Lineage-dependent effects of aryl hydrocarbon receptor agonists contribute to liver tumorigenesis.
Lineage-dependent effects of aryl hydrocarbon receptor agonists contribute to liver tumorigenesis.
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DOI：
10.1002/hep.27547
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发表时间：
2015-02
期刊：
影响因子：
13.5
通讯作者：
Thomas, Russell S.
中科院分区：
文献类型：
--
作者：
Harrill, Joshua A.;Parks, Bethany B.;Wauthier, Eliane;Rowlands, J. Craig;Reid, Lola M.;Thomas, Russell S.
啮齿动物癌症生物测定表明，芳香烃受体（AHR）激动剂，2，3，7，8-四氯二苯并-p-二恶英（TCDD），导致肝细胞和胆管细胞肿瘤的增加。已经评估了AHR激活对啮齿动物肝干细胞（rHpSC）与其后代成肝细胞（rHB）的影响，成肝细胞是具有重叠但也不同的表型性状的多能肝前体细胞的两个谱系阶段。这是通过定义第一个成功的培养条件，由透明质酸基质和久保田培养基（KM），设计用于内胚层干细胞/祖细胞的无血清培养基组成的rHpScs的离体维持。补充KM与白血病抑制因子引起谱系限制rHBs。用各种AHR激动剂处理培养物，包括TCDD、6-甲酰吲哚并[3，2-B]咔唑（FICZ）和3- 3 '-二吲哚甲烷（DIM），然后结合免疫细胞化学、基因表达和高含量图像分析进行分析。AHR激动剂在产生持续AHR激活的浓度下增加rHpSC的增殖，如Cyp 1a 1诱导所示。相比之下，用TCDD治疗导致rHBs活力的快速丧失，即使在没有激动剂的情况下，培养条件允许rHBs存活和扩增。没有观察到FICZ和较低浓度的DIM. Conclusion的影响：我们的研究结果是一致的，通过选择性扩增的rHpSCs结合毒性诱导的丧失活力的rHBs的啮齿动物肝脏肿瘤发生的AHR激动剂的作用方式的谱系依赖性。这些谱系依赖性效应与肝肿瘤发生频率增加相关。（肝病学2015;61：548-560）
Rodent cancer bioassays indicate that the aryl hydrocarbon receptor (AHR) agonist, 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD), causes increases in both hepatocytic and cholangiocytic tumors. Effects of AHR activation have been evaluated on rodent hepatic stem cells (rHpSCs) versus their descendants, hepatoblasts (rHBs), two lineage stages of multipotent, hepatic precursors with overlapping but also distinct phenotypic traits. This was made possible by defining the first successful culture conditions for ex vivo maintenance of rHpScs consisting of a substratum of hyaluronans and Kubota's medium (KM), a serum-free medium designed for endodermal stem/progenitor cells. Supplementation of KM with leukemia inhibitory factor elicited lineage restriction to rHBs. Cultures were treated with various AHR agonists including TCDD, 6-formylindolo-[3,2-b]carbazole (FICZ), and 3-3'-diindolylmethane (DIM) and then analyzed with a combination of immunocytochemistry, gene expression, and high-content image analysis. The AHR agonists increased proliferation of rHpSCs at concentrations producing a persistent AHR activation as indicated by induction of Cyp1a1. By contrast, treatment with TCDD resulted in a rapid loss of viability of rHBs, even though the culture conditions, in the absence of the agonists, were permissive for survival and expansion of rHBs. The effects were not observed with FICZ and at lower concentrations of DIM. Conclusion: Our findings are consistent with a lineage-dependent mode of action for AHR agonists in rodent liver tumorigenesis through selective expansion of rHpSCs in combination with a toxicity-induced loss of viability of rHBs. These lineage-dependent effects correlate with increased frequency of liver tumors. (Hepatology 2015;61:548-560)
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影响因子：
5.6
作者：
HILTON, DJ;NICOLA, NA;METCALF, D
通讯作者：
METCALF, D
DOI：
10.1073/pnas.97.22.12132
发表时间：
2000-10-24
影响因子：
11.1
作者：
Kubota, H;Reid, LM
通讯作者：
Reid, LM
影响因子：
5.2
作者：
Kubota, Hiroshi;Yao, Hsin-Lei;Reid, Lola M.
通讯作者：
Reid, Lola M.
影响因子：
3.8
作者：
Denison, Michael S.;Soshilov, Anatoly A.;Zhao, Bin
通讯作者：
Zhao, Bin
DOI：
10.1006/bbrc.2001.5987
发表时间：
2001-11-30
影响因子：
3.1
作者：
Ma, Q;Baldwin, KT;Dong, LQ
通讯作者：
Dong, LQ