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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 &lt;i&gt;KCTD17&lt;\/i&gt; deficient mice were treated with diethylnitrosamine (DEN) to assess its effect on HCC progression. Additionally, we tested &lt;i&gt;KCTD17&lt;\/i&gt;-directed antisense oligonucleotides for their therapeutic potential in vivo.Results: Our investigation revealed the upregulation of &lt;i&gt;KCTD17&lt;\/i&gt; 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 &lt;i&gt;KCTD17&lt;\/i&gt; deficient mice or liver cancer xenograft models were less susceptible to carcinogenesis or tumor growth. Similarly, treatment with &lt;i&gt;KCTD17&lt;\/i&gt;-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.<\/jats:p>","DOI":"10.3350\/cmh.2024.0364","type":"journal-article","created":{"date-parts":[[2024,8,5]],"date-time":"2024-08-05T02:27:31Z","timestamp":1722824851000},"page":"895-913","update-policy":"https:\/\/doi.org\/10.3350\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["KCTD17-mediated Ras stabilization promotes hepatocellular carcinoma progression"],"prefix":"10.3350","volume":"30","author":[{"given":"Young Hoon","family":"Jung","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun 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