Zinc fingers and homeoboxes 2 is required for diethylnitrosamine-induced liver tumor formation in C57BL/6 mice.
Zinc fingers and homeoboxes 2 is required for diethylnitrosamine-induced liver tumor formation in C57BL/6 mice.
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DOI：
10.1002/hep4.2106
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发表时间：
2022-12
影响因子：
5.1
通讯作者：
Spear, Brett T.
中科院分区：
文献类型：
--
作者：
Jiang, Jieyun;Turpin, Courtney;Qiu, Guofang (Shirley);Xu, Mei;Lee, Eun;Hinds, Terry D., Jr.;Peterson, Martha L.;Spear, Brett T.
肝癌主要由肝细胞癌（HCC）组成，是全球第三大癌症死亡原因，并且在西方国家呈上升趋势。我们之前发现转录因子锌指和同源盒 2 (Zhx2) 是肝基因表达的调节因子，并且许多 Zhx2 靶基因在 HCC 中失调。在这里，我们使用二乙基亚硝胺（DEN）诱导的肝肿瘤模型研究了 Zhx2 缺陷小鼠的 HCC。我们使用全身 Zhx2 敲除 (Zhx2 KO) 小鼠的研究表明，在 DEN 暴露后 9 个月和 10 个月，肝脏肿瘤完全消失。 DEN 处理后不久的分析显示，Zhx2 KO 和野生型 (Zhx2 wt ) 小鼠之间 DEN 生物活性酶细胞色素 P450 2E1 (CYP2E1) 和 DNA 聚合酶 delta 2 的表达或磷酸化组蛋白变体 H2AX 灶的数量没有差异。因此，Zhx2 的缺失不会改变 DEN 生物激活或 DNA 损伤。与 Zhx2 wt 肝脏相比，Zhx2 KO 肝脏的 Ki67 染色阳性灶较少，白细胞介素 6 和 AKT 丝氨酸/苏氨酸激酶 2 表达减少，表明 Zhx2 缺失减少了肝细胞增殖，并可能导致肿瘤形成减少。在 DEN 治疗的肝脏特异性 Zhx2 敲除小鼠中，肿瘤有所减少，但并非不存在，这表明 Zhx2 在肝细胞和非实质细胞中发挥作用，抑制肿瘤形成。癌症基因组图谱和临床蛋白质组学肿瘤联盟的数据分析表明，HCC 患者中 ZHX2 信使 RNA 和蛋白质水平显着较高，并且与临床病理参数相关。结论：与之前在人肝癌细胞系和其他 HCC 小鼠模型中显示 Zhx2 作为肿瘤抑制因子的研究相比，我们的数据表明 Zhx2 在 DEN 诱导的 HCC 模型中作为癌基因，并且与 HCC 患者中较高的 ZHX2 表达一致。
Liver cancer, comprised primarily of hepatocellular carcinoma (HCC), is the third leading cause of cancer deaths worldwide and increasing in Western countries. We previously identified the transcription factor zinc fingers and homeoboxes 2 (Zhx2) as a regulator of hepatic gene expression, and many Zhx2 target genes are dysregulated in HCC. Here, we investigate HCC in Zhx2‐deficient mice using the diethylnitrosamine (DEN)–induced liver tumor model. Our study using whole‐body Zhx2 knockout (Zhx2 KO ) mice revealed the complete absence of liver tumors 9 and 10 months after DEN exposure. Analysis soon after DEN treatment showed no differences in expression of the DEN bioactivating enzyme cytochrome P450 2E1 (CYP2E1) and DNA polymerase delta 2, or in the numbers of phosphorylated histone variant H2AX foci between Zhx2 KO and wild‐type (Zhx2 wt ) mice. The absence of Zhx2, therefore, did not alter DEN bioactivation or DNA damage. Zhx2 KO livers showed fewer positive foci for Ki67 staining and reduced interleukin‐6 and AKT serine/threonine kinase 2 expression compared with Zhx2 wt livers, suggesting that Zhx2 loss reduces liver cell proliferation and may account for reduced tumor formation. Tumors were reduced but not absent in DEN‐treated liver‐specific Zhx2 knockout mice, suggesting that Zhx2 acts in both hepatocytes and nonparenchymal cells to inhibit tumor formation. Analysis of data from the Cancer Genome Atlas and Clinical Proteomic Tumor Consortium indicated that ZHX2 messenger RNA and protein levels were significantly higher in patients with HCC and associated with clinical pathological parameters. Conclusion: In contrast to previous studies in human hepatoma cell lines and other HCC mouse models showing that Zhx2 acts as a tumor suppressor, our data indicate that Zhx2 acts as an oncogene in the DEN‐induced HCC model and is consistent with the higher ZHX2 expression in patients with HCC.
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影响因子：
2.7
作者：
Nagel, Stefan;Schneider, Bjoern;MacLeod, Roderick A. F.
通讯作者：
MacLeod, Roderick A. F.
影响因子：
13.5
作者：
Creeden, Justin F.;Kipp, Zachary A.;Xu, Mei;Flight, Robert M.;Moseley, Hunter N. B.;Martinez, Genesee J.;Lee, Wang-Hsin;Alganem, Khaled;Imami, Ali S.;McMullen, Megan R.;Roychowdhury, Sanjoy;Nawabi, Atta M.;Hipp, Jennifer A.;Softic, Samir;Weinman, Steven A.;McCullumsmith, Robert;Nagy, Laura E.;Hinds, Terry D., Jr.
通讯作者：
Hinds, Terry D., Jr.
影响因子：
25.7
作者：
Connor F;Rayner TF;Aitken SJ;Feig C;Lukk M;Santoyo-Lopez J;Odom DT
通讯作者：
Odom DT
DOI：
10.1161/atvbaha.118.311266
发表时间：
2018-09
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Erbilgin A;Seldin MM;Wu X;Mehrabian M;Zhou Z;Qi H;Dabirian KS;Sevag Packard RR;Hsieh W;Bensinger SJ;Sinha S;Lusis AJ
通讯作者：
Lusis AJ
影响因子：
13.5
作者：
Morford, Lorri A.;Davis, Christina;Spear, Brett T.
通讯作者：
Spear, Brett T.