Introduction: Chronic hepatitis B virus (HBV) infection is the leading cause of primary liver cancer (PLC), notably hepatocellular carcinoma. G-protein coupled receptor-associated sorting protein 1 (GPRASP1), a G protein-coupled receptor-associated protein, has been implicated in multiple malignancies. However, its role in PLC, particularly in hepatitis B surface antigen (HBsAg)-positive patients, remains unclear. Objective: To explore the GPRASP1 expression pattern and its clinical significance in PLC, with a focus on HBsAg-positive cases, and to evaluate its potential as a candidate biomarker. Methods: Tumor center tissues and paired adjacent non-tumor liver tissues were collected from 12 pathologically confirmed PLC patients, including seven with active HBV infection or chronic carrier status. GPRASP1 mRNA expression levels were quantified using reverse-transcription quantitative polymerase chain reaction. Associations between GPRASP1 expression and clinicopathological variables were statistically analyzed. Results: GPRASP1 mRNA expression was significantly up-regulated in central tumor tissues and paired adjacent non-tumor liver tissues (p = 0.034). Elevated GPRASP1 expression was detected in 80% of HBsAg-positive PLC patients. GPRASP1 levels were significantly inversely correlated with hepatitis B surface antibody titers. Higher GPRASP1 expression was positively correlated with lymphocyte infiltration (τ = 0.816, p = 0.007). Moreover, GPRASP1 expression was negatively correlated with serum total bilirubin (r = −0.636, p = 0.026), direct bilirubin (r = −0.622, p = 0.031), and indirect bilirubin (r = −0.727, p = 0.007). Conclusion: GPRASP1 is overexpressed in PLC tissues, particularly in HBsAg-positive patients, and its expression is associated with host immune response and hepatic functional markers. GPRASP1 may serve as a potential diagnostic biomarker for PLC and may provide novel insights into its diagnosis.

Abstract Background The purpose is to define the contribution of the interferon regulatory factor‐1–dual‐specificity tyrosine phosphorylation‐regulated kinase 1α (IRF‐1–DYRK1α) axis to hepatocellular ferroptosis during liver ischemia/reperfusion injury (LIRI). Methods Ferroptosis was induced in AML12 hepatocytes with erastin. After gain‐ or loss‐of‐function manipulation of IRF‐1 and DYRK1α, we quantified glutathione peroxidase 4 (GPX4) and acyl‐CoA synthetase long‐chain family member 4 (ACSL4), reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH). In vivo, wild‐type (WT) mice, IRF‐1 knockout (Irf1−/−) mice, and WT mice treated with the DYRK1α inhibitor harmine underwent a 70% warm LIRI model. Liver and blood were collected for histology, serum transaminases, cytokine ELISA, protein analyses, and flow cytometry. Results IRF‐1 knockdown attenuated LIRI, accompanied by suppression of hepatocellular ferroptosis. DYRK1α inhibition reversed IRF‐1–mediated decreases in GSH and GPX4 and prevented increases in MDA, ROS, and ACSL4 in AML12 cells, indicating DYRK1α participation in IRF‐1–driven ferroptosis. In mice, pharmacologic inhibition of DYRK1α with harmine reduced hepatic ferroptosis and ameliorated LIRI. Conclusion IRF‐1 aggravates LIRI, at least in part, by promoting hepatocellular ferroptosis via DYRK1α. Targeting the IRF‐1–DYRK1α axis may offer a therapeutic strategy to limit perioperative liver injury.

