Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea.
Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea.
Clin Mol Hepatol. 2024 Oct;30(4):895-913. doi: 10.3350/cmh.2024.0364. Epub 2024 Aug 5.
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.
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.
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.
KCTD17 induces the stabilization of Ras and downstream signaling pathways and HCC progression and may represent a novel therapeutic target for HCC.
背景/目的：钾通道四聚化结构域包含 17 蛋白（KCTD17）是一种衔接物，可与 Cullin3（Cul3）泛素连接酶复合物结合，已被认为与多种人类疾病有关；然而，其在肝细胞癌（HCC）中的作用仍不清楚。在这里，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。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，我们还测试了针对 KCTD17 的反义寡核苷酸在体内的治疗潜力。
我们的研究表明，与非肿瘤对照相比，KCTD17 在 HCC 患者的肿瘤和 HCC 小鼠模型中均上调表达。我们鉴定了亮氨酸拉链样转录调节剂 1（Lztr1）蛋白，作为 KCTD17-Cul3 复合物的底物，Lztr1 蛋白是一种先前被鉴定的 Ras 稳定剂。KCTD17 介导的 Lztr1 降解导致 Ras 稳定，从而导致肝癌细胞增殖、迁移和伤口愈合增加。肝细胞特异性 KCTD17 缺陷小鼠或 HCC 异种移植模型对致癌作用或肿瘤生长的敏感性降低。同样，在 HCC 小鼠模型中用 KCTD17 靶向反义寡核苷酸（ASO）治疗与用对照 ASO 治疗的小鼠相比，肿瘤体积以及 Ras 蛋白水平显著降低。
KCTD17 诱导 Ras 及其下游信号通路的稳定，并促进 HCC 进展，可能成为 HCC 的一个新的治疗靶点。
