Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy.
Research Unit of Diabetes and Endocrine Diseases and 2 Unit of Biostatistics, Fondazione IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.
Acta Diabetol. 2019 Dec;56(12):1265-1274. doi: 10.1007/s00592-019-01382-x. Epub 2019 Jul 10.
Obesity and low-grade inflammation are associated with an increased risk of hepatocellular carcinoma (HCC), a leading cause of cancer-related death worldwide. The tissue inhibitor of metalloproteinase (TIMP) 3, an endogenous inhibitor of protease activity that represents a key mediator of inflammation, is reduced in inflammatory metabolic disorders and cancer. In contrast, Timp3-deficient mice (Timp3) are highly resistant to developing HCC in response to a diethylnitrosamine (DEN); therefore, we aimed to elucidate the biological role of genetic loss of Timp3 in obesity-related hepatocarcinogenesis.
Fourteen-day-old male wild-type (wt) and Timp3 mice were injected with 25 mg/kg DEN or an equal volume of saline. After 4 weeks, mice were randomized into two dietary groups and fed either normal or high-fat diet and allowed to grow until 32 weeks of age. Liver histological features were analyzed, and differentially expressed genes in the liver were quantified.
In Timp3 mice fed with the obesogenic diet, despite the increase in liver steatosis and inflammation, both the number of tumors and the total tumor size are significantly reduced 30 weeks post-DEN injection, compared to control mice. Moreover, Timp3 deletion in hepatocarcinogenesis during obesity is associated with a reduction in FoxM1 transcriptional activity through H19/miR-675/p53 pathway.
This study suggests that Timp3 ablation leads to cell cycle perturbation, at least in part by repressing FoxM1 transcriptional activity through H19/miR-675/p53 pathway.
肥胖和低度炎症与肝细胞癌（HCC）风险增加有关，HCC 是全球癌症相关死亡的主要原因。组织金属蛋白酶抑制剂（TIMP）3 是一种内源性蛋白酶活性抑制剂，是炎症的关键介质，在炎症代谢紊乱和癌症中减少。相比之下，Timp3 缺陷小鼠（Timp3）对二乙基亚硝胺（DEN）诱导的 HCC 具有高度抗性；因此，我们旨在阐明遗传缺失 Timp3 在肥胖相关肝癌发生中的生物学作用。
14 天大的雄性野生型（wt）和 Timp3 小鼠接受 25mg/kg DEN 或等量生理盐水注射。4 周后，将小鼠随机分为两组饮食组，分别给予正常或高脂肪饮食，并允许生长至 32 周龄。分析肝组织学特征，并定量分析肝内差异表达基因。
在肥胖饮食喂养的 Timp3 小鼠中，尽管肝脂肪变性和炎症增加，但与对照组相比，DEN 注射后 30 周时肿瘤数量和总肿瘤大小均显著减少。此外，肥胖时肝癌发生过程中 Timp3 的缺失与 FoxM1 转录活性的降低有关，这至少部分是通过 H19/miR-675/p53 通路抑制 FoxM1 转录活性。
这项研究表明，Timp3 缺失导致细胞周期紊乱，至少部分是通过 H19/miR-675/p53 通路抑制 FoxM1 转录活性。
