Predictive Value of the Hepatic Immune Predictive Index for Patients with Primary Liver Cancer Treated with Immune Checkpoint Inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have improved survival outcomes and resulted in long-term responses in primary liver cancer in some patients. Nevertheless, not all patients with PLC could benefit from immunotherapy. Therefore, it is necessary to identify patients suitable for such therapy. METHODS: 215 patients with primary liver cancer with immunotherapy from Nanfang Hospital were screened between August 2018 and October 2020 as a training set and our validation set included 71 patients of hepatocellular carcinoma from Jiangxi Cancer Hospital from May 2019 to July 2021. The primary endpoint was the disease control rate (DCR), and the secondary endpoints were overall survival (OS) and progression-free survival. RESULTS: In the training set, neutrophil-lymphocyte ratio (NLR) ≥3 and alpha-fetoprotein (AFP) level ≥20 ng/mL were independently associated with non-DCR in the training set after adjusting for distant metastasis at baseline and targeted therapy combination. Furthermore, a hepatic immune predictive index (HIPI) based on NLR and AFP level was developed and patients with poor HIPI associated with worse clinical outcomes. In validation set, high HIPI was associated with poor OS. CONCLUSION: HIPI, based on NLR and AFP level, is an effective indicator in ICI-treated patients with primary liver cancer. Our findings may help guide the selection and on-treatment strategies for immunotherapies for primary liver cancer patients.

Reciprocal regulation of HIF-1α and Uroplakin 1A promotes glycolysis and proliferation in Hepatocellular Carcinoma.

Uroplakin 1A (UPK1A) has recently been found dysregulation in many cancers. However, the functions of UPK1A and its underlying mechanisms in hepatocellular carcinoma (HCC) remain poorly understand. In the present study, we found that UPK1A was highly expressed in HCC tumor tissues compared with adjacent non-tumor tissues. Datasets from the Cancer Genome Atlas project (TCGA) and Gene expression Omnibus confirmed that UPK1A was highly expressed in HCC. High expression of UPK1A predicted poor overall survival (OS) in patients with HCC. Univariate and multivariate analysis showed that UPK1A was a significant and independent prognostic predictor for OS of patients with HCC. Functionally, silencing UPK1A suppressed HCC cell glycolysis and proliferation. Mechanistically, hypoxia-inducible factor 1α (HIF-1α) directly bound to the hypoxia response elements (HRE) of UPK1A promoter region, which led to the up-regulation of UPK1A under hypoxia. Furthermore, downregulation of UPK1A reduced key enzyme of glycolysis via regulating HIF-1α. Taken together, these data indicates the existence of a positive feedback loop between HIF-1α and UPK1A that modulates glycolysis and proliferation under hypoxia in HCC cells.

Long noncoding RNA UPK1A-AS1 indicates poor prognosis of hepatocellular carcinoma and promotes cell proliferation through interaction with EZH2.

BACKGROUND: Dysregulation of long non-coding RNAs (lncRNAs) is responsible for cancer initiation and development, positioning lncRNAs as not only biomarkers but also promising therapeutic targets for cancer treatment. A growing number of lncRNAs have been reported in hepatocellular carcinoma (HCC), but their functional and mechanistic roles remain unclear. METHODS: Gene Set Enrichment Analysis was used to investigate the molecular mechanism of UPK1A antisense RNA 1 (UPK1A-AS1). Cell Counting Kit-8 assays, EdU assays, flow cytometry, western blotting, and xenograft assays were used to confirm the role of UPK1A-AS1 in the proliferation of HCC cells in vitro and in vivo. Bioinformatics analyses and quantitative polymerase chain reaction (qRT-PCR) were performed to explore the interplay between UPK1A-AS1 and enhancer of zeste homologue 2 (EZH2). RNA immunoprecipitation (RIP), RNA pull-down assays, western blotting, and qRT-PCR were conducted to confirm the interaction between UPK1A-AS1 and EZH2. The interaction between UPK1A-AS1 and miR-138-5p was examined by luciferase reporter and RIP assays. Finally, the expression level and prognosis value of UPK1A-AS1 in HCC were analyzed using RNA sequencing data from The Cancer Genome Atlas datasets. RESULTS: We showed that UPK1A-AS1, a newly identified lncRNA, promoted cellular proliferation and tumor growth by accelerating cell cycle progression. Cell cycle-related genes, including CCND1, CDK2, CDK4, CCNB1, and CCNB2, were significantly upregulated in HCC cells overexpressing UPK1A-AS1. Furthermore, overexpression of UPK1A-AS1 could protect HCC cells from cis-platinum toxicity. Mechanistically, UPK1A-AS1 interacted with EZH2 to mediate its nuclear translocation and reinforce its binding to SUZ12, leading to increased H27K3 trimethylation. Targeting EZH2 with specific small interfering RNA impaired the UPK1A-AS1-mediated upregulation of proliferation and cell cycle progression-related genes. Moreover, miR-138-5p was identified as a direct target of UPK1A-AS1. Additionally, UPK1A-AS1 was significantly upregulated in HCC, and the upregulation of UPK1A-AS1 predicted poor prognosis for patients with HCC. CONCLUSIONS: Our study revealed that UPK1A-AS1 promotes HCC development by accelerating cell cycle progression through interaction with EZH2 and sponging of miR-138-5p, suggesting that UPK1A-AS1 possesses substantial potential as a novel biomarker for HCC prognosis and therapy.

