PDZ-binding kinase aggravates pancreatic neuroendocrine neoplasm progression by activating the AKT/mTOR pathway.

The therapeutic effects of existing drug regimens against pancreatic neuroendocrine neoplasms (pNENs) remain limited, and identifying ideal therapeutic targets is warranted. PDZ binding kinase (PBK) may play an oncogenic role in most solid tumors. However, its function in pNEN remains unclear. In this study, pNEN samples and International Cancer Genome Consortium data were used to determine the clinical significance of PBK. Cell counting and CCK8 assays were used to assess cell proliferation. Flow cytometry was used to assess drug-induced apoptosis and cell cycle arrest. An in vivo PBK-targeting experiment was performed in mice bearing pNENs. Western blotting, quantitative PCR, and immunohistochemistry were performed to assess the molecular mechanisms. PBK was significantly upregulated in pNEN tissues compared with paracancerous tissues. Additionally, PBK was a poor prognostic factor for pNEN patients. PBK was found to promote the proliferation of pNEN cells by activating the AKT/mTOR pathway. Furthermore, PBK inhibition combined with everolimus treatment had enhanced antitumour effects on pNEN via inhibiting AKT/mTOR pathway and inducing G0/G1 phase cell cycle arrest. This study highlights that PBK plays an oncogenic role in and is a promising therapeutic target for pNEN.

The predictive value of the modified AFP model for liver transplantation outcomes in multinodular hepatocellular carcinoma patients.

BACKGROUND: There is a lack of studies focusing on the benefit of liver transplantation (LT) in hepatocellular carcinoma (HCC) patients with > 3 tumors. This study aims to establish a model to effectively predict overall survival in Chinese HCC patients with multiple tumors (> 3 tumors) who undergo LT. METHODS: This retrospective study included 434 HCC liver transplant recipients from the China Liver Transplant Registry. All HCC patients had more than 3 tumor nodules. Three selection criteria systems (i.e., AFP, Metroticket 2.0, and Up-to-7) were compared regarding the prediction of HCC recurrence. The modified AFP model was established by univariate and multivariate competing risk analyses. RESULTS: The AFP score 2 and the AFP score ≥ 3 groups had 5-year recurrence rates of 19.6% and 40.5% in our cohort. The prediction of HCC recurrence based on the AFP model was associated with a c-statistic of 0.606, which was superior to the Up-to-7 and Metroticket 2.0 models. AFP level > 1000 ng/mL, largest tumor size ≥ 8 cm, vascular invasion, and MELD score ≥ 15 were associated with overall survival. The 5-year survival rate in the modified AFP score 0 group was 71.7%. CONCLUSIONS: The AFP model is superior in predicting tumor recurrence in HCC patients with > 3 tumors prior to LT. With the modified AFP model, patients likely to derive sufficient benefit from LT can be identified.

Prognostic implication of early posttransplant hypercholesterolemia in liver transplantation for patients with hepatocellular carcinoma.

BACKGROUND: Hyperlipidemia is a common complication after liver transplantation (LT) and develops mostly in the early posttransplant period. Recently, some studies have reported a positive correlation between hyperlipidemia and favorable prognosis in patients with hepatocellular carcinoma (HCC) undergoing hepatectomy. This study aimed to evaluate the possibility of predicting prognosis in HCC patients receiving LT by early posttransplant dyslipidemia. METHODS: From January 2015 to December 2017, a total of 806 HCC patients from China Liver Transplant Registry database were retrospectively enrolled. The prognostic relevance of early posttransplant hypertriglyceridemia or hypercholesterolemia was examined using survival analysis, and subgroup analysis was implemented based on LT criteria. RESULTS: Early posttransplant hypercholesterolemia (EPHC) was independently inversely associated with the risk of recurrence [hazard ratio (HR) = 0.630; P = 0.022], but was not significantly correlated with the mortality. However, early posttransplant hypertriglyceridemia was not related to prognosis. Intriguingly, with further classification, we found that borderline EPHC (B-EPHC), instead of significant EPHC, was a predictor of lower risk for both recurrence (HR = 0.504; P = 0.006) and mortality (HR = 0.511; P = 0.023). Compared with non-EPHC patients, B-EPHC patients achieved significantly superior 1-year and 3-year tumor-free survival (89.6% and 83.7% vs. 83.8% and 72.7% respectively; P = 0.023), and 1-year and 3-year overall survival (95.8% and 84.8% vs. 94.6% and 77.6% respectively; P = 0.039). In the subgroup analysis, B-EPHC remained an independent predictor of better prognosis in patients beyond Milan criteria and those within Hangzhou criteria; whereas there was no significant relationship between B-EPHC and prognosis in patients within Milan criteria and those beyond Hangzhou criteria. More interestingly, patients beyond Milan criteria but within Hangzhou criteria were identified as the crucial subpopulation who benefited from B-EPHC (recurrence HR = 0.306, P = 0.011; mortality HR = 0.325, P = 0.031). CONCLUSIONS: B-EPHC could assist transplant teams in dynamically evaluating prognosis after LT for HCC as a postoperative non-oncological biomarker, especially in patients beyond Milan criteria but within Hangzhou criteria.

