Early detection and prognosis evaluation for hepatocellular carcinoma by circulating tumour DNA methylation: A multicentre cohort study.

BACKGROUND: Early diagnosis of hepatocellular carcinoma (HCC) can significantly improve patient survival. We aimed to develop a blood-based assay to aid in the diagnosis, detection and prognostic evaluation of HCC. METHODS: A three-phase multicentre study was conducted to screen, optimise and validate HCC-specific differentially methylated regions (DMRs) using next-generation sequencing and quantitative methylation-specific PCR (qMSP). RESULTS: Genome-wide methylation profiling was conducted to identify DMRs distinguishing HCC tumours from peritumoural tissues and healthy plasmas. The twenty most effective DMRs were verified and incorporated into a multilocus qMSP assay (HepaAiQ). The HepaAiQ model was trained to separate 293 HCC patients (Barcelona Clinic Liver Cancer (BCLC) stage 0/A, 224) from 266 controls including chronic hepatitis B (CHB) or liver cirrhosis (LC) (CHB/LC, 96), benign hepatic lesions (BHL, 23), and healthy controls (HC, 147). The model achieved an area under the curve (AUC) of 0.944 with a sensitivity of 86.0% in HCC and a specificity of 92.1% in controls. Blind validation of the HepaAiQ model in a cohort of 523 participants resulted in an AUC of 0.940 with a sensitivity of 84.4% in 205 HCC cases (BCLC stage 0/A, 167) and a specificity of 90.3% in 318 controls (CHB/LC, 100; BHL, 102; HC, 116). When evaluated in an independent test set, the HepaAiQ model exhibited a sensitivity of 70.8% in 65 HCC patients at BCLC stage 0/A and a specificity of 89.5% in 124 patients with CHB/LC. Moreover, HepaAiQ model was assessed in paired pre- and postoperative plasma samples from 103 HCC patients and correlated with 2-year patient outcomes. Patients with high postoperative HepaAiQ score showed a higher recurrence risk (Hazard ratio, 3.33, p < .001). CONCLUSIONS: HepaAiQ, a noninvasive qMSP assay, was developed to accurately measure HCC-specific DMRs and shows great potential for the diagnosis, detection and prognosis of HCC, benefiting at-risk populations.

scRank infers drug-responsive cell types from untreated scRNA-seq data using a target-perturbed gene regulatory network.

Cells respond divergently to drugs due to the heterogeneity among cell populations. Thus, it is crucial to identify drug-responsive cell populations in order to accurately elucidate the mechanism of drug action, which is still a great challenge. Here, we address this problem with scRank, which employs a target-perturbed gene regulatory network to rank drug-responsive cell populations via in silico drug perturbations using untreated single-cell transcriptomic data. We benchmark scRank on simulated and real datasets, which shows the superior performance of scRank over existing methods. When applied to medulloblastoma and major depressive disorder datasets, scRank identifies drug-responsive cell types that are consistent with the literature. Moreover, scRank accurately uncovers the macrophage subpopulation responsive to tanshinone IIA and its potential targets in myocardial infarction, with experimental validation. In conclusion, scRank enables the inference of drug-responsive cell types using untreated single-cell data, thus providing insights into the cellular-level impacts of therapeutic interventions.

Extraction and Isolation of Two Polysaccharides from Chloranthus japonicus Sieb. and Evaluation of Their Anti-Gastric Cancer Activities.

Two unreported heteropolysaccharides, denoted as YCJP-1 and YCJP-2, were isolated from the herbs of Chloranthus japonicus. YCJP-1 was a heteropolysaccharide composed of glucose, galactose, arabinose, mannose, rhamnose, and a minor proportion of uronic acids, with the molecular weight mainly distributed in the 74,475-228,443 Da range. YCJP-2 was mainly composed of glucose, mannose, and galactose, with the molecular weights ranging from 848 to 5810 Da. To further evaluate the anti-gastric cancer effects of C. japonicus, the inhibitory effects of the crude polysaccharide (YCJP) and the purified polysaccharides (YCJP-1 and YCJP-2) were determined using a CCK-8 assay and colon-forming assay on MGC-803 and AGS gastric cancer cell lines. Our results showed that YCJP, YCJP-1, and YCJP-2 possess prominent inhibitory effects on the proliferation of MGC-803 and AGS cells, and the AGS cell was more sensitive to YCJP, YCJP-1, and YCJP-2. Moreover, YCJP-2 demonstrated superior anti-gastric cancer effects compared to YCJP-1. This could potentially be attributed to YCJP-2's higher glucose content and narrower molecular weight distribution.

