{"doi":"10.1002/cac2.12251","title":"Two distinct stem cell‐like subtypes of hepatocellular carcinoma with clinical significance and their therapeutic potentials","abstract":"Hepatocellular carcinoma (HCC) is among the most common cancers worldwide, causing about 600,000 deaths annually [1]. In HCC, stem cell-like characteristics, which drive early recurrence and therapy resistance, are major contributors to poor prognosis [2]. In this current study, we integrated and analyzed gene expression data from human fetal liver cells and primary HCC tumors (n = 1231) and uncovered two clinically and biologically distinct hepatic stem cell (HS) subtypes, potential biomarkers associated with these subtypes, and a potential new therapeutic intervention for these subtypes. By analyzing gene expression data from human fetal liver cells [3], we identified 609-, 2538-, and 1139-gene signatures for gestational 10-week fetal liver cells, 17-week fetal liver cells, and mature hepatocytes, respectively (Supplementary Fig. S1A). Because 10- and 17-week fetal liver cells reflect different degrees of stemness of hepatic lineage, as reflected by α-fetoprotein expression (Supplementary Fig. S1B), we renamed the gene signatures specific to the 10- and 17-week cells hepatic stem cell type 1 (HS1) and hepatic stem cell type 2 (HS2), respectively. To estimate the clinical relevance of stem cell-like characteristics in primary HCC, we trichotomized HCC tumors as HS1, HS2, or differentiated HCC (dHCC) subtypes according to their degree of stemness by applying the prediction algorithm to the gene expression data from HCC tumors (n = 1226) (Supplementary Fig. S1C). The HS1 subtype was associated with worst overall survival, the HS2 subtype exhibited moderate overall survival, and the dHCC subtype exhibited the best overall survival (P < 0.001, Figure 1A). When patients with Barcelona Clinic Liver Cancer stage A or B disease were stratified by HS subtype, the subtypes successfully stratified high-risk patients at both stages (Supplementary Fig. S2). In addition to clinical stage and resection status, the HS subtypes were significant predictors of overall survival, except HS2 for recurrence-free survival, in multivariate Cox proportional hazards regression analyses (Supplementary Table S1 and S2). The HS subtypes were also significantly associated with some clinicopathological variables (Supplementary Fig. S3). Clinical and biological significance of hepatic stem cell subtypes. (A) Kaplan-Meier plot of the OS for patients with hepatocellular carcinoma (HCC; n = 1226). HCC patients were trichotomized by Bayesian compound covariate prediction. P-values were estimated using log-rank tests. (B) Non-synonymous mutation rates and copy number alterations in stem cell subtypes of HCC in The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort (n = 371). (C) Waterfall plots showing the rates of immunotherapy response predicted by the tumor immune dysfunction and exclusion (TIDE) algorithm in the TCGA-LIHC cohort. The percentages of patients with each subtype who were responders are shown below the plots. (D) Western blots of YAP1 and MYC after JQ1 treatment. The bromodomain and extra-terminal domain (BET) inhibitor JQ1 downregulated YAP1 expression but not MYC expression in SK-Hep1 and SNU449 cells. (E) Viability of HCC cells treated with JQ1. P-values were estimated using the Student t-test. (F) The depletion of three BET proteins (BRD2, BRD3, and BRD4) was necessary for the suppression of YAP1 expression in HepG2 cells. BET protein expression was depleted by single-guide RNAs specific to each BET protein. Abbreviations: OS, overall survival; HCC, hepatocellular carcinoma; dHCC, differentiated hepatocytes; HS2, hepatic stem cell type 2; HS1, hepatic stem cell type 1; TCGA-LIHC, The Cancer Genome Atlas Liver Hepatocellular Carcinoma; TIDE, tumor immune dysfunction and exclusion; BET, bromodomain and extraterminal domain; sgBRD, single-guide RNA against BRD mRNAs; DMSO, dimethyl sulfoxide Interestingly, while there was no significant difference in the subtypes’ mutation rates, HS1 subtype showed significantly different copy ","journal":"Cancer Communications","year":2022,"id":277439,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9223,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":949529,"name":"Yun Seong Jeong","orcid":null,"position":1,"is_corresponding":false},{"id":485050,"name":"Sunyoung Lee","orcid":"0000-0002-6893-3136","position":2,"is_corresponding":false},{"id":949530,"name":"Bo Hwa Sohn","orcid":null,"position":3,"is_corresponding":false},{"id":949045,"name":"Ho Kyoung Hwang","orcid":"0000-0003-4064-7776","position":4,"is_corresponding":false},{"id":646833,"name":"Gi Hong Choi","orcid":"0000-0002-1593-3773","position":5,"is_corresponding":false},{"id":949046,"name":"Chang Moo Kang","orcid":"0000-0002-5382-4658","position":6,"is_corresponding":false},{"id":776397,"name":"Jin Sub Choi","orcid":"0000-0002-6467-6494","position":7,"is_corresponding":false},{"id":949047,"name":"Woo Jung Lee","orcid":"0000-0001-9273-261X","position":8,"is_corresponding":false},{"id":31969,"name":"Jae-Ho Cheong","orcid":"0000-0002-1703-1781","position":9,"is_corresponding":false},{"id":949531,"name":"Hee Jin Jang","orcid":null,"position":10,"is_corresponding":false},{"id":54196,"name":"Ahmed O. Kaseb","orcid":"0000-0002-9491-0587","position":11,"is_corresponding":false},{"id":13968,"name":"Lewis R. Roberts","orcid":"0000-0001-7885-8574","position":12,"is_corresponding":false},{"id":776394,"name":"Sun Young Yim","orcid":"0000-0001-7346-5974","position":13,"is_corresponding":false},{"id":381197,"name":"Yun Shin Chun","orcid":"0000-0003-1384-8927","position":14,"is_corresponding":false},{"id":278888,"name":"Ju‐Seog Lee","orcid":"0000-0002-5666-9753","position":15,"is_corresponding":false},{"id":278883,"name":"Sung Hwan Lee","orcid":"0000-0003-3365-0096","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-19T00:28:39.226969Z","pmid":"35032367","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":[]}