Objectives The purpose of this study was to compare the efficacy and safety of transarterial chemoembolization combined with radiofrequency ablation (TACE-RFA) plus tyrosine kinase inhibitors (TKI) with or without programmed cell death protein-1 (PD-1) inhibitors in the treatment of unresectable hepatocellular carcinoma (uHCC).Methods From January 2020 to October 2024, 87 patients with uHCC who received TACE-RFA plus TKI with or without PD-1 inhibitors in our center were retrospectively analyzed, and divided into TACE-RFA + TKI (TRK) group and TACE-RFA + TKI + PD-1 (TRKP) group. Kaplan-Meier method and log-rank test were used to analyze overall survival (OS) and progression-free survival (PFS) of the 2 groups. Adverse events (AEs) between the 2 groups were evaluated according to Common Adverse Event Evaluation Criteria (CTCAEs) Version 5.0.Results The patients in the TRKP group had longer median OS (mOS) (24 [95% confidence interval (CI): 17.7-30.3] vs. 18 [95% CI: 15.1-20.9] months, P = .04) and median PFS (mPFS) (15[95% CI: 13.4-16.6] vs. 12 [95% CI: 10.8-13.2] months, P = .01) than that in the TRK group. The objective response rate (ORR) (44.19% vs 36.36%, P = .03) and disease control rate (DCR) (86.05% vs. 70.45%, P = .08) in the TRKP group were better than those in the TRK group. There was no significant difference in the frequency and severity of AEs between the 2 groups.Conclusions The treatment of TACE-RFA + TKI + PD-1 inhibitors is effective and safe for uHCC.Advances in knowledge This study advances knowledge by showing that the TACE-RFA + TKI + PD-1 (TRKP) regimen is more effective than TACE-RFA + TKI (TRK) in improving median overall survival, median progression-free survival, and objective response rate for unresectable hepatocellular carcinoma (uHCC) with controllable adverse events, and identifies TRKP as an independent favorable prognostic factor, while AFP >= 400 ng/mL and BCLC stage C as adverse prognostic factors for uHCC.

OBJECTIVE:The purpose of this study was to compare the efficacy and safety of transarterial chemoembolization combined with radiofrequency ablation (TACE-RFA) plus tyrosine kinase inhibitors (TKI) with or without programmed cell death protein-1(PD-1) inhibitors in the treatment of unresectable hepatocellular carcinoma (uHCC). MATERIALS AND METHODS:From January 2020 to October 2024, 87 patients with uHCC who received TACE-RFA plus TKI with or without PD-1 inhibitors in our center were retrospectively analyzed, and divided into TACE-RFA + TKI (TRK) group and TACE-RFA + TKI + PD-1 (TRKP) group. Kaplan-Meier method and log-rank test were used to analyze overall survival (OS) and progression-free survival (PFS) of the two groups. Adverse events (AEs) between the two groups were evaluated according to Common Adverse Event Evaluation Criteria (CTCAEs) Version 5.0. RESULTS:The patients in the TRKP group had longer median OS (mOS) (24 [95% confidence interval (CI): 17.7-30.3] vs 18[95% CI: 15.1-20.9]months, p = 0.04) and median PFS (mPFS) (15[95% CI: 13.4-16.6] vs 12 [95% CI: 10.8-13.2]months, p = 0.01) than that in the TRK group. The objective response rate (ORR) (44.19% vs 36.36%, p = 0.03) and disease control rate (DCR) (86.05% vs. 70.45%, p = 0.08) in the TRKP group were better than those in the TRK group. There was no significant difference in the frequency and severity of AEs between the two groups. CONCLUSIONS:The treatment of TACE-RFA+TKI+PD-1 inhibitors is effective and safe for uHCC. ADVANCES IN KNOWLEDGE:This study advances knowledge by showing that the TACE-RFA+TKI+PD-1 (TRKP) regimen is more effective than TACE-RFA+TKI (TRK) in improving median overall survival, median progression-free survival and objective response rate for unresectable hepatocellular carcinoma (uHCC) with controllable adverse events, and identifies TRKP as an independent favorable prognostic factor, while AFP ≥ 400 ng/mL and BCLC stage C as adverse prognostic factors for uHCC.