Lnc-CCNH-8 promotes immune escape by up-regulating PD-L1 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common malignancy with poor prognosis. In recent years, immune checkpoint inhibitors (ICIs) have enabled breakthroughs in the clinical treatment of patients with HCC, but the overall response rate to ICIs in HCC patients is still low, and no validated biomarker is available to guide clinical decision making. Here, we demonstrated that the long non-coding RNA Lnc-CCNH-8 is highly expressed in HCC and correlates with poor prognosis. Functionally, elevated Lnc-CCNH-8 inactivated co-cultured T cells in vitro and compromised antitumor immunity in an immunocompetent mouse model. Mechanistically, up-regulated Lnc-CCNH-8 can sponge microRNA (miR)-217 to regulate the expression of PD-L1. In addition, Lnc-CCNH-8 can also stabilize PD-L1 through miR-3173/PKP3 axis. Furthermore, mice bearing tumors with high Lnc-CCNH-8 expression had significant therapeutic sensitivity to anti-PD-L1 monoclonal antibody treatment. More important, HCC patients with high levels of plasma exosomal Lnc-CCNH-8 had a better therapeutic response to ICIs. Taken together, our results reveal the function of Lnc-CCNH-8 in inducing immune escape from CD8+ T-cell-mediated killing by up-regulating PD-L1 in a miR-217/miR-3173-dependent manner, which also reveals a novel mechanism of PD-L1 regulation in HCC, and exosomal Lnc-CCNH-8 can serve as a predictive marker for immunotherapy response in HCC.

Proteomic Analysis Identifies GSN as a Noninvasive Circulating Serum Biomarker for Predicting Early Recurrence of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is susceptible to early recurrence, but it lacks effective predictive biomarkers. In this study, we retrospectively selected 179 individuals as a discovery cohort (126 HCC patients and 53 liver cirrhosis (LC) patients) for screening candidate serum biomarkers of early recurrence based on data independent acquisition-mass spectrometry strategy. And then, the candidate biomarkers were validated in an additional independent cohort with 192 individuals (142 HCC patients and 50 LC patients) using parallel reaction monitoring targeted quantitative techniques (PXD047852). Eventually, we validated that gelsolin (GSN) concentrations were significantly lower in HCC than in LC (p < 0.0001), patients with low GSN concentrations had a poor prognosis (p < 0.0001), and GSN concentrations were significantly lower in early recurrence HCC than in late recurrence HCC (p < 0.0001). These trends were also observed in alpha-fetoprotein (AFP)-negative HCC patients. The area under the curve of machine-learning-based predictive model (GSN and microvascular invasion) for predicting early recurrence risk reached 0.803 (95% confidence interval (CI): 0.786-0.820) and maintained the same efficacy in AFP-negative patients. In conclusion, GSN is a novel serum biomarker for early recurrence of HCC. The model could provide timely warning to HCC patients at high risk of recurrence.

Cell-free DNA testing for early hepatocellular carcinoma surveillance.

