CircZCCHC2 (hsa_circ_0000854) promotes hepatocellular carcinoma progression through modulating miR-936/BTBD7 axis and activating Rho/ROCK2 pathway.

Hepatocellular carcinoma (HCC) is one of the most aggressive and refractory cancers due to its high propensity to metastasize and the unavailability of efficacious treatments. Circular RNAs (circRNAs) participate in diverse biological activities in human cancers. Here, we detected the upregulation of a novel circRNA, circZCCHC2 (hsa_circ_0000854), in HCC samples and cells. The upregulation indicated an unfavorable prognosis in HCC patients. CircZCCHC2 accelerated cell growth and metastasis in vitro and tumorigenicity in vivo. Mechanistic investigations revealed that circZCCHC2 regulated BTBD7 expression by sponging miR-936. Moreover, the suppression of malignancy caused by circZCCHC2 knockdown could be sufficiently reversed by miR-936 inhibition. Additionally, the suppressed Rho/ROCK2 pathway conferred by circZCCHC2 knockdown could be restored by inhibiting miR-936 expression. Collectively, our findings reveal that circZCCHC2 plays an oncogenic role of in HCC progression by modulating the miR-936/BTBD7/Rho/ROCK2 pathway.

The adverse impact of perioperative body composition abnormalities on outcomes after split liver transplantation: a multi-center retrospective cohort study.

BACKGROUND: Split liver transplantation increases graft availability, but its safe and effective utilization is insufficiently documented. This study aimed to investigate the association between perioperative body composition abnormalities and outcomes in adult split liver transplantation. MATERIALS AND METHODS: 240 recipients who underwent split liver transplantation in three centers were enrolled in this retrospective cohort study. Body composition abnormalities including sarcopenia, myosteatosis, visceral obesity, and sarcopenic obesity were evaluated at baseline and one month after surgery using computed tomography. Their impact on outcomes including early allograft dysfunction, early complications, intensive care unit stay, graft regeneration rate and survival was analyzed. RESULTS: Recipients with sarcopenia or myosteatosis had a higher risk of early allograft dysfunction, higher early complication rate, and longer length of intensive care unit stay (all P<0.05), while there was no difference in graft regeneration rate. Recipient and graft survival were significantly worse for recipients with body composition abnormalities (all P<0.05). In multivariable Cox-regression analysis, sarcopenia (hazard ratio=1.765, P=0.015), myosteatosis (hazard ratio=2.066, P=0.002), and visceral obesity (hazard ratio=1.863, P=0.008) were independently associated with shorter overall survival. Piling up of the three factors increased the mortality risk stepwise (P<0.001). Recipients experienced skeletal muscle loss and muscle fat infiltration one month after surgery. Postoperative worsening sarcopenia (hazard ratio=2.359, P=0.009) and myosteatosis (hazard ratio=1.878, P=0.026) were also identified as independent risk factors for mortality. CONCLUSION: Sarcopenia, myosteatosis and their progression negatively affect outcomes including early allograft dysfunction, early complications, intensive care unit stay and survival after SLT. Systemic evaluation and dynamic monitoring of body composition are valuable.

Post-transplant hepatitis B virus reactivation impacts the prognosis of patients with hepatitis B-related hepatocellular carcinoma: a dual-centre retrospective cohort study in China.

BACKGROUND: Highly active hepatitis B virus (HBV) is known to be associated with poor outcomes in patients with hepatocellular carcinoma (HCC). This study aims to investigate the relationship between HBV status and HCC recurrence after liver transplantation. METHODS: The study retrospectively analyzed HCC patients undergoing liver transplantation in two centres between January 2015 and December 2020. The authors reviewed post-transplant HBV status and its association with outcomes. RESULTS: The prognosis of recipients with hepatitis B surface antigen (HBsAg) reappearance ( n =58) was poorer than those with HBsAg persistent negative ( n =351) and positive ( n =53). In HBsAg persistent positive group, recipients with HBV DNA reappearance or greater than 10-fold increase above baseline had worse outcomes than those without ( P <0.01). HBV reactivation was defined as (a) HBsAg reappearance or (b) HBV DNA reappearance or greater than 10-fold increase above baseline. After propensity score matching, the 5-year overall survival rate and recurrence-free survival rate after liver transplantation in recipients with HBV reactivation were significantly lower than those without (32.0% vs. 62.3%; P <0.01, and 16.4% vs. 63.1%; P <0.01, respectively). Moreover, HBV reactivation was significantly related to post-transplant HCC recurrence, especially lung metastasis. Cox regression analysis revealed that beyond Milan criteria, microvascular invasion and HBsAg-positive graft were independent risk factors for post-transplant HBV reactivation, and a novel nomogram was established accordingly with a good predictive efficacy (area under the time-dependent receiver operating characteristic curve=0.78, C-index =0.73). CONCLUSIONS: Recipients with HBV reactivation had worse outcomes and higher tumour recurrence rates than those without. The nomogram could be used to evaluate the risk of post-transplant HBV reactivation effectively.

FGF21-mediated autophagy: Remodeling the homeostasis in response to stress in liver diseases.