A mixed blessing for liver transplantation patients - Rapamycin.

BACKGROUND: Liver transplantation (LT) is an effective treatment option for end-stage liver disease. Mammalian target of rapamycin (mTOR) inhibitors, such as rapamycin, are widely used post LT. DATA SOURCES: In this review, we focused on the anti-cancer activities and metabolic side effects of rapamycin after LT. The literature available on PubMed for the period of January 1999-September 2022 was reviewed. The key words were rapamycin, sirolimus, liver transplantation, hepatocellular carcinoma, diabetes, and lipid metabolism disorder. RESULTS: Rapamycin has shown excellent effects and is safer than other immunosuppressive regimens. It has exhibited excellent anti-cancer activity and has the potential in preventing hepatocellular carcinoma (HCC) recurrence post LT. Rapamycin is closely related to two long-term complications after LT, diabetes and lipid metabolism disorders. CONCLUSIONS: Rapamycin prevents HCC recurrence post LT in some patients, but it also induces metabolic disorders. Reasonable use of rapamycin benefits the liver recipients.

E2F7 promotes mammalian target of rapamycin inhibitor resistance in hepatocellular carcinoma after liver transplantation.

The mammalian target of rapamycin (mTOR) pathway is frequently deregulated and has critical roles in cancer progression. mTOR inhibitor has been widely used in several kinds of cancers and is strongly recommended in patients with hepatocellular carcinoma (HCC) after liver transplantation (LT). However, the poor response to mTOR inhibitors due to resistance remains a challenge. Hypoxia-associated resistance limits the therapeutic efficacy of targeted drugs. The present study established models of HCC clinical samples and cell lines resistance to mTOR inhibitor sirolimus and screened out E2F7 as a candidate gene induced by hypoxia and promoting sirolimus resistance. E2F7 suppressed mTOR complex 1 via directly binding to the promoter of the TSC1 gene and stabilizes hypoxia-inducible factor-1α activating its downstream genes, which are responsible for E2F7-dependent mTOR inhibitor resistance. Clinically, low E2F7 expression could be an effective biomarker for recommending patients with HCC for anti-mTOR-based therapies after LT. Targeting E2F7 synergistically inhibited HCC growth with sirolimus in vivo. E2F7 is a promising target to reverse mTOR inhibition resistance. Collectively, our study points to a role for E2F7 in promoting mTOR inhibitor resistance in HCC and emphasizes its potential clinical significance in patients with HCC after LT.

Bispecific and split CAR T cells targeting CD13 and TIM3 eradicate acute myeloid leukemia.

Chimeric antigen receptor (CAR) T cells have radically improved the treatment of B cell-derived malignancies by targeting CD19. The success has not yet expanded to treat acute myeloid leukemia (AML). We developed a Sequentially Tumor-Selected Antibody and Antigen Retrieval (STAR) system to rapidly isolate multiple nanobodies (Nbs) that preferentially bind AML cells and empower CAR T cells with anti-AML efficacy. STAR-isolated Nb157 specifically bound CD13, which is highly expressed in AML cells, and CD13 CAR T cells potently eliminated AML in vitro and in vivo. CAR T cells bispecific for CD13 and TIM3, which are upregulated in AML leukemia stem cells, eradicated patient-derived AML, with much reduced toxicity to human bone marrow stem cells and peripheral myeloid cells in mouse models, highlighting a promising approach for developing effective AML CAR T cell therapy.