BACKGROUND: Liver cirrhosis (LC) is the highest risk factor for hepatocellular carcinoma (HCC) development worldwide. The efficacy of the guideline-recommended surveillance methods for patients with LC remains unpromising. METHODS: A total of 4367 LCs not previously known to have HCC and 510 HCCs from 16 hospitals across 11 provinces of China were recruited in this multi-center, large-scale, cross-sectional study. Participants were divided into Stage Ⅰ cohort (510 HCCs and 2074 LCs) and Stage Ⅱ cohort (2293 LCs) according to their enrollment time and underwent Tri-phasic CT/enhanced MRI, US, AFP, and cell-free DNA (cfDNA). A screening model called PreCar Score was established based on five features of cfDNA using Stage Ⅰ cohort. Surveillance performance of PreCar Score alone or in combination with US/AFP was evaluated in Stage Ⅱ cohort. FINDINGS: PreCar Score showed a significantly higher sensitivity for the detection of early/very early HCC (Barcelona stage A/0) in contrast to US (sensitivity of 51.32% [95% CI: 39.66%-62.84%] at 95.53% [95% CI: 94.62%-96.38%] specificity for PreCar Score; sensitivity of 23.68% [95% CI: 14.99%-35.07%] at 99.37% [95% CI: 98.91%-99.64%] specificity for US) (P < 0.01, Fisher's exact test). PreCar Score plus US further achieved a higher sensitivity of 60.53% at 95.08% specificity for early/very early HCC screening. INTERPRETATION: Our study developed and validated a cfDNA-based screening tool (PreCar Score) for HCC in cohorts at high risk. The combination of PreCar Score and US can serve as a promising and practical strategy for routine HCC care. FUNDING: A full list of funding bodies that contributed to this study can be found in Acknowledgments section.

RNA Methyltransferase FTSJ3 Regulates the Type I Interferon Pathway to Promote Hepatocellular Carcinoma Immune Evasion.

Immunotherapies such as immune checkpoint blockade have achieved remarkable success in treating cancer. Unfortunately, response rates have been limited in multiple cancers including hepatocellular carcinoma (HCC). The critical function of epigenetics in tumor immune evasion and antitumor immunity supports harnessing epigenetic regulators as a potential strategy to enhance the efficacy of immunotherapy. Here, we discovered a tumor-promoting function of FTSJ3, an RNA 2'-O-methyltransferase, in HCC by suppressing antitumor immune responses. FTSJ3 was upregulated in hepatocellular carcinoma, and high FTSJ3 expression correlated with reduced patient survival. Deletion of FTSJ3 blocked HCC growth and induced robust antitumor immune responses. Mechanistically, FTSJ3 suppressed double-stranded RNA (dsRNA)-induced IFNß signaling in a 2'-O-methyltransferase manner. Deletion of RNA sensors in HCC cells or systemic knockout of type I IFN receptor IFNAR in mice rescued the in vivo tumor growth defect caused by FTSJ3 deficiency, indicating that FTSJ3 deletion suppresses tumor growth by activating the RNA sensor-mediated type I IFN pathway. Furthermore, FTSJ3 deletion significantly enhanced the efficacy of programmed cell death protein 1 (PD-1) immune checkpoint blockade. The combination of FTSJ3 deficiency and anti-PD-1 antibody treatment effectively eradicated tumors and increased the survival time. In conclusion, this study reveals an epigenetic mechanism of tumor immune evasion and, importantly, suggests FTSJ3-targeting therapies as potential approach to overcome immunotherapy resistance in patients with HCC. SIGNIFICANCE: Hepatocellular carcinoma cells use 2'-O-methylation catalyzed by FTSJ3 for immune evasion by suppressing abnormal dsRNA-mediated type I IFN responses, providing a potential target to activate antitumor immunity and enhance immunotherapy efficacy.

LncRNA NKILA inhibits HBV replication by repressing NF-κB signalling activation.

Hepatitis B virus (HBV) infection results in liver cirrhosis and hepatocellular carcinoma (HCC). HBx/nuclear factor (NF)-κB pathway plays a role in HBV replication. However, whether NF-κB-interacting long noncoding RNA (NKILA), a suppressor of NF-κB activation, regulates HBV replication remains largely unknown. In this study, gain-and-loss experiments showed that NKILA inhibited HBV replication by inhibiting NF-κB activity. In turn, HBV infection down-regulated NKILA expression. In addition, expression levels of NKILA were lower in the peripheral blood-derived monocytes (PBMCs) of HBV-positive patients than in healthy individuals, which were correlated with HBV viral loads. And a negative correlation between NKILA expression level and HBV viral loads was observed in blood serum from HBV-positive patients. Lower levels of endogenous NKILA were also observed in HepG2 cells expressing a 1.3-fold HBV genome, HBV-infected HepG2-NTCP cells, stable HBV-producing HepG2.2.15 and HepAD38 â€‹cells, compared to those HBV-negative cells. Furthermore, HBx was required for NKILA-mediated inhibition on HBV replication. NKILA decreased HBx-induced NF-κB activation by interrupting the interaction between HBx and p65, whereas NKILA mutants lack of essential domains for NF-ĸB inhibition, lost the ability to inhibit HBV replication. Together, our data demonstrate that NKILA may serve as a suppressor of HBV replication via NF-ĸB signalling.