Hepatocellular carcinoma (HCC) remains a leading cause of malignancy-related mortality worldwide, primarily due to the high incidence of postoperative recurrence and the absence of standardized adjuvant therapeutic protocols. While lenvatinib (LT) is established as a first-line targeted therapy for advanced HCC, its clinical efficacy is frequently compromised by poor aqueous solubility and significant systemic adverse effects. To bridge this therapeutic gap, we developed a dual-functional nano-delivery platform, designated as Gel@LTNPS, which integrates rapid localized hemostasis with sustained, targeted antitumor activity for postoperative wound management. In this study, pH-sensitive nanoparticles (LTNPS) were successfully fabricated using the amphiphilic copolymer PAE-PEG-NH2 via ultrasonic emulsification, achieving a high drug loading (DL) rate of 38.9% and an encapsulation efficiency (EE) of 73.9%. These nanoparticles were subsequently incorporated into a gelatin/hyaluronic acid (Gel-HA) hydrogel scaffold through covalent cross-linking. Physicochemical analysis demonstrated that LTNPS exhibit highly sensitive pH-dependent release kinetics, with 67.3% of LT released at a pH of 5.5 (simulating the acidic tumor microenvironment) compared to only 18.3% at physiological pH 7.4 within 96 h. The optimized Gel@LTNPS formulation (containing 15% gelatin) exhibited superior swelling properties, a controlled biodegradation profile of 21 days, and a robust compressive strength of 0.13 MPa, satisfying the mechanical prerequisites for surgical applications. Functional evaluations in mouse tail-bleeding models confirmed that Gel@LTNPS significantly expedited the coagulation process and minimized blood loss, demonstrating hemostatic performance equivalent to clinical-grade gelatin. Furthermore, in vitro and in vivo assays against H22 HCC models revealed that the platform effectively suppressed tumor cell viability and inhibited proliferation, as evidenced by a marked reduction in proliferating cell nuclear antigen (PCNA) expression. Crucially, the platform exhibited an excellent biosafety profile, with no observable systemic toxicity or histopathological damage to major organs. Collectively, this study offers a sophisticated strategy for the postoperative management of HCC by combining localized wound care with microenvironment-responsive chemotherapy, presenting significant potential for clinical translation.

Objectives: Transplant centers are increasingly using livers from donors aged >60 years, but long-term outcomes remain unclear. Materials and Methods: We collected data from 957 adult deceased donor liver transplant recipients (conducted at our center from January 2015 through October 2023). The cohort was divided into early, middle, and late transplant era groups, each covering a 3-year interval based on transplant date. We compared 183 donors aged >= 60 years (older group [average age 64.9 +/- 3.4 y]) versus 774 donors aged 18 to 59 years (young group), which we also compared after propensity score matching. We compared outcomes of older organs transplanted into older recipients versus older organs transplanted into young recipients. We conducted multivariate logistic regression analysis to identify potential factors influencing liver transplant outcomes. Results: Over the time period, average donor age increased significantly, cold ischemia time and warm ischemia time decreased, postoperative complications decreased among older donor liver transplant recipients, and cumulative recipient and graft survival rates improved. The older donor group had fewer male donors, more donors with diabetes, and lower average donor liver weight versus the young donor group. Recipients in the older donor group had significantly lower body mass index and higher prevalence of alcoholic cirrhosis versus recipients in the young donor group. Three-month postoperative mortality rate was significantly higher in the older donor group. Subgroup analysis showed significant differences in outcomes between older donors assigned to older recipients and older donors assigned to young recipients, including higher incidence of major postoperative complications and lower 3-month mortality rate. Recipient-donor age differences, early transplant era, and postoperative peak bilirubin level may affect differences. Conclusions: Livers from older donors can yield positive outcomes for young and old recipients. Use of organs from older donors is a viable approach to mitigate organ shortages, including for younger recipients.

Cirrhosis is a healing response to persistent liver injury, and the widely used clinical indicators of cirrhosis severity are limited. The lactate/albumin ratio (LAR) can be used as a marker of early prognosis in critically ill patients. The aim of this study was to explore the clinical significance of LAR for predicting the prognosis of patients with cirrhosis and to provide new insights. Patients diagnosed with liver cirrhosis were extracted from the MIMIC- IV database. The cox regression models were used to analyze the association between the LAR and all-cause mortality in cirrhosis patients. We analyzed potential nonlinear relationships between LAR and outcome indicators using restricted cubic spline cures (RCS). The predictive power was investigated using receiver operating characteristic(ROC) analysis. Additionally, we calculated the incremental effect of the LAR index. The study included a total of 2402 patients with cirrhosis. According to the Kaplan-Meier curves and cox regression analysis indicated that the risk of 28-day, 90-day, 180-day, 1-year all-cause mortality was significantly higher in the highest quartile of LAR. The result of the multivariable RCS model showed the LAR index have a linear relationship (p for nonlinear = 0.115) with 28d all-cause mortality. The area under the ROC curve (AUC) of LAR (66.44% [95% CI 0.64-68.88%]) was superior to lactate (63.51% [95% CI 61.01-66.01%]) and albumin (64.46% [95% CI 62.01-66.92%]). The predictive ability of scoring tools for 28d mortality was significantly improved after considering either the LAR index using integrated discrimination improvement index (IDI). The LAR index can serve as a significant predictor for all-cause mortality in critically ill patients with liver cirrhosis.