Novel γδ T cell-based prognostic signature to estimate risk and aid therapy in hepatocellular carcinoma.

BACKGROUND: Numerous studies have revealed that gamma delta (γδ) T cell infiltration plays a crucial regulatory role in hepatocellular carcinoma (HCC) development. Nonetheless, a comprehensive analysis of γδ T cell infiltration in prognosis evaluation and therapeutic prediction remains unclear. METHODS: Multi-omic data on HCC patients were obtained from public databases. The CIBERSORT algorithm was applied to decipher the tumor immune microenvironment (TIME) of HCC. Weighted gene co-expression network analysis (WGCNA) was performed to determine significant modules with γδ T cell-specific genes. Kaplan-Meier survival curves and receiver operating characteristic analyses were used to validate prognostic capability. Additionally, the potential role of RFESD inhibition by si-RFESD in vitro was investigated using EdU and CCK-8 assays. RESULTS: A total of 16,421 genes from 746 HCC samples (616 cancer and 130 normal) were identified based on three distinct cohorts. Using WGCNA, candidate modules (brown) with 1755 significant corresponding genes were extracted as γδ T cell-specific genes. Next, a novel risk signature consisting of 11 hub genes was constructed using multiple bioinformatic analyses, which presented great prognosis prediction reliability. The risk score exhibited a significant correlation with ICI and chemotherapeutic targets. HCC samples with different risks experienced diverse signalling pathway activities. The possible interaction of risk score with tumor mutation burden (TMB) was further analyzed. Subsequently, the potential functions of the RFESD gene were explored in HCC, and knockdown of RFESD inhibited cell proliferation in HCC cells. Finally, a robust prognostic risk-clinical nomogram was developed and validated to quantify clinical outcomes. CONCLUSIONS: Collectively, comprehensive analyses focusing on γδ T cell patterns will provide insights into prognosis prediction, the mechanisms of immune infiltration, and advanced therapy strategies in HCC.

Liver transplantation in patients with liver failure: Twenty years of experience from China.

Liver transplantation (LT) is the only effective method of treating end-stage liver disease, such as various types of liver failure. China has the largest number of patients with hepatitis B virus-related disease, which is also the main cause of liver failure. From the first LT performed in 1977, and especially over the past two decades, LT has experienced rapid development as a result of continuous research and innovation in China. China performs the second-highest number of LTs every year worldwide, and the quality of LT continues to improve. Starting January 1, 2015, all donor's livers have been from deceased donors and familial donors. Thus, China entered into a new era of LT. However, LT is still a challenging procedure in China. In this review, we introduced the brief history of LT in China, the epidemiology, aetiology and clinical outcomes of LT for liver failure in China and summarized the experience of LT from Chinese LT surgeons and scholars. The future perspectives of LT were also discussed, and it is expected that China's LT research could be further integrated elsewhere in the world.

Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma: A single-arm, multicenter, prospective study.

Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.

USP22 promotes hypoxia-induced hepatocellular carcinoma stemness by a HIF1α/USP22 positive feedback loop upon TP53 inactivation.

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.

Glutamine synthetase promotes tumor invasion in hepatocellular carcinoma through mediating epithelial-mesenchymal transition.

AIM: Glutamine synthetase (GS) levels increase gradually with the development of hepatocellular carcinogenesis. In this study, we aimed to investigate the clinical significance of GS and the underlying mechanism of GS promoting hepatocellular carcinoma (HCC) invasion. METHODS: Serum concentration of GS and α-fetoprotein (AFP) in HCC patients, liver cirrhosis patients, and healthy individuals were detected. The GS-mRNA level and its prognostic value were explored in an independent HCC cohort from The Cancer Genome Atlas database. GS expression in HCC tissue and matched para-tumor tissue was determined. The effect of GS on HCC invasion was assessed in vitro and in vivo. RESULTS: The serum GS and AFP level in HCC patients was higher than that in healthy controls and liver cirrhosis patients. The area under the receiver operating characteristic curve for HCC diagnosis was 0.848 and 0.861 for GS and AFP, respectively. The area under the receiver operating characteristic curve of GS for diagnosis of AFP-negative HCC was 0.913. Combining GS with AFP achieved a diagnostic sensitivity and specificity of 82.5% and 93%, respectively. The GS level was higher in tumor tissues than that in para-tumor tissues. High GS expression was associated with poor prognosis of moderately differentiated HCC patients. In vitro, GS exerted an influence on HCC cell migration by mediating epithelial-mesenchymal transition. The lung and liver metastatic model of HCC further confirmed that GS expression affected the invasion of HCC cells in vivo. CONCLUSIONS: GS is a useful biomarker for HCC diagnosis, especially for AFP-negative patients. In addition, GS affects HCC metastasis through mediating epithelial-mesenchymal transition.