Hypoxia induces hepatocellular carcinoma metastasis via the HIF-1α/METTL16/lnc-CSMD1-7/RBFOX2 axis.

Hypoxic microenvironment is clinically associated with metastasis and poor prognosis of numerous cancers. The mechanisms by which intratumoral hypoxia regulates metastasis are not fully understood. Our study identifies a downregulation of Lnc-CSMD1-7 in hepatocellular carcinoma (HCC) and correlated with poor prognosis of HCC patients. Lnc-CSMD1-7 negatively regulated HCC cell migration and invasion in vitro and suppressed lung metastasis in vivo. Mechanistically, Lnc-CSMD1-7 directly binds to RBFOX2, thereby affecting RBFOX2-regulated alternative splicing in epithelial and mesenchymal-specific events. More importantly, hypoxic microenvironment and m6A methylation mediate the downregulation of Lnc-CSMD1-7 expression. Specifically, hypoxia transcriptionally upregulates the expression of the m6A methyltransferase METTL16 via HIF-1α, and METTL16 directly binds to Lnc-CSMD1-7 and downregulates the RNA stability of Lnc-CSMD1-7 via m6A methylation, ultimately promoting HCC metastasis. Our findings highlight the regulatory function of the METTL16/Lnc-CSMD1-7/RBFOX2 axis in modulating hypoxia-induced HCC progression, which may provide potential prognostic and therapeutic targets for HCC treatment.

Integrated omics landscape of hepatocellular carcinoma suggests proteomic subtypes for precision therapy.

Patients with hepatocellular carcinoma (HCC) at the same clinical stage can have extremely different prognoses, and molecular subtyping provides an opportunity for individualized precision treatment. In this study, genomic, transcriptomic, proteomic, and phosphoproteomic profiling of primary tumor tissues and paired para-tumor tissues from HCC patients (N = 160) are integrated. Proteomic profiling identifies three HCC subtypes with different clinical prognosis, which are validated in three publicly available external validation sets. A simplified panel of nine proteins associated with metabolic reprogramming is further identified as a potential subtype-specific biomarker for clinical application. Multi-omics analysis further reveals that three proteomic subtypes have significant differences in genetic alterations, microenvironment dysregulation, kinase-substrate regulatory networks, and therapeutic responses. Patient-derived cell-based drug tests (N = 26) show personalized responses for sorafenib in three proteomic subtypes, which can be predicted by a machine-learning response prediction model. Overall, this study provides a valuable resource for better understanding of HCC subtypes for precision clinical therapy.

Proteomics-driven noninvasive screening of circulating serum protein panels for the early diagnosis of hepatocellular carcinoma.

Early diagnosis of hepatocellular carcinoma (HCC) lacks highly sensitive and specific protein biomarkers. Here, we describe a staged mass spectrometry (MS)-based discovery-verification-validation proteomics workflow to explore serum proteomic biomarkers for HCC early diagnosis in 1002 individuals. Machine learning model determined as P4 panel (HABP2, CD163, AFP and PIVKA-II) clearly distinguish HCC from liver cirrhosis (LC, AUC 0.979, sensitivity 0.925, specificity 0.915) and healthy individuals (HC, AUC 0.992, sensitivity 0.975, specificity 1.000) in an independent validation cohort, outperforming existing clinical prediction strategies. Furthermore, the P4 panel can accurately predict LC to HCC conversion (AUC 0.890, sensitivity 0.909, specificity 0.877) with predicting HCC at a median of 11.4 months prior to imaging in prospective external validation cohorts (No.: Keshen 2018_005_02 and NCT03588442). These results suggest that proteomics-driven serum biomarker discovery provides a valuable reference for the liquid biopsy, and has great potential to improve early diagnosis of HCC.

Hsa_circ_0001687 Function as a ceRNA to Facilitate Hepatocellular Carcinoma Progression via miR-140- 3p/FOXQ1 Axis.