Introduction Post-transplant lymphoproliferative disorders (PTLD) are severe complications of transplantation associated with poor outcomes. Compared to early-onset PTLDs, late-onset PTLDs are much less associated with allograft localization. Herein, we report a case of Epstein-Barr virus (EBV)-negative lymphoma involving a graft 7 years after liver transplantation. Case presentation A 45-year-old man presented with hepatomegaly 7 years after liver transplantation. Liver puncture biopsy revealed B-cell lymphoma with a high proliferation index and a germinal center B-cell-like subtype. Tissue and other donor information were unavailable. Next-generation sequencing was performed on the tumor and recipient tissues, and the single nucleotide polymorphism (SNP) sites were identical, thereby confirming the recipient origin. The patient received a reduction in immunosuppression and six cycles of rituximab, reduced doses of cyclophosphamide, doxorubicin, vincristine, and prednisone, and achieved complete remission after the fourth cycle of treatment. The patient remained in good condition for 7 months after the last chemotherapy dose. Conclusion This rare case report describes a late-onset EBV-negative recipient-derived PTLD involving a transplanted liver. SNP analysis is a useful method for determining tumor origin in situations where donor tissue is unavailable.

Nowadays, hepatocellular carcinoma (HCC) is still a major threat to human health globally, with a disappointing prognosis. Regular monitoring of patients at high risk, utilizing abdominal ultrasonography combined with alpha-fetoprotein (AFP) serum analysis, enables the early detection of potentially treatable tumors. However, the approach has limitations due to its lack of sensitivity. Meanwhile, the current standard procedure for obtaining a tumor biopsy in cases of HCC is invasive and lacks the ability to assess the dynamic progression of cancer or account for tumor heterogeneity. Hence, there is a pressing need to develop non-invasive, highly sensitive biomarkers for HCC which can improve the accuracy of early diagnosis, assess treatment response and accurately predict the prognosis. In contrast to the conventional method of tissue biopsy, liquid biopsy offers a non-invasive approach that can be readily repeated. As a liquid biopsy approach, the analysis of cell-free DNA (cfDNA) offers real-time insights that can accurately portray the tumor burden and provide a comprehensive depiction of the genetic profile associated with HCC. In this review, we present a comprehensive summary of the recent research findings pertaining to the significance and potential practicality of cfDNA analysis in the early detection and effective management of HCC.

Pancreatic cancer is one of the most fatal cancers in the world. A growing number of studies have begun to demonstrate that mitochondria play a key role in tumorigenesis. Our previous study reveals that NDUFS2 (NADH: ubiquinone oxidoreductase core subunit S2), a core subunit of the mitochondrial respiratory chain complex I, is upregulated in Pancreatic adenocarcinoma (PAAD). However, its role in the development of PAAD remains unknown. Here, we showed that NDUFS2 played a critical role in the survival, proliferation and migration of pancreatic cancer cells by inhibiting mitochondrial cell death. Additionally, protein mass spectrometry indicated that the NDUFS2 was interacted with a deubiquitinase, OTUB1. Overexpression of OTUB1 increased NDUFS2 expression at the protein level, while knockdown of OTUB1 restored the effects in vitro. Accordingly, overexpression and knockdown of OTUB1 phenocopied those of NDUFS2 in pancreatic cancer cells, respectively. Mechanically, NDUFS2 was deubiquitinated by OTUB1 via K48-linked polyubiquitin chains, resulted in an elevated protein stability of NDUFS2. Moreover, the growth of OTUB1-overexpressed pancreatic cancer xenograft tumor was promoted in vivo, while the OTUB1-silenced pancreatic cancer xenograft tumor was inhibited in vivo. In conclusion, we revealed that OTUB1 increased the stability of NDUFS2 in PAAD by deubiquitylation and this axis plays a pivotal role in pancreatic cancer tumorigenesis and development.