Ubiquitin-Specific Protease 22/Silent Information Regulator 1 Axis Plays a Pivotal Role in the Prognosis and 5-Fluorouracil Resistance in Hepatocellular Carcinoma.

BACKGROUND: Ubiquitin-specific protease 22 (USP22) is described as a key subunit of the Spt-Ada-Gcn5 acetyl transferase complex, which plays an important role in the prognosis and resistance to chemotherapy drugs in hepatocellular carcinoma (HCC). Silent information regulator 1 (SIRT1) is a member of the sirtuin family that is deubiquitinated by USP22. However, it is still unknown whether USP22 and SIRT1 co-expression is associated with disease progression and 5-Fluorouracil (5-FU) resistance in HCC. METHODS: 141 patients who received hepatectomy at our hospital from January 2010 to December 2014 were enrolled in this study. The expression of USP22 and SIRT1 was detected by immunohistochemical staining. Clinicopathological features, including age, gender, tumor number, tumor size, tumor differentiation, tumor stage, alpha-fetoprotein and microscopic vascular invasion, were assessed. Further experiments confirmed the role of SIRT1 in 5-FU drug resistance in vivo. RESULTS: Immunohistochemical staining showed that the high expression of USP22 and SIRT1 was frequently observed in HCC tissues relative to normal liver tissues. Overexpression of USP22 is associated with microscopic vascular invasion (MVI). Further analysis showed that the co-expression of USP22 and SIRT1 was more effective in predicting the prognosis of HCC. The SIRT1 inhibitor EX-527 dramatically inhibited the expression of Cyclin B1 and resistance-associated protein 3 (MRP3) to reduce 5-FU drug resistance in vivo. CONCLUSION: These findings suggest that the co-expression of USP22 and SIRT1 is significantly associated with unfavorable HCC progression. The inhibition of SIRT1 in vivo could be valuable in improving 5-FU drug sensitivity and inhibiting tumor cell proliferation and inducing apoptosis.

Hangzhou criteria as downstaging criteria in hepatocellular carcinoma before liver transplantation: A multicenter study from China.

BACKGROUND: The downstaging of hepatocellular carcinoma (HCC) has been confirmed to benefit liver transplantation (LT) patients whose tumors are beyond the transplantation criteria. Milan criteria (MC), a tumor size and number-based assessment, is currently used as the endpoint in these patients. However, many studies believe that tumor biological behavior should be added to the evaluation criteria for downstaging efficacy. Hence, this study aimed to explore the feasibility of Hangzhou criteria (HC), which introduced tumor grading and alpha-fetoprotein in addition to tumor size and number, as an endpoint of downstaging. METHODS: We performed a multicenter and retrospective study of 206 patients accepted locoregional therapy (LRT) as downstaging/bridge treatment prior to LT in three centers of China. RESULTS: Recipients were divided into four groups: failed downstaging to the HC (group A, n = 46), successful downstaging to the HC (group B, n = 30), remained within the HC all the time (group C, n = 113), and tumor progressed (group D, n = 17). The 3-year HCC recurrence probabilities of groups B and C were not significantly different (10.3% vs. 11.6%, P = 0.87). The HCC recurrent rate was significantly higher in group A (52.3%) compared with that in group B/C (P < 0.05). Seven patients (7/76, 9.2%) whose tumor exceeded the the HC were successfully downstaged to the MC, and 39.5% (30/76) to the the HC. In group B, 23 patients remained beyond the MC and their survivals were as well as those of patients within the MC. CONCLUSIONS: Compared to the MC, HC downstaging criteria can give more HCC patients access to LT and furthermore, the outcome of these patients is the same as those matching MC downstaging criteria. Hangzhou downstaging criteria therefore is applicable in clinical practice.