Liver diseases are worldwide problems closely associated with various stresses, such as endoplasmic reticulum stress. The exact interplay between stress and liver diseases remains unclear. Autophagy plays an essential role in maintaining homeostasis, and recent studies indicate tight crosstalk between stress and autophagy in liver diseases. Once the balance between damage and autophagy is broken, autophagy can no longer resist injury or maintain homeostasis. In recent years, FGF21 (fibroblast growth factor 21)-induced autophagy has attracted much attention. FGF21 is regarded as a stress hormone and can be up-regulated by an abundance of signaling pathways in response to stress. Also, increased FGF21 activates autophagy by a complicated signaling network in which mTOR plays a pivotal role. This review summarizes the mechanism of FGF21-mediated autophagy and its derived application in the defense of stress in liver diseases and offers a glimpse into its promising prospect in future clinical practice.

Double-negative T cells: a promising avenue of adoptive cell therapy in transplant oncology. / 双阴性Tç»†èƒžï¼šç§»æ¤è‚¿ç˜¤å­¦ä¸­ä¸€ç§é¢‡å ·å‰æ™¯çš„è¿‡ç»§ç»†èƒžç–—æ³•.

Tumor recurrence is one of the major life-threatening complications after liver transplantation for liver cancer. In addition to the common mechanisms underlying tumor recurrence, another unavoidable problem is that the immunosuppressive therapeutic regimen after transplantation could promote tumor recurrence and metastasis. Transplant oncology is an emerging field that addresses oncological challenges in transplantation. In this context, a comprehensive therapeutic management approach is required to balance the anti-tumor treatment and immunosuppressive status of recipients. Double-negative T cells (DNTs) are a cluster of heterogeneous cells mainly consisting of two subsets stratified by T cell receptor (TCR) type. Among them, TCRαß+ DNTs are considered to induce immune suppression in immune-mediated diseases, while TCRγδ+ DNTs are widely recognized as tumor killers. As a composite cell therapy, healthy donor-derived DNTs can be propagated to therapeutic numbers in vitro and applied for the treatment of several malignancies without impairing normal tissues or being rejected by the host. In this work, we summarized the biological characteristics and functions of DNTs in oncology, immunology, and transplantation. Based on the multiple roles of DNTs, we propose that a new balance could be achieved in liver transplant oncology using them as an off-the-shelf adoptive cell therapy (ACT).

TNFR2 is a potent prognostic biomarker for post-transplant lung metastasis in patients with hepatocellular carcinoma.

Objective: Lung metastasis is a common and fatal complication of liver transplantation for hepatocellular carcinoma (HCC). The precise prediction of post-transplant lung metastasis in the early phase is of great value. Methods: The mRNA profiles of primary and paired lung metastatic lesions were analyzed to determine key signaling pathways. We enrolled 241 HCC patients who underwent liver transplantation from three centers. Tissue microarrays were used to evaluate the prognostic capacity of tumor necrosis factor (TNF), tumor necrosis factor receptor 1 (TNFR1), and TNFR2, particularly for post-transplant lung metastasis. Results: Comparison of primary and lung metastatic lesions revealed that the TNF-dependent signaling pathway was related to lung metastasis of HCC. The expression of TNF was degraded in comparison to that in para-tumor tissues (P<0.001). The expression of key receptors in the TNF-dependent signaling pathway, TNFR1 and TNFR2, was higher in HCC tissues than in para-tumor tissues (P<0.001). TNF and TNFR1 showed no relationship with patients' outcomes, whereas elevated TNFR2 in tumor tissue was significantly associated with worse overall survival (OS) and increased recurrence risk (5-year OS rate: 31.9% vs. 62.5%, P<0.001). Notably, elevated TNFR2 levels were also associated with an increased risk of post-transplant lung metastasis (hazard ratio: 1.146; P<0.001). Cox regression analysis revealed that TNFR2, Hangzhou criteria, age, and hepatitis B surface antigen were independent risk factors for post-transplant lung metastasis, and a novel nomogram was established accordingly. The nomogram achieved excellent prognostic efficiency (area under time-dependent receiver operating characteristic =0.755, concordance-index =0.779) and was superior to conventional models, such as the Milan criteria. Conclusions: TNFR2 is a potent prognostic biomarker for predicting post-transplant lung metastasis in patients with HCC. A nomogram incorporating TNFR2 deserves to be a helpful prognostic tool in liver transplantation for HCC.

Metabolomic biomarkers for the diagnosis and post-transplant outcomes of AFP negative hepatocellular carcinoma.