Background NUDT21 (Nudix Hydrolase 21) has been shown to play an essential role in multiple biological processes. Pancreatic adenocarcinoma (PAAD) is one of the most fatal cancers in the world. However, the biological function of NUDT21 in PAAD remains rarely understood. The aim of this research was to identify the prediction value of NUDT21 in diagnosis, prognosis, immune infiltration, and signal pathway in PAAD. Methods Combined with the data in online databases, we analyzed the expression, immune infiltration, function enrichment, signal pathway, diagnosis, and prognosis of NUDT21 in PAAD. Then, the biological function of NUDT21 and its interacted protein in PAAD was identified through plasmid transduction system and protein mass spectrometry. Expression of NUDT21 was further verified in clinical specimens by immunofluorescence. Results We found that NUDT21 was upregulated in PAAD tissues and was significantly associated with the diagnosis and prognosis of pancreatic cancer through bioinformatic data analysis. We also found that overexpression of NUDT21 enhanced PAAD cells proliferation and migration, whereas knockdown NUDT21 restored the effects through in vitro experiment. Moreover, NDUFS2 was recognized as a potential target of NUDT21.We further verified that the expression of NDUFS2 was positively correlated with NUDT21 in PAAD clinical specimens. Mechanically, we found that NUDT21 stabilizes NDUFS2 and activates the PI3K-AKT signaling pathway. Conclusion Our investigation reveals that NUDT21 is a previously unrecognized oncogenic factor in the diagnosis, prognosis, and treatment target of PAAD, and we suggest that NUDT21 might be a novel therapeutic target in PAAD.

Up to half of hepatocellular carcinoma (HCC) cases are diagnosed at an advanced stage, for which effective treatment options are lacking, resulting in a poor prognosis. Over the past few years, the combination of immune checkpoint inhibitors and anti-angiogenic targeted therapy has proven highly efficacious in treating advanced HCC, significantly extending patients' survival and providing a potential for sequential curative surgery. After sequential curative hepatectomy or liver transplantation following conversion therapy, patients can receive long-term survival benefits. In order to improve the long-term survival rate of the overall population with liver cancer and achieve the goal of a 15% increase in the overall 5-year survival rate outlined in the Healthy China 2030 blueprint, the Professional Committee for Prevention and Control of Hepatobiliary and Pancreatic Diseases of Chinese Preventive Medicine Association, Chinese Society of Liver Cancer, and the Liver Study Group of Surgery Committee of Beijing Medical Association organized in-depth discussions among relevant domestic experts in the field. These discussions focused on the latest progress since the release of the Chinese expert consensus on conversion therapy of immune checkpoint inhibitors combined antiangiogenic targeted drugs for advanced hepatocellular carcinoma (2021 Edition) and resulted in a new consensus on the modifications and supplements to related key points. This consensus aims to further guide clinical practice, standardize medical care, and promote the development of the discipline.

Pancreatic ductal adenocarcinoma is a highly malignant cancer with poor prognosis, for which effective therapeutic strategies are urgently needed. The dual-specificity phosphatase PTPMT1 is localized in mitochondria and highly expressed in various cancers. Here, we investigated the function of PTPMT1 in pancreatic ductal adenocarcinoma. We inhibited its expression in pancreatic cancer cell lines using siRNAs or the specific PTPMT1 inhibitor alexidine dihydrochloride and observed that PTPMT1 silencing in pancreatic cancer cell lines drastically reduced cell viability, caused mitochondrial damage, and impaired mitochondrial function. Co-immunoprecipitation analysis demonstrated that PTPMT1 could interact with SLC25A6 and NDUFS2, indicating that it may modulate mitochondrial function via the SLC25A6-NDUFS2 axis. Collecively, our data highlight PTPMT1 as an important factor in pancreatic ductal adenocarcinoma and a potential therapeutic target.

Novel coronavirus infection (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since 2019, the disease has spread worldwide and has become a public health epidemic of international concern. In 2022, the infection of SARS-CoV-2 variant Omicron reached its peak, posing a huge challenge to organ donation and transplantation. Organ transplant recipients have a high risk of immunosuppression and face with high risk of SARS-CoV-2 infection. There are some particularities in the diagnosis and treatment of COVID-19 in organ transplant recipients. This article reviewed the diagnosis and treatment of COVID-19 in liver transplantation recipients, and the progression of liver donation under the COVID-19.

