한빛사논문
- 조회176
Young Hoon Jung1,2,3, Yun Ji Lee1,2,3, Tam Dao4, Kyung Hee Jung1,3, Junjie Yu5,6, Ah-Reum Oh1,2,3, Yelin Jeong1,2,3, HyunJoon Gi1,2,3, Young Un Kim1,2,3, Dongryeol Ryu4, Michele Carrer7, Utpal B. Pajvani5, Sang Bae Lee8, Soon-Sun Hong1,2,3, KyeongJin Kim1,2,3
1Department of Biomedical Sciences, College of Medicine, College of Medicine, Inha University, Incheon 22212, Republic of Korea
2Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon 22212, Republic of Korea
3Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon 22212, Republic of Korea
4Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
5Department of Medicine, Columbia University, New York, NY 10032, USA
6Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, China
7Ionis Pharmaceuticals Inc., Carlsbad, CA 92010, USA
8Division of Life Sciences, Jeonbuk National University, Jeonju 54896, Republic of Korea
Correspondence : Sang Bae Lee , Soon-Sun Hong , KyeongJin Kim
*Young Hoon Jung and Yun Ji Lee contributed equally to this work.
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.
Conclusions: KCTD17 induces the stabilization of Ras and downstream signaling pathways and HCC progression and may represent a novel therapeutic target for HCC.
논문정보
- Research article
- 2024년 08월 (BRIC 등록일 2024-08-05)
- 국내 연구진
- 의약학 > 분자세포의학
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