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Background: Microvascular invasion (MVI) is an independent detrimental risk factor for tumor recurrence and poor survival in hepatocellular carcinoma (HCC). Competitive endogenous RNA (ceRNA) networks play a pivotal role in the modulation of carcinogenesis and progression among diverse tumor types. However, whether the ceRNA mechanisms are engaged in promoting the MVI process in patients with HCC remains unknown., Methods: A ceRNA regulatory network was constructed based on RNA-seq data of patients with HCC from The Cancer Genome Atlas (TCGA) database. In total, 10 hub genes of the ceRNA network were identified using four algorithms: "MCC," "Degree," "Betweenness," and "Stress." Transcriptional expressions were verified by in situ hybridization using clinical samples. Interactions between ceRNA modules were validated by luciferase reporting assay. Logistic regression analysis, correlation analysis, enrichment analysis, promoter region analysis, methylation analysis, and immune infiltration analysis were performed to further investigate the molecular mechanisms and clinical transformation value., Results: The ceRNA regulatory network featuring a tumor invasion phenotype consisting of 3 long noncoding RNAs, 3 microRNAs, and 93 mRNAs was constructed using transcriptional data from the TCGA database. Systemic analysis and experimentally validation identified a ceRNA network (PVT1/miR-1258/DUSP13 axis) characterized by lipid regulatory potential, immune properties, and abnormal methylation states in patients with HCC and MVI. Meanwhile, 28 transcriptional factors were identified as potential promotors of PVT1 with 3 transcriptional factors MXD3, ZNF580, and KDM1A promising as therapeutic targets in patients with HCC and MVI. Furthermore, miR-1258 was an independent predictor for MVI in patients with HCC., Conclusion: The PVT1/DUSP13 axis is significantly associated with MVI progression in HCC patients. This study provides new insight into mechanisms related to lipids, immune phenotypes, and abnormal epigenetics in oncology research., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies; its recurrence is associated with high mortality and poor recurrence-free survival and is affected by multisystem and multilevel pathological changes. To identify the key proteins associated with tumor recurrence and the underlying mechanisms, proteomic profiling of tumor specimens from early recurrence and nonrecurrence patients was performed in this study. Proteomics was applied to identify differentially expressed proteins during the early recurrence of HCC after surgery. Osteosarcoma amplified-9 (OS-9) was discovered, and the correlation between OS-9 expression and the clinicopathological characteristics of patients was analyzed. Invasion and migration were examined in SMMC-7721 cells with and without OS-9 overexpression. Proteomics was performed once again using SMMC-7721 cells with OS-9 overexpression to further analyze the proteins with altered expression. OS-9 was overexpressed in the early recurrence group, and OS-9 overexpression was associated with high serum alpha-fetoprotein levels and poor recurrence-free survival in 196 patients with HCC. The invasion and migration abilities of SMMC-7721 cells were enhanced in the OS-9 overexpression group. Bioinformatic functional enrichment methods, including Gene Ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway analysis, revealed that the hypoxia-inducible factor 1 (HIF-1) and tumor necrosis factor (TNF) signaling pathways were activated in the OS-9 overexpression group. The migration and invasion capacities of OS-9 overexpressed HCC cell line were weakened while treated with HIF-1α or TNF-α inhibitors. Conclusion: Our results suggest that the overexpression of OS-9 is related to HCC recurrence, thereby contributing to the migration and invasion capacities of HCC cell line by regulating the HIF-1 and TNF pathways., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background and Aim: Donor shortage has become worldwide limitation in liver transplantation (LT). Use of hepatitis B virus surface antigen positive (HBsAg+) donors could