Background: Early diagnosis for α-fetoprotein (AFP) negative hepatocellular carcinoma (HCC) remains a critical problem. Metabolomics is prevalently involved in the identification of novel biomarkers. This study aims to identify new and effective markers for AFP negative HCC. Methods: In total, 147 patients undergoing liver transplantation were enrolled from our hospital, including liver cirrhosis patients (LC, n=25), AFP negative HCC patients (NEG, n=44) and HCC patients with AFP over 20 ng/mL (POS, n=78). 52 Healthy volunteers (HC) were also recruited in this study. Metabolomic profiling was performed on the plasma of those patients and healthy volunteers to select candidate metabolomic biomarkers. A novel diagnostic model for AFP negative HCC was established based on Random forest analysis, and prognostic biomarkers were also identified. Results: 15 differential metabolites were identified being able to distinguish NEG group from both LC and HC group. Random forest analysis and subsequent Logistic regression analysis showed that PC(16:0/16:0), PC(18:2/18:2) and SM(d18:1/18:1) are independent risk factor for AFP negative HCC. A three-marker model of Metabolites-Score was established for the diagnosis of AFP negative HCC patients with an area under the time-dependent receiver operating characteristic curve (AUROC) of 0.913, and a nomogram was then established as well. When the cut-off value of the score was set at 1.2895, the sensitivity and specificity for the model were 0.727 and 0.92, respectively. This model was also applicable to distinguish HCC from cirrhosis. Notably, the Metabolites-Score was not correlated to tumor or body nutrition parameters, but difference of the score was statistically significant between different neutrophil-lymphocyte ratio (NLR) groups (≤5 vs. >5, P=0.012). Moreover, MG(18:2/0:0/0:0) was the only prognostic biomarker among 15 metabolites, which is significantly associated with tumor-free survival of AFP negative HCC patients (HR=1.160, 95%CI 1.012-1.330, P=0.033). Conclusion: The established three-marker model and nomogram based on metabolomic profiling can be potential non-invasive tool for the diagnosis of AFP negative HCC. The level of MG(18:2/0:0/0:0) exhibits good prognosis prediction performance for AFP negative HCC.

Liver Organoids, Novel and Promising Modalities for Exploring and Repairing Liver Injury.

The past decades have witnessed great advances in organoid technology. Liver is the biggest solid organ, performing multifaceted physiological functions. Nowadays, liver organoids have been applied in many fields including pharmaceutical research, precision medicine and disease models. Compared to traditional 2-dimensional cell line cultures and animal models, liver organoids showed the unique advantages. More importantly, liver organoids can well model the features of the liver and tend to be novel and promising modalities for exploring liver injury, thus finding potential treatment targets and repairing liver injury. In this review, we reviewed the history of the development of liver organoids and summarized the application of liver organoids and recent studies using organoids to explore and further repair the liver injury. These novel modalities could provide new insights about the process of liver injury.

Multi-omics profiling reveals Chitinase-3-like protein 1 as a key mediator in the crosstalk between sarcopenia and liver cancer.

Sarcopenia is prevalent in patients with hepatocellular carcinoma (HCC), and can adversely affect their outcomes. This study aims to explore the key mechanisms in the crosstalk between sarcopenia and HCC based on multi-omics profiling. A total of 136 male patients with HCC were enrolled. Sarcopenia was an independent risk factor for poor outcomes after liver transplantation (p < 0.05). Inflammatory cytokine and metabolomic profiling on these patients identified elevated plasma sTNF-R1/CHI3L1 and dysregulated lipid metabolism as related to sarcopenia and tumor recurrence risk concurrently (p < 0.05). Integrated analysis revealed close relationship between CHI3L1 and fatty acid metabolism. In mouse cachectic models by intraperitoneal injection of H22 cells, CHI3L1 was significantly elevated in the atrophic muscle tissue, as well as in circulation. In-vitro, CHI3L1 was up-regulated in muscle cells to protect itself from inflammatory damage through TNF-α/TNF-R1 signaling. CHI3L1 secreted by the muscle cells promoted the invasion of co-cultured HCC cells. Tumor tissue transcriptome data for 73 out of the 136 patients revealed that CHI3L1 may regulate fatty acid metabolism and oxidative stress. In vitro, CHI3L1 caused ROS and lipid accumulation. Targeted lipid profiling further proved that CHI3L1 was able to activate arachidonic acid metabolism, leading to lipid peroxide (LPO) accumulation. Meanwhile, LPO inhibition could compromise the remarkable pro-cancerous effects of CHI3L1. In conclusion, sarcopenia adversely affects the outcomes of liver transplantation for HCC. In sarcopenic patients, CHI3L1 was up-regulated and secreted by the skeletal muscle to protect itself through TNF-α/TNF-R1 signaling, which, in turn, can promote HCC tumor progression by inducing LPO accumulation.

One Shoot, Two Birds: Alleviating Inflammation Caused by Ischemia/Reperfusion Injury to Reduce the Recurrence of Hepatocellular Carcinoma.

Inflammation is crucial to tumorigenesis and the development of metastasis. Hepatic ischemia/reperfusion injury (IRI) is an unresolved problem in liver resection and transplantation which often establishes and remodels the inflammatory microenvironment in liver. More and more experimental and clinical evidence unmasks the role of hepatic IRI and associated inflammation in promoting the recurrence of hepatocellular carcinoma (HCC). Meanwhile, approaches aimed at alleviating hepatic IRI, such as machine perfusion, regulating the gut-liver axis, and targeting key inflammatory components, have been proved to prevent HCC recurrence. This review article highlights the underlying mechanisms and promising therapeutic strategies to reduce tumor recurrence through alleviating inflammation induced by hepatic IRI.