BACKGROUND: Increasingly convincing evidence has revealed that circular RNAs (circRNAs) are critical regulatory components of hepatocellular carcinoma (HCC) genesis. However, the expression of circRNAs in HCC and the relevance of circRNAs to HCC progression remain largely unexplained. METHODS: qRT-PCR or western blotting was utilized to confirm circ_0001687, miR-140-3p, and Forkhead Box q1 (FOXQ1) levels in HCC tissues or cells. Cell proliferation ability was evaluated via CCK-8 and colony formation assay. The correlation of circ_0001687 or FOXQ1 and miR-140- 3p was determined using dual luciferase reporter assay. Nude mice xenograft tumor model was constructed to verify the effect of circ_0001687 on tumor growth. RESULTS: Circ_0001687 was elevated in HCC. Function assays and the nude mice xenograft tumor model indicated that circ_0001687 acts as a promoting gene in HCC to regulate the proliferation of the tumor cell and foster tumor growth. Further mechanistic exploration revealed that the tumor growth-promoting mechanism of circ_0001687 relied on blocking the inhibitory effect of miR-140- 3p on FOXQ1 and activating FOXQ1 expression. CONCLUSION: This research indicated the role of circ_0001687/miR-140-3p/FOXQ1 network in regulating HCC development. These may provide new insights into the treatment of HCC.

LncRNA TIALD contributes to hepatocellular carcinoma metastasis via inducing AURKA lysosomal degradation.

The N6-methyladenosine (m6A) RNA methyltransferase METTL16 is an emerging player in RNA modification landscape and responsible for the deposition of m6A in a few transcripts. AURKA (aurora kinase A) has been confirmed as an oncogene in cancer development including hepatocellular carcinoma (HCC). Nevertheless, it remains unclear whether METTL16 mediated m6A modification of lncRNAs can regulate AURKA activation in cancer progression. Here we aimed to investigate the functional links between lncRNAs and the m6A modification in AURKA signaling and HCC progression. Here we show that LncRNA TIALD (transcript that induced AURKA Lysosomal degradation) was down-regulated in HCC tissues by METTL16 mediated m6A methylation to facilitate its RNA degradation, and correlates with poor prognosis. Functional assays reveal that TIALD inhibits HCC metastasis both in vitro and in vivo. Mechanistically, TIALD directly interacts with AURKA and facilitate its degradation through the lysosomal pathway to inhibited EMT and metastasis of HCC. AURKA's specific inhibitor alisertib exerts effective therapeutic effect on liver cancer with low TIALD expression, which might provide a new insight into HCC therapy. Our study uncovers a negative functional loop of METTL16-TIALD-AURKA axis, and identifies a new mechanism for METTL16 mediated m6A-induced decay of TIALD on AURKA signaling in HCC progression, which may provide potential prognostic and therapeutic targets for HCC.

Lnc-PLA2G4A-4 facilitates the progression of hepatocellular carcinoma by inducing versican expression via sponging miR-23b-3p.

Aberrant expression of long non-coding RNAs (lncRNAs) is associated with progression of multiple human cancers including hepatocellular carcinoma (HCC). However, the role of lncRNAs in HCC is not been fully understood. Our study aimed to investigate the biological function and potential molecular mechanism of Lnc-PAL2G4A-4 in HCC. In the current study, we show that Lnc-PLA2G4A-4 was significantly up-regulated in HCC tissues and high Lnc-PLA2G4A-4 expression was remarkably associated with tumor size, microvascular invasion and poor prognosis of HCC patients. Functionally, Lnc-PLA2G4A-4 positively regulated cell proliferation, invasion and migration in vitro, and facilitated lung metastasis of HCC in vivo. Mechanistically, Lnc-PLA2G4A-4 functioned as a competing endogenous RNA (ceRNA) to bind to miR-23b-3p and subsequently facilitate miR-23b-3p's target gene versican (VCAN) expression in HCC cells. Over-expression of miR-23b-3p could reverse Lnc-PLA2G4A-4 induced cell phenotypes in HCC and suppress versican expression of by rescue analysis. Collectively, Lnc-PLA2G4A-4 promotes HCC progression by targeting the miR-23b-3p/versican axis, which may be a potential biomarker and therapeutic target for HCC.

