{"doi":"10.3350/cmh.2024.0364","title":"KCTD17-mediated Ras stabilization promotes hepatocellular carcinoma progression","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.","journal":"Clinical and Molecular Hepatology","year":2024,"id":440897,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9108,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1252870,"name":"Yun Ji Lee","orcid":"0000-0003-2702-7599","position":1,"is_corresponding":false},{"id":909141,"name":"Tam Dao","orcid":"0000-0001-6611-0497","position":2,"is_corresponding":false},{"id":1252871,"name":"Kyung Hee Jung","orcid":"0000-0002-1291-0461","position":3,"is_corresponding":false},{"id":444991,"name":"Junjie Yu","orcid":"0000-0001-5603-6094","position":4,"is_corresponding":false},{"id":909140,"name":"Ah‐Reum Oh","orcid":"0000-0001-5783-0345","position":5,"is_corresponding":false},{"id":909735,"name":"Yelin Jeong","orcid":null,"position":6,"is_corresponding":false},{"id":1253366,"name":"HyunJoon Gi","orcid":null,"position":7,"is_corresponding":false},{"id":1253367,"name":"Young Un Kim","orcid":null,"position":8,"is_corresponding":false},{"id":1252872,"name":"Dongryeol Ryu","orcid":"0000-0002-5335-6209","position":9,"is_corresponding":false},{"id":970469,"name":"Michele Carrer","orcid":"0000-0002-6464-9584","position":10,"is_corresponding":false},{"id":109694,"name":"Utpal B. Pajvani","orcid":"0000-0001-5991-2723","position":11,"is_corresponding":false},{"id":339177,"name":"Sang Bae Lee","orcid":"0000-0002-4031-8051","position":12,"is_corresponding":false},{"id":1252873,"name":"Soon‐Sun Hong","orcid":"0000-0001-7679-1388","position":13,"is_corresponding":false},{"id":444990,"name":"KyeongJin Kim","orcid":"0000-0001-6865-9141","position":14,"is_corresponding":false},{"id":667807,"name":"Young Hoon Jung","orcid":"0000-0002-0781-3608","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T02:01:01.842286Z","pmid":"39098817","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}