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吲哚胺2,3-双加氧酶在二乙基亚硝胺诱导的肝癌发生中的作用

The Role of Indoleamine 2,3-Dioxygenase in Diethylnitrosamine-Induced Liver Carcinogenesis.

作者信息

Shibata Yuhei, Hara Takeshi, Nagano Junji, Nakamura Nobuhiko, Ohno Tomohiko, Ninomiya Soranobu, Ito Hiroyasu, Tanaka Takuji, Saito Kuniaki, Seishima Mitsuru, Shimizu Masahito, Moriwaki Hisataka, Tsurumi Hisashi

机构信息

First Departments of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.

Departments of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.

出版信息

PLoS One. 2016 Jan 4;11(1):e0146279. doi: 10.1371/journal.pone.0146279. eCollection 2016.

Abstract

Indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing intracellular enzyme of the L-kynurenine pathway, causes preneoplastic cells and tumor cells to escape the immune system by inducing immune tolerance; this mechanism might be associated with the development and progression of human malignancies. In the present study, we investigated the role of IDO in diethylnitrosamine (DEN)-induced hepatocarcinogenesis by using IDO-knockout (KO) mice. To induce hepatocellular carcinoma (HCC), hepatic adenoma, and preneoplastic hepatocellular lesions termed foci of cellular alteration (FCA), male IDO-wild-type (WT) and IDO-KO mice with a C57BL/6J background received a single intraperitoneal injection of DEN at 2 weeks of age. The mice were sacrificed to evaluate the development of FCA and hepatocellular neoplasms. HCC overexpressed IDO and L-kynurenine compared to surrounding normal tissue in the DEN-treated IDO-WT mice. The number and cell proliferative activity of FCAs, and the incidence and multiplicity of HCC were significantly greater in the IDO-WT than in the IDO-KO mice. The expression levels of the IDO protein, of L-kynurenine, and of IFN-γ, COX-2, TNF-α, and Foxp3 mRNA were also significantly increased in the DEN-induced hepatic tumors that developed in the IDO-WT mice. The mRNA expression levels of CD8, perforin and granzyme B were markedly increased in hepatic tumors developed in IDO-KO mice. Moreover, Foxp3-positive inflammatory cells had infiltrated into the livers of DEN-treated IDO-WT mice, whereas fewer cells had infiltrated into the livers of IDO-KO mice. Induction of IDO and elevation of L-kynurenine might play a critical role in both the early and late phase of liver carcinogenesis. Our findings suggest that inhibition of IDO might offer a promising strategy for the prevention of liver cancer.

摘要

吲哚胺2,3-双加氧酶(IDO)是L-犬尿氨酸途径中一种分解色氨酸的细胞内酶,它通过诱导免疫耐受使癌前细胞和肿瘤细胞逃避免疫系统;这种机制可能与人类恶性肿瘤的发生和发展有关。在本研究中,我们通过使用IDO基因敲除(KO)小鼠来研究IDO在二乙基亚硝胺(DEN)诱导的肝癌发生中的作用。为了诱导肝细胞癌(HCC)、肝腺瘤以及称为细胞改变灶(FCA)的癌前肝细胞病变,具有C57BL/6J背景的雄性IDO野生型(WT)和IDO-KO小鼠在2周龄时接受单次腹腔注射DEN。处死小鼠以评估FCA和肝细胞肿瘤的发生情况。在DEN处理的IDO-WT小鼠中,与周围正常组织相比,HCC中IDO和L-犬尿氨酸过表达。IDO-WT小鼠中FCA的数量和细胞增殖活性以及HCC的发生率和多发性均显著高于IDO-KO小鼠。在IDO-WT小鼠发生的DEN诱导的肝肿瘤中,IDO蛋白、L-犬尿氨酸以及IFN-γ、COX-2、TNF-α和Foxp3 mRNA的表达水平也显著升高。在IDO-KO小鼠发生的肝肿瘤中,CD8、穿孔素和颗粒酶B的mRNA表达水平明显升高。此外,Foxp3阳性炎性细胞浸润到DEN处理的IDO-WT小鼠的肝脏中,而浸润到IDO-KO小鼠肝脏中的细胞较少。IDO的诱导和L-犬尿氨酸的升高可能在肝癌发生的早期和晚期阶段都起关键作用。我们的研究结果表明,抑制IDO可能为预防肝癌提供一种有前景的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc6f/4699706/6db39e75d6fb/pone.0146279.g001.jpg

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