KCTD17-mediated Ras stabilization promotes hepatocellular carcinoma progression.

IF 14 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Clinical and Molecular Hepatology Pub Date : 2024-10-01 Epub Date: 2024-08-05 DOI:10.3350/cmh.2024.0364
Young Hoon Jung, Yun Ji Lee, Tam Dao, Kyung Hee Jung, Junjie Yu, Ah-Reum Oh, Yelin Jeong, HyunJoon Gi, Young Un Kim, Dongryeol Ryu, Michele Carrer, Utpal B Pajvani, Sang Bae Lee, Soon-Sun Hong, KyeongJin Kim
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引用次数: 0

Abstract

Background/aims: Potassium channel tetramerization domain containing 17 (KCTD17) protein, an adaptor for the cullin3 (Cul3) ubiquitin ligase complex, has been implicated in various human diseases; however, its role in hepatocellular carcinoma (HCC) remains elusive. Here, we aimed to elucidate the clinical features of KCTD17, and investigate the mechanisms by which KCTD17 affects HCC progression.

Methods: We analyzed transcriptomic data from patients with HCC. Hepatocyte-specific KCTD17 deficient mice were treated with diethylnitrosamine (DEN) to assess its effect on HCC progression. Additionally, we tested KCTD17-directed antisense oligonucleotides for their therapeutic potential in vivo.

Results: Our investigation revealed the upregulation of KCTD17 expression in both tumors from patients with HCC and mouse models of HCC, in comparison to non-tumor controls. We identified the leucine zipper-like transcriptional regulator 1 (Lztr1) protein, a previously identified Ras destabilizer, as a substrate for KCTD17-Cul3 complex. KCTD17-mediated Lztr1 degradation led to Ras stabilization, resulting in increased proliferation, migration, and wound healing in liver cancer cells. Hepatocyte-specific KCTD17 deficient mice or liver cancer xenograft models were less susceptible to carcinogenesis or tumor growth. Similarly, treatment with KCTD17-directed antisense oligonucleotides (ASO) in a mouse model of HCC markedly lowered tumor volume as well as Ras protein levels, compared to those in control ASO-treated mice.

Conclusion: KCTD17 induces the stabilization of Ras and downstream signaling pathways and HCC progression and may represent a novel therapeutic target for HCC.

KCTD17 介导的 Ras 稳定促进了肝细胞癌的进展。
背景/目的:含钾通道四聚体化结构域17(KCTD17)蛋白是cullin3(Cul3)泛素连接酶复合物的适配体,已与多种人类疾病有关联;然而,它在肝细胞癌(HCC)中的作用仍然难以捉摸。在此,我们旨在阐明KCTD17的临床特征,并研究KCTD17影响HCC进展的机制:我们分析了HCC患者的转录组数据。方法:我们分析了HCC患者的转录组数据,并用二乙基亚硝胺(DEN)处理肝细胞特异性KCTD17缺陷小鼠,以评估其对HCC进展的影响。此外,我们还测试了 KCTD17 定向反义寡核苷酸在体内的治疗潜力:结果:我们的研究发现,与非肿瘤对照组相比,KCTD17在HCC患者的肿瘤和HCC小鼠模型中均有上调表达。我们发现亮氨酸拉链样转录调节因子 1(Lztr1)蛋白是 KCTD17-Cul3 复合物的底物。KCTD17 介导的 Lztr1 降解导致 Ras 稳定,从而增加了肝癌细胞的增殖、迁移和伤口愈合。肝细胞特异性 KCTD17 缺陷小鼠或肝癌异种移植模型不易发生癌变或肿瘤生长。同样,在肝癌小鼠模型中使用 KCTD17 引导的反义寡核苷酸(ASO)治疗,与 ASO 处理的对照小鼠相比,可显著降低肿瘤体积和 Ras 蛋白水平:结论:KCTD17能诱导Ras及下游信号通路的稳定和HCC的进展,可能是HCC的新型治疗靶点。
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来源期刊
Clinical and Molecular Hepatology
Clinical and Molecular Hepatology Medicine-Hepatology
CiteScore
15.60
自引率
9.00%
发文量
89
审稿时长
10 weeks
期刊介绍: Clinical and Molecular Hepatology is an internationally recognized, peer-reviewed, open-access journal published quarterly in English. Its mission is to disseminate cutting-edge knowledge, trends, and insights into hepatobiliary diseases, fostering an inclusive academic platform for robust debate and discussion among clinical practitioners, translational researchers, and basic scientists. With a multidisciplinary approach, the journal strives to enhance public health, particularly in the resource-limited Asia-Pacific region, which faces significant challenges such as high prevalence of B viral infection and hepatocellular carcinoma. Furthermore, Clinical and Molecular Hepatology prioritizes epidemiological studies of hepatobiliary diseases across diverse regions including East Asia, North Asia, Southeast Asia, Central Asia, South Asia, Southwest Asia, Pacific, Africa, Central Europe, Eastern Europe, Central America, and South America. The journal publishes a wide range of content, including original research papers, meta-analyses, letters to the editor, case reports, reviews, guidelines, editorials, and liver images and pathology, encompassing all facets of hepatology.
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