Silk-Gel Powered Adenoviral Vector Enables Robust Genome Editing of PD-L1 to Augment Immunotherapy across Multiple Tumor Models.

Immune checkpoint blockade based on antibodies has shown great clinical success in patients, but the transitory working manner leads to restricted therapeutic benefits. Herein, a genetically engineered adenovirus is developed as the vector to deliver CRISPR/Cas9 (sgCas9-AdV) to achieve permanent PD-L1 gene editing with efficiency up to 78.7% exemplified in Hepa 1-6 liver cancer cells. Furthermore, the sgCas9-AdV is loaded into hydrogel made by silk fiber (SgCas9-AdV/Gel) for in vivo application. The silk-gel not only promotes local retention of sgCas9-AdV in tumor tissue, but also masks them from host immune system, thus ensuring effectively gene transduction over 9 days. Bearing these advantages, the sgCas9-AdV/Gel inhibits Hepa 1-6 tumor growth with 100% response rate by single-dose injection, through efficient PD-L1 disruption to elicit a T cell-mediated antitumor response. In addition, the sgCas9-AdV/Gel is also successfully extended into other refractory tumors. In CT26 colon tumor characterized by poor response to anti-PD-L1, sgCas9-AdV/Gel is demonstrated to competent and superior anti-PD-L1 antibody to suppress tumor progression. In highly aggressive orthotopic 4T1 mouse breast tumor, such a therapeutic paradigm significantly inhibits primary tumor growth and induces a durable immune response against tumor relapse/metastasis. Thus, this study provides an attractive and universal strategy for immunotherapy.

The development of a cSMART-based integrated model for hepatocellular carcinoma diagnosis.

BACKGROUND: Hepatocellular carcinoma (HCC) generally arises from a background of liver cirrhosis (LC). Patients with cirrhosis and suspected HCC are recommended to undergo serum biomarker tests and imaging diagnostic evaluation. However, the performance of routine diagnostic methods in detecting early HCC remains unpromising. METHODS: Here, we conducted a large-scale, multicenter study of 1675 participants including 490 healthy controls, 577 LC patients, and 608 HCC patients from nine clinical centers across nine provinces of China, profiled gene mutation signatures of cell-free DNA (cfDNA) using Circulating Single-Molecule Amplification and Resequencing Technology (cSMART) through detecting 931 mutation sites across 21 genes. RESULTS: An integrated diagnostic model called "Combined method" was developed by combining three mutation sites and three serum biomarkers. Combined method outperformed AFP in the diagnosis of HCC, especially early HCC, with sensitivities of 81.25% for all stages and 66.67% for early HCC, respectively. Importantly, the integrated model exhibited high accuracy in differentiating AFP-negative, AFP-L3-negative, and PIVKA-II-negative HCCs from LCs.

[Efficacy and safety of rituximab in children and adolescents with mature B-cell non-Hodgkin's lymphoma: a Meta analysis]. / 利妥昔单抗治疗儿童及青少年成熟Bç»†èƒžéžéœå¥‡é‡‘æ·‹å·´ç˜¤ç–—æ•ˆåŠå®‰å ¨æ€§çš„Meta分析.

OBJECTIVES: To study the efficacy and safety of rituximab combined with chemotherapy in the treatment of children and adolescents with mature B-cell non-Hodgkin's lymphoma (B-NHL) through a Meta analysis. METHODS: The databases including PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, Web of Science, China National Knowledge Infrastructure, Wanfang Data, and Weipu were searched to obtain 10 articles on rituximab in the treatment of mature B-NHL in children and adolescents published up to June 2022, with 886 children in total. With 3-year event-free survival (EFS) rate, 3-year overall survival (OS) rate, complete remission rate, mortality rate, and incidence rate of adverse reactions as outcome measures, RevMan 5.4 software was used for Meta analysis, subgroup analysis, sensitivity analysis, and publication bias analysis. RESULTS: The rituximab+chemotherapy group showed significant increases in the 3-year EFS rate (HR=0.38, 95%CI: 0.25-0.59, P<0.001), 3-year OS rate (HR=0.29, 95%CI: 0.14-0.61, P=0.001), and complete remission rate (OR=3.72, 95%CI: 1.89-7.33, P<0.001) as well as a significant reduction in the mortality rate (OR=0.31, 95%CI: 0.17-0.57, P<0.001), as compared with the chemotherapy group without rituximab. There was no significant difference in the incidence rate of adverse reactions between the two groups (OR=1.28, 95%CI: 0.85-1.92, P=0.24). CONCLUSIONS: The addition of rituximab to the treatment regimen for children and adolescents with mature B-cell non-Hodgkin's lymphoma can bring significant survival benefits without increasing the incidence of adverse reactions.

