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Hepatocellular carcinoma (HCC) is an immunotherapy-resistant malignancy characterized by high cellular heterogeneity. The diversity of cell types and the interplay between tumor and non-tumor cells remain to be clarified. Single cell RNA sequencing of human and mouse HCC tumors revealed heterogeneity of cancer-associated fibroblast (CAF). Cross-species analysis determined the prominent CD36+ CAFs exhibited high-level lipid metabolism and expression of macrophage migration inhibitory factor (MIF). Lineage-tracing assays showed CD36+CAFs were derived from hepatic stellate cells. Furthermore, CD36 mediated oxidized LDL uptake-dependent MIF expression via lipid peroxidation/p38/CEBPs axis in CD36+ CAFs, which recruited CD33+myeloid-derived suppressor cells (MDSCs) in MIF- and CD74-dependent manner. Co-implantation of CD36+ CAFs with HCC cells promotes HCC progression in vivo. Finally, CD36 inhibitor synergizes with anti-PD-1 immunotherapy by restoring antitumor T-cell responses in HCC. Our work underscores the importance of elucidating the function of specific CAF subset in understanding the interplay between the tumor microenvironment and immune system. [ABSTRACT FROM AUTHOR]

We studied the value of circulating tumor DNA (ctDNA) in predicting early postoperative tumor recurrence and monitoring tumor burden in patients with hepatocellular carcinoma (HCC). Plasma‐free DNA, germline DNA, and tissue DNA were isolated from 41 patients with HCC. Serial ctDNAs were analyzed by next‐generation sequencing before and after operation. Whole‐exome sequencing was used to detect the DNA of HCC and adjacent tissues. In total, 47 gene mutations were identified in the ctDNA of the 41 patients analyzed before surgery. ctDNA was detected in 63.4% and 46% of the patient plasma pre‐ and postoperation, respectively. The preoperative ctDNA positivity rate was significantly lower in the nonrecurrence group than in the recurrence group. With a median follow‐up of 17.7 months, nine patients (22%) experienced tumor recurrence. ctDNA positivity at two time‐points was associated with significantly shorter recurrence‐free survival (RFS). Tumors with NRAS, NEF2L2, and MET mutations had significantly shorter times to recurrence than those without mutations and showed high recurrence prediction performance by machine learning. Multivariate analyses showed that the median variant allele frequency (VAF) of mutations in preoperative ctDNA was a strong independent predictor of RFS. ctDNA is a real‐time monitoring indicator that can accurately reflect tumor burden. The median VAF of baseline ctDNA is a strong independent predictor of RFS in individuals with HCC. [ABSTRACT FROM AUTHOR]

Background: N6-methyladenosine (m6A) RNA methylation, associated with cancer initiation and progression, is dynamically regulated by the m6A RNA regulators. However, its role in liver carcinogenesis is poorly understood. Methods: Three hundred seventy-one hepatocellular carcinoma (HCC) patients from The Cancer Genome Atlas database with sequencing and copy number variations/mutations data were included. Survival analysis was performed using Cox regression model. We performed gene set enrichment analysis to explore the functions associated with different HCC groups. Finally, we used a machine-learning model on selected regulators for developing a risk signature (m6Ascore) The prognostic value of m6Ascore was finally validated in another two GEO datasets. Results: We demonstrated that 11 m6A RNA regulators are significantly differentially expressed among 371 HCC patients stratified by clinicopathological features (P<0.001). We then identified two distinct HCC clusters by applying consensus clustering to m6A RNA regulators. Compared with the cluster2 subgroup, the cluster1 subgroup correlates with poorer prognosis (P < 0.001). Moreover, the cell cycle, splicesome and notch signaling pathway are significantly enriched in the cluster1 subgroup. We further derived m6Ascore, using four m6A regulators, predicting HCC prognosis well at three (AUC = 0.7) or 5 years (AUC=0.7) in validation. The prognostic value of m6Ascore also was validated successfully in two GEO datasets (P < 0.05). Finally, we discovered that mutations and copy number variations of m6A regulators, conferring worse survival, are strongly associated with TP53 mutations in HCC. Conclusions: We find a significant relationship between the alterations and different expressions causing increased m6A level and worse survival, especially in TP53-mutated HCC patients. Genetic alterations of m6A genes might cooperate with TP53 and its regulator targets in the HCC pathogenesis. Our m6Ascore may be applied in the clinical trials for patient stratification in HCC. [ABSTRACT FROM AUTHOR]

Our previous study demonstrated that heterogeneous nuclear ribonucleoprotein AB (HNRNPAB) is a key gene that facilitates metastasis of hepatocellular carcinoma (HCC). However, the molecular mechanisms behind this relationship are not fully understood. In our study, we utilized long‐noncoding RNA (lncRNA) microarrays to identify a HNRNPAB‐regulated lncRNA named lnc‐ELF209. Our findings from chromatin immunoprecipitation assays indicate that HNRNPAB represses lnc‐ELF209 transcription by directly binding to its promoter region. We also analyzed clinical samples from HCC patients and cell lines with quantitative real‐time polymerase chain reactions, RNA in situ hybridization and immunohistochemistry, and found that there is a negative relationship between HNRNPAB and lnc‐ELF209 expression. Up/downregulation assays and rescue assays indicate that lnc‐ELF209 inhibits cell migration, invasion and epithelial–mesenchymal transition regulated by HNRNPAB. This suggests a new regulatory mechanism for HNRNPAB‐promoted HCC progression. RNA pull‐down and LC–MS/MS were used to determine triosephosphate isomerase, heat shock protein 90‐beta and vimentin may be involved in the tumor‐suppressed function of lnc‐ELF209. Furthermore, we found lnc‐ELF209 could stabilize TPI protein expression. We also found that lnc‐ELF209 overexpression in HCCLM3 cell resulted in a lower rate of lung metastatic, which suggested a less aggressive HCC phenotype. Collectively, these findings offer new insights into the regulatory mechanisms that underlie HNRNPAB cancer‐promoting activities and demonstrate that lnc‐ELF209 is a HNRNPAB‐regulated lncRNA that may play an important role in the inhibition of HCC progression. What's new? Increased levels of the protein HNRNPAB can facilitate metastasis of hepatocellular carcinoma (HCC). But how does it do this? In this study, the authors found that HNRNPAB can repress a previously uncharacterized long noncoding RNA (lncRNA), called lnc‐ELF209. They then found that lnc‐ELF209 plays a crucial role in inhibiting the migration, invasion, and epithelial‐mesenchymal transition (EMT) of HCC tumor cells. Further analysis of this HNRNPAB‐lncELF209 regulatory axis should enhance our understanding of the molecular mechanisms involved in HCC, which may in turn lead to new therapeutic candidates. [ABSTRACT FROM AUTHOR]