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Background: Treatment for de novo or recurrent tumors of liver transplantation (LT) recipients is challenging and immune checkpoint inhibitor (ICI) is recently well developed and could be a potentially effective option for this population. There remains limited evidence on the safety and efficacy of ICI therapy in LT recipients., Methods: A systematic literature search was conducted on PubMed database through April 1, 2022, to identify publications reporting ICI treatment for malignant tumors in LT recipients. We summarized the allograft rejection, mortality, and tumor response of ICI treatment., Results: 24 articles with 41 LT recipients were identified. The age of LT recipients ranged from 14 to 78, 76.2% were male, 56.1% had recurrent HCC, and 87.8% received anti-PD-1 therapy. Allograft rejection occurred in 31.7% of patients, death was reported in 46.3% and 6 cases died secondary to allograft rejection. Progressive disease rate of this population was 48.8% and 10 patients responded to immunotherapy. Half of recipients with positive PD-L1 staining (4/8) experienced allograft rejection., Conclusions: ICI therapy has potential therapeutic value on malignant tumors for LT recipients, accompanied by a high rate of allograft rejection and mortality. PD-L1 expression, type of ICI, and immunosuppression agent should be taken into consideration before initiation of immunotherapy. Further studies are needed to optimize this anticancer treatment approach in these patients., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Multi-drug resistance (MDR) is a complicated cellular defense mechanism for tumor cells to resist chemotherapy drugs, which is also the main cause of chemotherapy failure. In this study, a local injectable hydrogel delivery system was used to construct an on-demand sustained-release platform with the advantages of chemotherapy, photothermal therapy (PTT), and magnetic resonance imaging (MRI). It could achieve synergistic chemo-photothermal therapy and real-time evaluation of the therapeutic effects ( via MRI) for MDR hepatocellular carcinoma (HCC). Furthermore, after a single administration, the prepared hydrogel with a theranostic nanoprobe could release the therapeutic agents on demand for up to 14 d. Firstly, doxorubicin (DOX) and gold-manganese oxide (Au-MnO) nanoparticles (NPs) were incorporated into liposome-based self-assembled micelles, then loaded into the thermosensitive hydrogel (F127) to form DOX@Au-MnO-L NPs/F127 hydrogel (DAML/H). The prepared NP complex showed a spherical morphology with a narrow size distribution. The prepared hydrogel drug delivery system had injectable properties and stable photothermal conversion. Both the DOX@Au-MnO-L NPs and DAML/H showed controlled drug release under near infrared (NIR) laser irradiation. The in vitro MRI studies indicated that the prepared DAML/H had a high relaxation rate (14.38 mM -1 s -1 ) and good MRI scanning sensitivity conditions. The in vitro and in vivo results suggested the synergistic chemo-photothermal therapy of DAML/H with NIR irradiation (808 nm, 1 W cm -2 , 10 min) improved the antitumor efficacy for MDR HCC. The in vivo retention experiment of Au in tumors indicated that the prepared hydrogel drug delivery system (DAML/H) had a good ability to retain Au in the tumor for a long time (at least 14 d). The western blotting results revealed that DAML/H with laser treatment could effectively downregulate P-glycoprotein (P-gp), p53 and antiapoptotic protein (Bcl-2), whereas the expression level of proapoptotic protein (Bax) and caspase-3 were increased. Therefore, DAML/H could serve as a promising synergistic chemo-photothermal therapy for MDR HCC, and a single administration might achieve long-term (14 d), on-demand, sustained-release treatment of tumors.

Long non‑coding RNAs (lncRNAs) serve a pivotal role in hepatocellular carcinoma (HCC) progression and have been confirmed to participate in the carcinogenesis and development of HCC. Certain studies have focused on lncRNA nuclear enriched abundant transcript 1 (NEAT1) in HCC. However, the relationship between lncRNA NEAT1 and HCC remains unclear. The present study found that NEAT1 was significantly overexpressed in HCC cell lines compared with LX‑2 hepatic stellate cells. NEAT1 expression in Huh7 and MHCC‑97H cells was increased following transfection with lentivirus (LV)‑NEAT1 but inhibited by LV‑short hairpin NEAT1. Knockdown of NEAT1 significantly repressed HCC cell viability, increased cell apoptosis, and inhibited cell migration and invasion capacity. By contrast, upregulation of NEAT1 demonstrated the reverse effects. Furthermore, microRNA‑320a (miR‑230a) was predicted to be a direct target of NEAT1 and was significantly reduced in HCC cells. Additionally, a luciferase activity reporter assay and RNA immunoprecipitation assay were performed to confirm the interaction between miR‑320a and NEAT1. Using a dual‑luciferase activity assay, L antigen family member 3 (LAGE3) was found to be a target of miR‑320a. Finally, in vivo nude mouse models were established, and the results indicated that NEAT1 suppressed HCC progression by targeting miR‑320a. In conclusion, the present findings revealed that the NEAT1/miR‑320a/LAGE3 axis participates in HCC development and that NEAT1 could be used as a biomarker for HCC.