be an alternative source of donor organs. This study aims to investigate the safety and efficacy of LT using HBsAg+ liver grafts and associated long-term outcome., Methods: This was a retrospective study of adults LT registered in the database of the China Liver Transplant Registry between January 2015 and September 2018. By propensity score matching (1:1), 503 eligible patients who received HBsAg+ liver grafts were compared with 503 matched patients who received HBsAg- liver grafts., Results: The 1-, 3-, and 5-year patient survival rates were 81.52%, 72.04%, and 66.65% in HBsAg+ donor group, which were comparable with 83.93%, 77.27%, and 65.73% in HBsAg- donor group (P = 0.222). The 1-, 3-, and 5-year graft survival rates were also comparable between the two groups (81.49%, 71.45%, and 67.26% vs 83.62%, 77.11%, and 65.81%, respectively, P = 0.243). Most main complications were not increased in HBsAg+ donor group except for the retaining of HBsAg positivity after LT. Furthermore, transplanting HBsAg+ liver grafts did not result in inferior outcomes either in HBsAg+ or HBsAg- recipients. The risk of tumor recurrence after LT was not increased in hepatocellular carcinoma patients., Conclusions: The outcomes of using HBsAg+ liver grafts were comparable with those of HBsAg- liver grafts. Our study provided strong evidence for the safe use of HBsAg+ grafts in LT to expand the donor liver pool., (© 2022 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objective: We aimed to elucidate the mutual regulation mechanism of ubiquitin-specific protease 22 (USP22) and hypoxia inducible factor-1α (HIF1α), and the mechanism they promote the stemness of hepatocellular carcinoma (HCC) cells under hypoxic conditions., Design: Cell counting, migration, self-renewal ability, chemoresistance and expression of stemness genes were established to detect the stemness of HCC cells. Immunoprecipitation, ubiquitination assay and chromatin immunoprecipitation assay were used to elucidate the mutual regulation mechanism of USP22 and HIF1α. HCC patient samples and The Cancer Genome Atlas data were used to demonstrate the clinical significance. In vivo USP22-targeting experiment was performed in mice bearing HCC., Results: USP22 promotes hypoxia-induced HCC stemness and glycolysis by deubiquitinating and stabilising HIF1α. As direct target genes of HIF1α, USP22 and TP53 can be transcriptionally upregulated by HIF1α under hypoxic conditions. In TP53 wild-type HCC cells, HIF1α induced TP53-mediated inhibition of HIF1α-induced USP22 upregulation. In TP53-mutant HCC cells, USP22 and HIF1α formed a positive feedback loop and promote the stemness of HCC. HCC patients with a loss-of-function mutation at TP53 and high USP22 and/or HIF1α expression tend to have a worse prognosis. The USP22-targeting lipopolyplexes caused high tumour inhibition and high sorafenib sensitivity in mice bearing HCC., Conclusion: USP22 promotes hypoxia-induced HCC stemness by a HIF1α/USP22 positive feedback loop on TP53 inactivation. USP22 is a promising target for the HCC therapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Accumulating evidence indicates that long non-coding RNAs (lncRNAs) play a crucial role in hepatocellular carcinoma (HCC). Here, we reported a novel lncRNA, CTC-505O3 (lncRNA DRHC), that was downregulated in HCC and its low expression was associated with dismal survival. Gain-of-function studies indicated that it inhibited proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in HCC cell lines in vitro. lncRNA DRHC also inhibited tumorigenicity in vivo. In mechanistic experiments, GO analysis based on NGS indicated that MAPK signaling was most affected. The result was confirmed by Western blot and this effect was abolished either by MEK1/2 specific inhibitor Trametinib or ERK1/2 inhibitor SCH772984. In addition, differences in proliferation and invasion were abrogated by Trametinib. Moreover, we found that lncRNA DRHC interacted with MYBBP1A and modulated MEK/ERK signaling via c-Myb. Taken together, our findings indicate that the lncRNA DRHC play a key role in HCC progression and may serve as a novel therapeutic target., (© 2018 Wiley Periodicals, Inc.)