Liquid biopsy in hepatocellular carcinoma: circulating tumor cells and circulating tumor DNA.

Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of death worldwide. Due to latent liver disease, late diagnosis, and nonresponse to systemic treatments, surgical resection and/or biopsy specimens are still generally considered as the gold standard by clinicians for clinical decision-making until now. Since the conventional tissue biopsy is invasive and contains small tissue samples, it is unable to represent tumor heterogeneity or monitor dynamic tumor progression. Therefore, it is imperative to find a new less invasive or noninvasive diagnostic strategy to detect HCC at an early stage and to monitor HCC recurrence. Over the past years, a new diagnostic concept known as "liquid biopsy" has emerged with substantial attention. Liquid biopsy is noninvasive and allows repeated analyses to monitor tumor recurrence, metastasis or treatment responses in real time. With the advanced development of new molecular techniques, HCC circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) detection have achieved interesting and encouraging results. In this review, we focus on the clinical applications of CTCs and ctDNA as key components of liquid biopsy in HCC patients.

Surgical resection of the primary tumor leads to prolonged survival in metastatic pancreatic neuroendocrine carcinoma.

BACKGROUND: Palliative resection of the primary tumor for metastatic pancreatic neuroendocrine carcinoma (pNEC) patients is not recommended because of the poor prognosis compared to that of patients with well-differentiated, lower grade tumors. However, the published data supporting this recommendation regarding pNEC are limited. In the present study, we assessed whether palliative primary tumor resection in stage IV pNEC patients affects survival and identified other factors that affect survival in these patients. METHODS: We collected data from stage IV pNEC patients registered in the Surveillance, Epidemiology, and End Results (SEER) database between 1988 and 2014. Univariate and multivariate Cox regression analysis were used to compare overall survival (OS) and cancer-specific survival (CSS) of patients who did or did not undergo primary tumor resection. RESULTS: We identified 350 patients with metastatic, poorly differentiated, and undifferentiated pNEC. A total of 14.3% (50/350) of patients underwent primary tumor resection. Multivariate Cox regression analysis showed that primary tumor resection provided a significant benefit for both OS and CSS in stage IV pNEC patients. Additionally, chemotherapy and the presence of the primary tumor in the pancreatic tail were independent positive prognostic factors for metastatic pNEC patients in the multivariate Cox regression analysis. CONCLUSIONS: The present study suggests that chemotherapy, location of the primary tumor in the pancreatic tail, and, most importantly, surgical removal of the primary tumor are associated with prolonged survival in stage IV pNEC patients.

Metformin sensitizes hepatocellular carcinoma to arsenic trioxide-induced apoptosis by downregulating Bcl2 expression.

Hepatocellular carcinoma (HCC) is a highly malignant tumor that can evolve rapidly to acquire resistance to conventional chemotherapies. Arsenic trioxide (ATO) is a traditional Asian medicine, and a phase II study has shown that treatment with ATO alone was not effective against HCC. Bcl2 is an antiapoptotic protein that regulates chemotherapy in HCC. Metformin is reported to decrease Bcl2 expression, and the purpose of this study was to verify whether metformin could potentiate the anti-HCC efficacy of ATO in vitro. In the present study, we used metformin and ATO alone or in combination and then tested proliferation, apoptosis, and Bcl2 level of HCC cells. The results showed that metformin enhanced both the proliferation-inhibiting and apoptosis-inducing effects of ATO on HCC cell lines HepG2 and BEL7402. Furthermore, this activity proceeded via a mechanism involving metformin-induced downregulation of Bcl2. A combination of ATO and metformin is therefore a potentially promising approach for HCC therapy.

Advance of Metformin in Liver Disease.

Metformin is a first-line drug for the treatment of type 2 diabetes with a good safety profile and relatively low cost. In recent years, many other effects of metformin have been discovered. In this review, we provide the research advances in metformin in liver disease. High-dose metformin can activate AMPK by inhibiting mitochondrial complex 1. In addition, low-dose metformin could activate lysosomal AMPK through PEN2. Activated AMPK can reduce fatty acid synthesis, inhibit tumor proliferation and metastasis, and reshape the tumor microenvironment. In addition, metformin can reduce ROS production by inhibiting mitochondrial complex 1, which can reduce liver damage. Therefore, metformin has been found to alleviate nonalcoholic fatty liver disease and cirrhosis, relieve liver damage, and reduce the incidence of hepatocellular carcinoma and cholangiocarcinoma. This information suggests that metformin may represent a new possibility for the prevention and treatment of liver diseases.