In this study, we investigated the mechanistic role of the long non-coding RNA (lncRNA) AC092171.4 in hepatocellular carcinoma (HCC). AC092171.4 was significantly upregulated in HCC tumor tissues compared to normal liver tissues. HCC patients with high AC092171.4 expression showed poorer overall survival (OS) and disease-free survival (DFS) than those with low AC092171.4 expression. In vitro cell proliferation, migration and invasiveness were all higher in AC092171.4-overexpressing HCC cells, but lower in AC092171.4-silenced HCC cells, than in controls. Balb/c nude mice injected with AC092171.4-silenced HCC cells had smaller xenograft tumors, which showed less growth and pulmonary metastasis than control tumors. Bioinformatics analyses and dual luciferase reporter assays confirmed that AC092171.4 binds directly to miR-1271, which targets the 3'UTR of GRB2 mRNA. AC092171.4 expression correlates negatively with miR1271 expression and correlates positively with GRB2 mRNA expression in HCC tissues from patients. HCC cells co-transfected with miR-1271 mimics and sh-AC092171.4 show less proliferation, migration, invasiveness, GRB2 protein, and epithelial to mesencyhmal transition (EMT) than sh-AC092171.4-transfected HCC cells. These findings demonstrate that AC092171.4 promotes growth and progression of HCC by sponging miR-1271 and upregulating GRB2. This makes AC092171.4 a potential prognostic indicator and therapeutic target for HCC patients.

The epigenetic silencing mechanism of suppressor 3 of cytokine signaling (SOCS3) in cancers has not been fully elucidated. Polycomb repressive complexes 2 (PRC2), an important epigenetic regulatory factors, exerts a critical role in repressing the initial phase of gene transcription. Whether PRC2 participates the down- regulation of SOCS3 in Hepatocellular carcinoma (HCC) remains unclear and how does PRC2 be recruited target gene still needs to explore. In this study, Using TCGA HCC dataset, and detecting HCC tissue specimens and cell lines, we found that SOCS3 expression in HCC was inversely related to that of EZH2, and depended on its promoter methylation status. CTCF, vigilin, EZH2 and H3K27me3 were enriched at CTCF and EZH2 binding sites on the methylated SOCS3 gene promoter. The depletion of CTCF did not affect expression of EZH2 and DNMT1, but decrease recruitment of CTCF, vigilin, EZH2 and H3K27me3. Further, knockdown of CTCF led to a loss of methylation of the methylated SOCS3 promoter, which sequentially increased the expression of SOCS3 and decreased the expression of pSTAT3, the downstream effector. These findings suggest that the CTCF dependent recruitment of EZH2 to the SOCS3 gene promoter is likely to participate in the epigenetic silencing of SOCS3 and in regulating its gene expression., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Obg-like ATPase 1 (OLA1) has been found to have a dual role in cancers. However, the relationship between OLA1 and hepatocellular carcinoma (HCC) remains unclear., Results: High expression of OLA1 in HCC was detected in public datasets and clinical samples, and correlated with poor prognosis. Downregulation of OLA1 significantly inhibited the proliferation, migration, invasion and tumorigenicity of HCC cells. Mechanistically, GSEA showed that OLA1 might promote tumor progression by regulating the cell cycle and apoptosis. In addition, OLA1 knockdown resulted in G0/G1 phase arrest and high levels of apoptosis. OLA1 could bind with P21 and upregulate CDK2 expression to promote HCC progression., Conclusions: Overall, these findings uncover a role for OLA1 in regulating the proliferation and apoptosis of HCC cells., Materials and Methods: The Cancer Genome Atlas and Gene Expression Omnibus datasets were analyzed to identify gene expression. Immunohistochemistry staining, western blot and real-time polymerase chain reaction were performed to evaluate OLA1 expression in samples. Cell count Kit-8, wound-healing, transwell and flow cytometry assays were used to analyze HCC cell progression. Subcutaneous xenotransplantation models were used to investigate the role of OLA1 in vivo. Coimmunoprecipitation was used to analyze protein interactions.

