵抗和脂肪性肝炎，伴有显著的坏死性炎症和纤维化进展，以及发生增生性结节伴异型增生;并且该模型在病理组织学上表示为在癌前阶段从NASH向NASH-HCC的转变。在小鼠肝脏的发育不良区域中，多能和形态发生基因的高表达被化学染色可视化，其中存在许多OV-6阳性细胞，表明NASH中HOC的增殖伴随纤维化进展。此外，致癌转录因子（c-Myc，KLF-4和Nanog）共定位在这些肝祖细胞。总之，多能和形态发生基因可能有助于肝祖细胞的重编程，驱动这些细胞成为脂肪变性和炎症微环境中NASH-HCC的起源。
Nonalcoholic steatohepatitis is considered as a precancerous condition. However, hepatic carcinogenesis from NASH is poorly understood. This study aims to investigate the activation of pluripotent genes (c-Myc, Oct-4, KLF-4, and Nanog) and morphogenic gene (Gli-1) in hepatic progenitor cells from patient specimens and in an animal model to determine the possibility of normal stem/progenitor cells becoming the origin of NASH-HCC. In this study, expression of pluripotent and morphogenic genes in human NASH-HCC tissues was significantly upregulated compared to adjacent non-tumor liver tissues. After feeding high-fat/calorie diet plus high fructose/glucose in drinking water (HFC diet plus HF/G) for up to 12 months, mice developed obesity, insulin resistance, and steatohepatitis with significant necroptotic inflammation and fibrotic progression, as well as occurrence of hyperplastic nodules with dysplasia; and this model represents pathohistologically as a transition from NASH to NASH-HCC in a pre-carcinomatous stage. High expression of pluripotent and morphogenic genes was immunohistochemically visualized in the dysplasia areas of mouse liver, where there were many OV-6-positive cells, indicating proliferation of HOCs in NASH with fibrotic progression. Moreover, oncogenic transcription factors (c-Myc, KLF-4, and Nanog) were co-localized in these hepatic progenitor cells. In conclusion, pluripotent and morphogenic genes may contribute to the reprogramming of hepatic progenitor cells in driving these cells to be the origin of NASH-HCC in a steatotic and inflamed microenvironment.
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DOI：
10.1172/jci81979
发表时间：
2015
期刊：
J Clin Invest
影响因子：
--
作者：
Pingping Zhu;Yanying Wang;Lei He;Guanling Huang;Ying Du;Geng Zhang;Xinlong Yan;Pengyan Xia;Buqing Ye;Shuo Wang;Lu Hao;Jiayi Wu;Zusen Fan
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Zusen Fan
影响因子：
25.7
作者：
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DOI：
10.1016/s0093-3619(08)70915-8
发表时间：
2008
期刊：
Yearbook of Dermatology and Dermatologic Surgery
影响因子：
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作者：
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影响因子：
3.1
作者：
Ding, Jia;Wu, Jian
通讯作者：
Wu, Jian
影响因子：
11.2
作者：
Yahan Fan;Jia Ding;Jian Wu
通讯作者：
Yahan Fan;Jia Ding;Jian Wu