Insights into the history and tendency of liver transplantation for liver cancer: a bibliometric-based visual analysis.

Research on liver transplantation (LT) for liver cancer has gained increasing attention. This paper has comprehensively described the current status, hotspots and trends in this field. A total of 2991 relevant articles from 1 January 1963 to 28 February 2023 were obtained from the Web of Science Core Collection. VOSviewer and CiteSpace software were utilized as bibliometric tools to analyze and visualize knowledge mapping. Between 1963 and 2023, the number of papers in the area of LT for liver cancer increased continuously. A total of 70 countries/regions, 2303 institutions and 14 840 researchers have published research articles, with the United States and China being the two most productive countries. Our bibliometric-based visual analysis revealed the expansion of LT indications for liver cancer and the prevention/treatment of cancer recurrence as ongoing research hotspots over the past decades. Meanwhile, emerging studies also focus on downstaging/bridging treatments before LT and the long-term survival of LT recipient, in particular the precise application of immunosuppressants.

mTOR inhibitor reduces nontumour-related death in liver transplantation for hepatocellular carcinoma.

Sirolimus is a regularly applied immunosuppressant for patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC). Sirolimus not only significantly inhibits HCC recurrence but also protects renal function. However, the improvement effect of sirolimus on nontumour-related death in patients is still unknown. The aim of our study was to investigate the therapeutic effect of sirolimus on nontumour-related deaths. In this study, we retrospectively enrolled 403 LT patients with HCC from January 1, 2015, to December 31, 2018. The median follow-up time was 47.1 months. The patients were divided into the sirolimus group (N = 184) and the sirolimus-free group (N = 219). There were no significant differences between the sirolimus group and the sirolimus-free group in survival (P = 0.054). In transplant patients who exceeded the Milan or Hangzhou criteria, the sirolimus group achieved higher survival than the sirolimus-free group (P = 0.005; P = 0.02). Moreover, multivariate analysis showed that sirolimus strongly reduced the hazard ratio (HR) for nontumour-related death in LT patients who exceeded the Milan (HR: 0.42; 95% CI: 0.18-1; P = 0.05) or Hangzhou criteria (HR: 0.26; 95% CI: 0.08-0.89; P = 0.032). HCC recurrence increased the risk of nontumour-related death. In conclusion, sirolimus-based immunosuppression can significantly reduce nontumour-related death in LT patients who exceed the criteria for transplantation. In addition, this finding will further promote the application of sirolimus after liver transplantation for hepatocellular carcinoma.

Ubiquitin-specific protease 22 promotes tumorigenesis and progression by an FKBP12/mTORC1/autophagy positive feedback loop in hepatocellular carcinoma.

Ubiquitin-specific protease 22 (USP22) has been identified as a potential marker for cancer stem cells in hepatocellular carcinoma (HCC). It can promote HCC stemness, which is considered a driver of tumorigenesis. Here, we sought to determine the role of USP22 in tumorigenesis, elucidate its underlying mechanism, and explore its therapeutic significance in HCC. As a result, we found that tissue-specific Usp22 overexpression accelerated tumorigenesis, whereas Usp22 ablation decelerated it in a c-Myc/NRasGV12-induced HCC mouse model and that the mammalian target of rapamycin complex 1 (mTORC1) pathway was activated downstream. USP22 overexpression resulted in increased tumorigenic properties that were reversed by rapamycin in vitro and in vivo. In addition, USP22 activated mTORC1 by deubiquitinating FK506-binding protein 12 (FKBP12) and activated mTORC1, in turn, further stabilizing USP22 by inhibiting autophagic degradation. Clinically, HCC patients with high USP22 expression tend to benefit from mTOR inhibitors after liver transplantation (LT). Our results revealed that USP22 promoted tumorigenesis and progression via an FKBP12/mTORC1/autophagy positive feedback loop in HCC. Clinically, USP22 may be an effective biomarker for selecting eligible recipients with HCC for anti-mTOR-based therapy after LT.