BackgroundThe size and function of the future liver remnant (FLR) is an essential consideration for both eligibility for treatment and postoperative prognosis when planning surgical hepatectomy. Over time, a variety of preoperative FLR augmentation techniques have been investigated, from the earliest portal vein embolization (PVE) to the more recent Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) and liver venous deprivation (LVD) procedures. Despite numerous publications on this topic, no bibliometric analysis has yet been conducted.MethodsWeb of Science Core Collection (WoSCC) database was searched to identify studies related to preoperative FLR augmentation techniques published from 1997 to 2022. The analysis was performed using the CiteSpace [version 6.1.R6 (64-bit)] and VOSviewer [version 1.6.19].ResultsA total of 973 academic studies were published by 4431 authors from 920 institutions in 51 countries/regions. The University of Zurich was the most published institution while Japan was the most productive country. Eduardo de Santibanes had the most published articles, and Masato Nagino was the most frequently co-cited author. The most frequently published journal was HPB, and the most cited journal was Ann Surg, with 8088 citations. The main aspects of preoperative FLR augmentation technique is to enhance surgical technology, expand clinical indications, prevent and treat postoperative complications, ensure long-term survival, and evaluate the growth rate of FLR. Recently, hot keywords in this field include ALPPS, LVD, and Hepatobiliary Scintigraphy.ConclusionThis bibliometric analysis provides a comprehensive overview of preoperative FLR augmentation techniques, offering valuable insights and ideas for scholars in this field.

Objective:To explore the clinical characteristics, interventional diagnostic and therapeutic value of iatrogenic biliary hemorrhage.Methods:The clinical characteristics of 16 patients with iatrogenic massive biliary bleeding who received interventional treatment between July 2018 and June 2022 were reviewed. The clinical manifestations, laboratory examinations and digital subtraction angiography (DSA) findings of all patients were analyzed. The efficacy and safety were evaluated, using interventional therapy including replacement and adjustment of drainage tube, arterial embolization and stent-graft implantation for hemostasis.Results:Eleven of 16 patients had bleeding after PTBD, accounting for 68.8%. 4 hemorrhage cases had histories of biliary-related surgery (25.0%), including 1 case of hepatopancreatic trauma repair, 1 case of liver transplantation, 1 case of bile duct exploration and T-tube drainage, and 1 case of pancreatic necrotic tissue removal, and 1 hemorrhage case occurred after ERCP therapy (6.2%). The bleeding sites origin from portal vein bleeding in 7 cases, hepatic artery in 7 cases, and chronic bleeding of malignant tumor in 2 cases. Of the 7 hepatic artery bleeding cases, stent-graft implantation of hepatic artery was performed in 1 case, and hepatic artery embolization was performed in the other 6 cases. Of the 7 portal vein bleeding cases, the position of the drainage tube was adjusted in 5 cases, replacement of the drainage tube for the other 2 cases for compression hemostasis. At last, 2 cases with chronic tumor bleeding who were underwent empirical embolization. The technique success rate was 14/16 (87.5%), and the survival rate of 90 days was 13/16 (81.3%).Conclusions:Iatrogenic biliary hemorrhage usually is sudden onset and fatal. Interventional therapy was proved as a quickly diagnosis and serves as safely and efficiency methods for hemostasis.

