Krüppel-like Factor 9 (KLF9) Suppresses Hepatocellular Carcinoma (HCC)-Promoting Oxidative Stress and Inflammation in Mice Fed High-Fat Diet.
Krüppel-like Factor 9 (KLF9) Suppresses Hepatocellular Carcinoma (HCC)-Promoting Oxidative Stress and Inflammation in Mice Fed High-Fat Diet.
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DOI：
10.3390/cancers14071737
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发表时间：
2022-03-29
期刊：
影响因子：
5.2
通讯作者：
Simmen FA
中科院分区：
文献类型：
--
作者：
Brown AR;Alhallak I;Simmen RCM;Melnyk SB;Heard-Lipsmeyer ME;Montales MTE;Habenicht D;Van TT;Simmen FA
核蛋白Krüppel样因子9（KLF 9）抑制包括肝脏在内的多种组织中癌症的发展。然而，KLF 9如何减少癌症发生/发展的机制基础尚未阐明。在这里，我们使用了一个小鼠模型，其中Klf 9基因被消融，并将野生型和突变型动物的性别，高脂肪，肥胖饮食。然后，我们研究了KLF 9的存在或不存在如何影响肥胖，以及肝脏氧化应激和炎症以及全身氧化应激的指数。结果表明，KLF 9是肝脏氧化应激和炎症的抑制剂，这可能是其在肝脏和其他组织中的肿瘤抑制作用的基础。肥胖、氧化应激和炎症是肝细胞癌（HCC）的危险因素。我们在小鼠中研究了Krüppel样因子9（KLF 9）敲除对高脂饮食（HFD）背景下肥胖、肝脏和全身氧化应激以及促炎和NOX/DUOX家族基因的肝脏表达的影响。雄性和雌性Klf 9 +/+（野生型，WT）和Klf 9 −/−（敲除，KO）小鼠喂食HFD（从35日龄开始）12周，之后获得肝脏和脂肪组织，并评价血清脂联素和瘦素水平、肝脏脂肪含量和氧化应激标志物。与WT小鼠相比，Klf 9 −/−小鼠的体重增加、脂肪细胞大小、脂肪因子水平或肝脏脂肪含量均未发生显著变化。然而，两种性别的Klf 9 −/−小鼠的肝脏重量/大小增加（肝肿大）。这伴随着肝脏氧化应激增加，如GSH/GSSG比值降低和同型半胱氨酸、3-硝基酪氨酸、3-氯酪氨酸和4 HNE含量增加所示。在相应的Klf 9 −/−小鼠血清中观察到GSH与GSSG比值降低和同型半胱氨酸水平升高的趋势。基因表达分析显示Klf 9 −/−小鼠肝脏中的促炎状态增强。KLF 9抑制肝脏氧化应激和炎症，从而确定KLF 9抑制HCC和其他组织癌症的潜在机制。
The nuclear protein Krüppel-like factor 9 (KLF9) suppresses development of cancers in multiple tissues including the liver. However, a mechanistic basis for how KLF9 decreases cancer initiation/development has not been elucidated. Here, we used a mouse model in which the Klf9 gene was ablated and placed wild-type and mutant animals of both sexes on a high-fat, obesogenic diet. We then examined how the presence or absence of KLF9 affected adiposity, as well as indices of liver oxidative stress and inflammation, and systemic oxidative stress. Results demonstrate that KLF9 is a suppressor of liver oxidative stress and inflammation which may underlie its tumor suppressive actions in liver and other tissues. Obesity, oxidative stress, and inflammation are risk factors for hepatocellular carcinoma (HCC). We examined, in mice, the effects of Krüppel-like factor 9 (KLF9) knockout on: adiposity, hepatic and systemic oxidative stress, and hepatic expression of pro-inflammatory and NOX/DUOX family genes, in a high-fat diet (HFD) context. Male and female Klf9+/+ (wild type, WT) and Klf9−/− (knockout, KO) mice were fed HFD (beginning at age 35 days) for 12 weeks, after which liver and adipose tissues were obtained, and serum adiponectin and leptin levels, liver fat content, and markers of oxidative stress evaluated. Klf9−/− mice of either sex did not exhibit significant alterations in weight gain, adipocyte size, adipokine levels, or liver fat content when compared to WT counterparts. However, Klf9−/− mice of both sexes had increased liver weight/size (hepatomegaly). This was accompanied by increased hepatic oxidative stress as indicated by decreased GSH/GSSG ratio and increased homocysteine, 3-nitrotyrosine, 3-chlorotyrosine, and 4HNE content. Decreased GSH to GSSG ratio and a trend toward increased homocysteine levels were observed in the corresponding Klf9−/− mouse serum. Gene expression analysis showed a heightened pro-inflammatory state in livers from Klf9−/− mice. KLF9 suppresses hepatic oxidative stress and inflammation, thus identifying potential mechanisms for KLF9 suppression of HCC and perhaps cancers of other tissues.