Magnetically responsive nanoplatform targeting circRNA circ_0058051 inhibits hepatocellular carcinoma progression.

Circular RNAs (circRNAs) are a class of highly stable and closed-loop noncoding RNA that are involved in the occurrence and development of hepatocellular carcinoma (HCC). However, little is known about the therapeutic role of circRNAs in HCC. We found that high circ_0058051 expression was negatively correlated with the prognosis of HCC patients. Circ_0058051 knockdown attenuated the proliferation and colony formation, meanwhile inhibited migration of HCC cells. Circ_0058051 may be used as a target for HCC gene therapy. We synthesized a novel small interfering RNA (siRNA) delivery system, PEG-PCL-PEI-C14-SPIONs (PPPCSs), based on superparamagnetic iron oxide nanoparticles (SPIONs). PPPCSs protected the siRNA of circ_0058051 from degradation in serum and effectively delivered siRNA into SMMC-7721 cells. Meanwhile, intravenous injection of the PPPCSs/siRNA complex could inhibit tumor growth in the subcutaneous tumor model. In addition, the nanocomposite is not toxic to the organs of nude mice. The above results show that PPPCSs/si-circ_0058051 complex may provide a novel and promising method of HCC treatment.

Long non-coding RNA COX7C-5 promotes hepatocellular carcinoma progression via miR-581/ZEB2 axis.

Long non-coding RNAs (lncRNA) play crucial roles in hepatocellular carcinoma (HCC) progression. However, the functional roles of lncRNAs in HCC still remain largely unknown. Our study aimed to investigate the biological function and potential molecular mechanism of lnc-COX7C-5 in HCC. Here, we show that Lnc-COX7C-5 was significantly upregulated in HCC tissues, which was correlated with poor prognosis in HCC patients. Lnc-COX7C-5 positively regulated proliferation, migration, and invasion of HCC cells. Mechanistically, lnc-COX7C-5 function as a competing endogenous RNA (ceRNA) for miR-581 in HCC cells. Over-expression or knockdown of miR-581 could alter cell phenotypes caused by Lnc-COX7C-5 in HCC. Further investigations indicated that ZEB2 was demonstrated as a downstream target of miR-581. In mouse model, over-expression of Lnc-COX7C-5 facilitate lung metastasis of HCC. Collectively, Lnc-COX7C-5 promote HCC tumorigenesis and progression by targeting the miR-581/ZEB2 axis. Lnc-COX7C-5 may be a potential therapeutic target for HCC.

Fusobacterium nucleatum stimulates cell proliferation and promotes PD-L1 expression via IFIT1-related signal in colorectal cancer.

Fusobacterium nucleatum (F. nucleatum) is enriched in colorectal cancer (CRC) tissues and a high amount of F. nucleatum was associated with an immunosuppressive tumor environment. PD-L1 is an important immune checkpoint expressed on tumor cells and promotes tumor immune escape. Whether PD-L1 is regulated by F. nucleatum is still unclear. We demonstrated that F. nucleatum promoted CRC progression and upregulated PD-L1 protein expression in CRC cell lines. Combined m6A-seq and RNA-seq identified m6A-modified IFIT1 mediating F. nucleatum induced PD-L1 upregulation. IFIT1 mRNA was modified with m6A modifications in 3'UTR and the m6A levels were altered by F. nucleatum treatment. Our results also indicated that IFIT1 served as a potential oncogene in CRC and regulated PD-L1 protein levels through altering PD-L1 ubiquitination. Clinical CRC data confirmed the correlation among F. nucleatum abundance, IFIT1 and PD-L1 expressions. Our work highlighted the function of F. nucleatum in stimulating PD-L1 expression through m6A-modified IFIT1 and provided new aspects for understanding F. nucleatum mediated immune escape.