Identification and Functional Characterization of Long Non-coding RNA MIR22HG as a Tumor Suppressor for Hepatocellular Carcinoma.

Long non-coding RNAs (lncRNAs) have recently been identified as critical regulators in tumor initiation and development. However, the function of lncRNAs in human hepatocellular carcinoma (HCC) remains largely unknown. Our study was designed to explore the biological function and clinical implication of lncRNA MIR22HG in HCC. Methods: We evaluated MIR22HG expression in 52-patient, 145-patient, TCGA, and GSE14520 HCC cohorts. The effects of MIR22HG on HCC were analyzed in terms of proliferation, invasion, and metastasis, both in vitro and in vivo. The mechanism of MIR22HG action was explored through bioinformatics, luciferase reporter, and RNA immunoprecipitation analyses. Results:MIR22HG expression was significantly down-regulated in 4 independent HCC cohorts compared to that in controls. Its low expression was associated with tumor progression and poor prognosis of patients with HCC. Forced expression of MIR22HG in HCC cells significantly suppressed proliferation, invasion, and metastasis in vitro and in vivo. Mechanistically, MIR22HG derived miR-22-3p to target high mobility group box 1 (HMGB1), thereby inactivating HMGB1 downstream pathways. Additionally, MIR22HG directly interacted with HuR and regulated its subcellular localization. MIR22HG competitively bound to human antigen R (HuR), resulting in weakened expression of HuR-stabilized oncogenes, such as ß-catenin. Furthermore, miR-22-3p suppression, HuR or HMGB1 overexpression rescued the inhibitory effects caused by MIR22HG overexpression. Conclusion: Our findings revealed that MIR22HG plays a key role in tumor progression by suppressing the proliferation, invasion, and metastasis of tumor cells, suggesting its potential role as a tumor suppressor and prognostic biomarker in HCC.

[Expression of microRNA-107 in hepatocellular carcinoma and its clinical significance].

OBJECTIVE: To investigate the expression of microRNA-107 (miR-107) and its functional role in hepatocellular carcinoma(HCC). METHODS: The gene chip data of HCC obtained from the Gene Expression Omnibus (GEO) database and the Cancer Genome Atlas (TCGA) database were used to analyze the expression levels of miR-107 in liver cancer. Twenty-two pairs of fresh surgical specimens of HCC and adjacent tissues and 53 paraffin-embedded specimens of HCC were examined for miR-107 expression by qRT-PCR. The correlation of the expression levels of miR-107 with the clinicopathologic characteristics of the patients were analyzed. The role of miR-107 in regulating the proliferation of hepatocellular carcinoma cells were determined by MTT assay in Huh7 cells transfected with a miR-107 mimic or inhibitor. RESULTS: The expression levels of miR-107 were significantly up-regulated in HCC tissues as compared to the adjacent tissues (P<0.05) in positive correlation with the tumor size (P<0.032). Transfection with miR-107 mimics significantly promoted the cell proliferation (P<0.0001) while miR-107 inhibitor inhibited the cell proliferation (P<0.0001). CONCLUSION: The expression of miR-107 is up- regulated in HCC tissues and its expression levels are correlated with HCC cell proliferation, suggesting its role as a potential oncogene in liver cancer.