Spindle and kinetochore-related complex subunit 3 (SKA3) is a component of the spindle and kinetochore-related complexes and is essential for accurate timing of late mitosis. However, the relationship between SKA3 and hepatocellular carcinoma (HCC) has not yet been fully elucidated. Gene expression omnibus (GEO) (GSE62232, GSE45436, GSE6764, and GSE36376) and The Cancer Atlas (TCGA) datasets were analyzed to identify differential expression genes. Cell proliferation ability was analyzed using Cell Counting Kit-8 (CCK8) assay and plate clone formation assay, while scratch wound healing assay and transwell assay were used to analyze cell invasion. The role of SKA3 in vivo was explored using subcutaneous xenotransplantation model and lung metastasis model. Bioinformatics analysis found that hepatocellular carcinoma patients with high levels of expression of SKA3 have a poor prognosis. Similarly, immunohistochemical staining of 236 samples of tumors also found higher SKA3 expression in them, than in adjacent normal liver tissues. Significant levels of inhibition of in vivo and in vitro tumor proliferation and invasion result from the downregulation of SKA3. Mechanistically, SKA3 was found to affect tumor progression through the cell cycle and P53 signaling pathway as shown by the gene enrichment analysis (GSEA). G2/M phase arrest and severe apoptosis was also found to result from SKA3 knockdown, as shown by the inhibition of CDK2/p53 phosphorylation together with downregulation of BAX/Bcl-2 expression in HCC cells. Overall, these findings uncover the role of SKA3 in regulating the apoptosis and proliferation of hepatocellular carcinoma cells. This study was able to uncover new information on the tumorigenesis mechanism in hepatocellular carcinoma.

Non-SMC condensing I complex subunit H (NCAPH) is a member of the Barr protein family and part of the condensin I complex. The upregulation of NCAPH is associated with poor prognosis in patients with colon cancer. However, the relationship between NCAPH and hepatocellular carcinoma (HCC) remains unclear. This study aimed to explore NCAPH expression in HCC tissues and to investigate NCAPH functions in HCC cells. In this study, we found that high expression of NCAPH in HCC indicated worse prognosis via bioinformatics analysis. Consistently, quantitative real-time polymerase chain reaction assays in 20 pairs of HCC specimens and the immunohistochemical analysis of 100 HCC tissues showed the upregulation of NCAPH. We established stable NCAPH-overexpressing and NCAPH knockdown cell lines. Cell Counting Kit-8 assays and colony formation assay were performed to analyze cell proliferation. Migration and invasion were analyzed by Transwell assays. Subcutaneous xenograft models were used to explore the role of NCAPH in tumor formation in vivo. Our results showed that NCAPH promoted tumor proliferation, migration, and invasion in vitro and in vivo. In conclusion, our findings indicate that NCAPH could serve as a novel prognostic biomarker and a potential therapeutic target for patients with HCC., (© 2019 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc.)

Patients with advanced hepatocellular carcinoma (HCC) continue to have a dismal prognosis. Potential biomarkers to determine prognosis and select targeted therapies are urgently needed for patients with HCC. This study aimed to elucidate the role of UCK2 in HCC prognosis and tumor progression. We performed a screen of public databases to identify functional genes associated with HCC tumorigenesis, progression, and outcome. We identified uridine-cytidine kinase 2 (UCK2) as a gene of interest for further study. UCK2 promoting HCC aggressiveness was demonstrated by evaluation of clinical samples, in vitro experiments, in vivo tumorigenicity, and transcript analysis. UCK2 expression was generally elevated in HCC and was significantly correlated with poor survival and inferior clinicopathological characteristics of HCC patients. A multivariate analysis revealed that high UCK2 expression was an independent factor for poor prognosis. In HCC cell lines, UCK2 knockdown suppressed cell migration and invasion and inhibited cell proliferation, while UCK2 overexpression had an opposite effect. Animal model experiments confirmed that knockdown of UCK2 suppressed tumor growth in vivo. The bioinformatics analysis demonstrated that UCK2 might associated with metabolsim, splicesome, and adherens junction. UCK2 is highly associated with HCC malignant behavior and is a potential prognostic predictor for HCC patients in the clinic., (© 2018 Wiley Periodicals, Inc.)

