biostudies-literatureWu ZScience and Technology Projects in Guangzhou, ChinaTheme-based Research Scheme (TRS) of Hong KongNational Natural Science Foundation of ChinaInnovation Technology Commission of the Hong Kong SARInternational Partnership Program of The Chinese Academy of SciencesBasic Research Project of Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesUniversity Grants Committee/Research Grants Council of the Hong Kong Special Administrative RegionKey Technologies Research and Development ProgramOpen Project of State Key Laboratory of Respiratory DiseaseScience and Technology Planning Project of Guangdong ProvinceGuangdong Province Grant for Belt and Road Joint LaboratoryStrategic Priority Research Program of the Chinese Academy of SciencesBasic and Applied Basic Research Foundation of Guangdong ProvinceGuangdong-Hong Kong-Macau Joint Laboratory of Respiratory Infectious DiseasesGeneral Research Funding (GRF) of Hong KongMajor Research Project of Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesYouth Innovation Promotion Association of the Chinese Academy of Sciencese00335https://www.ebi.ac.uk/biostudies/studies/S-EPMC12752641biostudies-literatureUnknown12(48)TP53 mutations are highly associated with hepatocellular carcinoma (HCC), a common and deadly cancer. However, few primary drivers in the progression of HCC with mutant TP53 have been identified. To uncover tumor suppressors in human HCC, a genome-wide CRISPR/Cas9-based screening of primary human hepatocytes with MYC and TP53^R249S overexpression (MT-PHHs) is performed in xenografts. The screen identified RELA as one of the most significant genes, besides NF2 and CSK, two known tumor suppressor genes (TSG) in HCC. Ablation of RELA increased the expression of genes related to cell cycling and stemness in MT-PHHs, and induced PHHs to transform into HCC in situ in Fah-deficient immunodeficient mice. Additionally, loss of RELA facilitated HCC metastasis via Epithelial-Mesenchymal TraAdvanced science (Weinheim, Baden-Wurttemberg, Germany)RELA Ablation Contributes to Progression of Hepatocellular Carcinoma with TP53<sup>R249S</sup> Mutation and is a Potential Therapeutic Target.PMC12752641XDB1250000GIBHMRP25-0217109422323709962023B1212060050188GJHZ2022015GC2024A050504002182202031822733772023371171139242022B12120500042024B03J12322023B12121200092022A05050900062022A151511034932170946SKLRD-OP-2024052024B151504002082402150GIBHBRP23-03XDB09403012020B12120600522022A15150125692022A15150106042022YFE0210600T12-703/19R2022A151501248482341204188GJHZ2024031FNAoE/M-401/202022A15150123602019B121205010Yuan TZheng YLin SZhu YWu QJia HLi PMan KLv JDuan ZWu ZJiang ZYao YLong YCarson GThiery JPWang ZZheng DfalseRELA Ablation Contributes to Progression of Hepatocellular Carcinoma with TP53<sup>R249S</sup> Mutation and is a Potential Therapeutic Target.TP53 mutations are highly associated with hepatocellular carcinoma (HCC), a common and deadly cancer. However, few primary drivers in the progression of HCC with mutant TP53 have been identified. To uncover tumor suppressors in human HCC, a genome-wide CRISPR/Cas9-based screening of primary human hepatocytes with MYC and TP53^R249S overexpression (MT-PHHs) is performed in xenografts. The screen identified RELA as one of the most significant genes, besides NF2 and CSK, two known tumor suppressor genes (TSG) in HCC. Ablation of RELA increased the expression of genes related to cell cycling and stemness in MT-PHHs, and induced PHHs to transform into HCC in situ in Fah-deficient immunodeficient mice. Additionally, loss of RELA facilitated HCC metastasis via Epithelial-Mesenchymal Tra2025-01-01T00:00:00Z2025 Dec2026-06-06T06:05:34.574Z2026-05-27T03:11:57.506ZS-EPMC127526414091967610.1002/advs.202500335