Hepatocellular carcinoma (HCC) is the predominant pathological type of liver cancer. Several therapeutic treatments, including sorafenib and regorafenib, have only modestly improved survival in patients with HCC. The aim of this study was to investigate the expression profiles and the regulation of competitive endogenous RNAs (ceRNAs) of the sorafenib-related target genes in HCC. Based on clinical information and expression profiles of HCC clinical samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, shared differentially expressed genes (DEGs) were analyzed and identified. Sorafenib-associated DEGs (SADs) were obtained by intersecting the DEGs with the sorafenib target genes from SuperTarget database. The expression patterns of SADs were verified in the Oncomine database. The biological functions of the SADs were annotated by gene set enrichment analysis (GSEA). In addition, a ceRNA network associated with SADs was constructed. Long non-coding RNAs (lncRNAs) in network that were significantly associated with overall survival were identified as prognosis of patients by Cox regression analysis. Finally, the expression levels of prognostic genes in HCC tissues and cell lines were verified using qRT-PCR. Gene expression differential analysis yielded a total of 146 common DEGs were obtained, including 21 upregulated and 125 downregulated DEGs. Among them, ten SADs were detected to be differentially expressed between tumor and normal tissues, including AXL, CYP2C19, CYP2C8, CYP2C9, CYP3A4, FGFR2, GMNN, PDGFRA, and TTK. GSEA analysis grouped them into three categories by function. The first category (CYP2C19, CYP2C8, CYP2C9 and CYP3A4) and second category (GMNN, TTK and EGER2) had the opposite roles in the enriched terms and pathways, while the third class (AXL and PDGFRA) has enrichment terms and pathways that intersect with those of the first and second categories. A ceRNA network associated with SADs was also constructed including 49 lncRNAs, 14 miRNAs, and 8 mRNAs. Three of these lncRNAs, SNHG7, GAS5 and HCP5, were found upregulated in HCC tissues and to be independent predictors in HCC patients. Significant correlations were found in expression between the prognostic lncRNAs and SADs. Ten SADs were systematically identified using expression data from HCC and normal tissues from TCGA and GEO datasets. GSEA analysis provided us with insight into the function of SADs. In the future, we will continue to explore the mechanisms of coordinated regulation of SADs-related prognostic lncRNAs and SADs at the ceRNA axis level and their potential functions in the development of HCC.

Nowadays, primary liver cancer is still a major threat to human health. Anoikis is a particular form of programed cell death that has an inhibitory effect on neoplasm metastasis. Although several prognostic models based on anoikis-related genes for Hepatocellular carcinoma (HCC) have been established, signatures associated with anoikis-related lncRNAs have not been identified. To fill this blank space, the authors built up a prognostic signature and appraised its value in guiding immunotherapy. Eleven prognostic anoikis-related lncRNAs were identified through Least Absolute Shrinkage and Selection Operator Cox analysis. The accuracy of the risk signature in predicting prognosis was verified by K-M survival analysis and Receiver operating characteristic analysis. We further discovered that the high-risk group was often enriched in signal pathways related to cell growth and death and immune response; in addition, in the low-risk group, cells often undergo metabolic changes through gene set enrichment analysis. Finally, we realised that HCC patients in the high-risk group were upregulated in immune-checkpoint molecules and tend to have a higher tumour mutation burden level which indicated a higher sensitivity to immunotherapy. All in all, the anoikis-related lncRNAs risk signature showed excellent ability in predicting prognosis and may guide the application of immunotherapy in future clinical practice.

DNA methylation (DNAme) alterations are known to initiate from the precancerous stage of tumorigenesis. Herein, we investigated the global and local patterns of DNAme perturbations in tumorigenesis by analysing the genome-wide DNAme profiles of the cervix, colorectum, stomach, prostate, and liver at precancerous and cancer stages. We observed global hypomethylation in tissues of both two stages, except for the cervix, whose global DNAme level in normal tissue was lower than that of the other four tumour types. For alterations shared by both stages, there were common hyper-methylation (sHyperMethyl) and hypo-methylation (sHypoMethyl) changes, of which the latter type was more frequently identified in all tissues. Biological pathways interrupted by sHyperMethyl and sHypoMethyl alterations demonstrated significant tissue specificity. DNAme bidirectional chaos indicated by the enrichment of both sHyperMethyl and sHypoMethyl changes in the same pathway was observed in most tissues and was a common phenomenon, particularly in liver lesions. Moreover, for the same enriched pathways, different tissues may be affected by distinct DNAme types. For the PI3K-Akt signalling pathway, sHyperMethyl enrichment was observed in the prostate dataset, but sHypoMethyl enrichment was observed in the colorectum and liver datasets. Nevertheless, they did not show an increased possibility in survival prediction of patients in comparison with other DNAme types. Additionally, our study demonstrated that gene-body DNAme changes of tumour suppressor genes and oncogenes may persist from precancerous lesions to the tumour. Overall, we demonstrate the tissue specificity and commonality of cross-stage alterations in DNA methylation profiles in multi-tissue tumorigenesis.