In this study, we used proteomic profiling to compare hepatocellular carcinoma (HCC) and peri-tumoral tissues to identify potential tumor markers of HCC. We identified eight differentially expressed proteins (>3-fold), including Peroxiredoxin 6 (PRDX6). PRDX6 is a bifunctional enzyme with both peroxidase and calcium-independent phospholipase A2 (iPLA2) activity. We found that peri-tumoral tissues expressed higher levels of PRDX6 mRNA (n = 59, P = 0.018) and protein (n = 265, P < 0.001) than HCC tissues, and that decreased expression of PRDX6 in HCC tissues was an independent risk factor indicating a poor prognosis (n = 145, P = 0.007). Combining the examination of serum PRDX6 with α-fetoprotein improved the diagnostic sensitivity of tests for HCC compared to α-fetoprotein alone (85.0% vs 50.0%, n = 40). We found that PRDX6 induced S phase arrest in HCC cells and inhibited HCC tumorigenicity in mice injected with cancer cells. When treated with H2 O2 , PRDX6 inhibited apoptosis. When treated with tumor necrosis factor alpha (TNF-α), PRDX6 promoted apoptosis. Inhibition of iPLA2 activity of PRDX6 decreased the apoptosis induced by TNF-α. In conclusion, PRDX6 inhibited the carcinogenesis of HCC, and the iPLA2 activity of PRDX6 promoted cancer cell death induced by TNF-α. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Recurrence of hepatocellular carcinoma (HCC) is one of the leading causes of death after liver transplantation (LT). We aim to evaluate the association of donor and recipient single nucleotide polymorphisms (SNPs) with the risk of HCC recurrence after LT. A total of 155 adult patients who underwent primary LT for HCC were enrolled. Ten SNPs associated with HCC susceptibility were genotyped. Patients who received donor livers with the rs11614913 homozygous CC variant presented significantly higher recurrence rates of HCC (41.7 vs. 15.3%, p = 0.009) and lower cumulative tumor-free survival (p = 0.005) than those who received TT wild-type donor livers. The donor rs11614913 genetic variant was an independent risk factor for HCC recurrence (odds ratio = 2 per each C allele, p < 0.05) and could significantly improve the predictive abilities of clinical models (Milan, UCSF and Hangzhou criteria). Donor livers homozygous for rs11614913 CC were associated with a higher miR-196a expression than TT (p = 0.002). In a lentiviral infection of mouse liver and orthotopic mouse model of HCC, the liver miR-196a overexpression group showed a significantly larger tumor size than the control group (p = 0.001). There is a close association between the tumor size and expression of miR-196a in the liver (r = 0.693, p = 0.001). In conclusion, the donor miR-196a-2 rs11614913 polymorphism is associated with HCC recurrence after LT and improves the predictive value of clinical models. The overexpression of miR-196a in the liver might provide a tumor-favorable environment for the development of HCC., (© 2015 UICC.)

Background: Needle core biopsy (NCB) is one of the most widely used and accepted methods for the diagnosis of focal hepatic lesions. Although many studies have assessed the diagnostic accuracy of NCB in predicting the tumor grade, it is still under debate., Objective: To identify the influence of number of biopsies on NCB diagnostic accuracy., Methods: 153 patients with HCC were selected from patients who received preoperative NCB under the guidance of ultrasonography in our hospital. The diagnostic reference standard was the surgical pathologic diagnosis., Results: Using a 3-tier grading scheme (well, moderate and poor), the accuracy of NCB has no significant differences among different number of passes in HCC ≤5 cm. For HCC >5≤8 cm, the increasing number of passes could increase the diagnostic accuracy (63.3%, 81.8%, and 84.8% for passes one, two, and three, respectively). While in HCC>8 cm, the diagnostic accuracy of passes one, two, and three were 62.1%, 69%, and 75.8%, respectively., Conclusions: The accuracy of NCB in assessing tumor grading associated with tumor size and number of passes. Meanwhile, a minimum of two passes should be performed to get better accuracy in patients with HCC >5 cm.

Background and Aim: Our previous proteomic research found that chloride intracellular channel 1 (CLIC1) was upregulated in hepatocellular carcinoma (HCC) tissues with portal vein tumor thrombus. The present study aimed to determine the role of CLIC1 in HCC invasion., Methods: Immunohistochemistry was used to explore protein expression of CLIC1 in 15 cirrhotic tissues and 69 pairs of HCC and paracarcinoma tissues. Small interfering RNA (siRNA) and plasmids were transfected into HepG2 and SMMC7721 cells, and the in vitro function of CLIC1 in these cells were assessed with cell counting kit-8 assays, cell apoptosis assays, scratch assays, and transwell assays. Microarray analysis was also performed to further explore the candidate genes related to CLIC1., Results: Our results confirmed that upregulated CLIC1 expression was significantly correlated with vascular invasion (P = 0.034) in HCC tissues. Knockdown of CLIC1 decreased cell viability and the invasive potency of HepG2 cells, whereas CLIC1 overexpression resulted in an opposite effect in SMMC7721 cells. Microarray analysis identified 618 genes that were differentially expressed (fold change ≥ 2, P < 0.05) between HepG2 cells transfected with CLIC1 siRNA and the negative control. Further studies indicate that knockdown of CLIC1 increased maspin expression and reduced vascular endothelial growth factor (VEGF), matrixmetalloproteinase-2 (MMP2), MMP9, MMP11, and MMP12 expression. In contrast, overexpression of CLIC1 decreased maspin expression and increased VEGF, MMP2, MMP12, and MMP13 expression., Conclusions: CLIC1 protein expression is significantly correlated with vascular invasion, and the present study suggests a previously unknown mechanism of CLIC1-mediated control of HCC invasiveness by targeting maspin., (© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)