Exportin-T (XPOT) belongs to the RAN-GTPase exportin family that mediates export of tRNA from the nucleus to the cytoplasm. Up-regulation of XPOT indicates poor prognosis in breast cancer patients. However, the correlation between XPOT and hepatocellular carcinoma (HCC) remains unclear. Here, we found that high expression of XPOT in HCC indicated worse prognosis via bioinformatics analysis. Consistently, immunohistochemical staining of 95 pairs of tumors and adjacent normal liver tissues (ANLT) also showed up-regulation of XPOT. Small interfering (si) RNA transfection was used to down-regulate XPOT in HepG2 and 7721 cell lines. Cell Counting Kit-8 (CCK8) assays were performed to analyze cell proliferation. Cell migration and invasion were measured by scratch wound healing assays and migration assays. Subcutaneous xenograft models were using to explore the role of XPOT in tumor formation in vivo. Down-regulation of XPOT significantly inhibited tumor proliferation and invasion in vitro and vivo. Gene set enrichment analysis (GSEA) results indicated that XPOT may affect tumor progression through cell cycle and ubiquitin-mediated proteolysis. Furthermore, knockdown of XPOT caused a block in G0/G1 phase as evidenced by down-regulation of cyclin-dependent kinase 1 (CDK1), cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4), CyclinA1 (CCNA1), CyclinB1 (CCNB1), CyclinB2 (CCNB2), and CyclinE2 (CCNE2) in HCC cells. In conclusion, our findings indicate that XPOT could serve as a novel biomarker for prognoses and a potential therapeutic target for patients with HCC., (© 2018 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc.)

Dosage suppressor of Nnf1 (DSN1) is a component of the kinetochore protein complex that is required for proper chromosome segregation. Some studies have explored that DSN1 is related to colorectal cancer progression. However, the role of DSN1 in hepatocellular carcinoma (HCC) remains unknown. This study aimed to explore DSN1 expression in HCC tissues. We obtained data from The Cancer Genome Atlas and Gene Expression Omnibus to analyze DSN1 expression in HCC. DSN1 mRNA expression was assessed in 30 pairs of HCC samples via reverse-transcription quantitative polymerase chain reaction. Immunohistochemical analysis of 95 HCC tissue specimens was performed to assess DSN1 expression and examine the clinicopathological characteristics of DSN1 in HCC. Results showed that DSN1 was upregulated in HCC tissues and was strongly associated with sex (P = .031), α-fetoprotein (P < .001), tumor size (P = .032), tumor nodule number (P = .028), cancer embolus (P = .011), and differentiation grade (P = .001). Moreover, Kaplan-Meier and Cox proportional-hazards analyses indicated that high DSN1 expression was related to poor HCC patient survival and that DSN1 can serve as an independent prognostic factor for overall survival and disease-free survival. In conclusion, our findings indicate that DSN1 could serve as a novel prognostic biomarker for HCC patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

SOCS3 as an important negative regulator of IL6/JAK/STAT3 signaling pathway may be early critical determinants of carcinogenesis. This study aimed to explore the aberrant promoter methylation of SOCS3 gene in circulating DNA as a noninvasive biomarker for screening hepatocellular carcinoma (HCC) high-risk individuals and for prognosis of HCC patients after partial hepatectomy. We detected its methylation status in 116 liver tissues and 326 plasma specimens of different hepatic diseases and healthy subjects, and its mRNA and protein expression in tissues. Higher methylation rate was remarkably detected in HCC (47.92%), compared with corresponding non-tumor (25.0%), liver cirrhosis (LC) (10.0%), benign liver diseases (0%) and normal liver tissues (0%) (all P < 0.05). SOCS3 mRNA level was significantly lower in methylated HCC tissues (P < 0.05). The expressions of SOCS3 and pSTAT3 were affected by methylation status. Correlation and consistency of SOCS3 methylation were found between cancer tissue and corresponding plasma (P < 0.001, κ = 0.747). The detection rate of plasma for HCC reached 73.91%, with no false positive error. SOCS3 methylation status both in tissue and plasma was significantly associated with AFP400, tumor size, tumor differentiation, LC, metastasis and recurrence (all P < 0.05). Patients with SOCS3 methylation were followed up a markedly poorer prognosis than those unmethylated for disease-free survival (P < 0.05). These data indicate that methylation status of SOCS3 in plasma cell-free DNA can correctly reflect that in tissue DNA and be used as a noninvasive potential biomarker for chronic liver disease monitoring, predicting the degree of malignancy and poor prognosis of HCC.