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1.
Cell ; 181(6): 1423-1433.e11, 2020 06 11.
Article in English | MEDLINE | ID: mdl-32416069

ABSTRACT

Many COVID-19 patients infected by SARS-CoV-2 virus develop pneumonia (called novel coronavirus pneumonia, NCP) and rapidly progress to respiratory failure. However, rapid diagnosis and identification of high-risk patients for early intervention are challenging. Using a large computed tomography (CT) database from 3,777 patients, we developed an AI system that can diagnose NCP and differentiate it from other common pneumonia and normal controls. The AI system can assist radiologists and physicians in performing a quick diagnosis especially when the health system is overloaded. Significantly, our AI system identified important clinical markers that correlated with the NCP lesion properties. Together with the clinical data, our AI system was able to provide accurate clinical prognosis that can aid clinicians to consider appropriate early clinical management and allocate resources appropriately. We have made this AI system available globally to assist the clinicians to combat COVID-19.


Subject(s)
Artificial Intelligence , Coronavirus Infections/diagnosis , Pneumonia, Viral/diagnosis , Tomography, X-Ray Computed , COVID-19 , China , Cohort Studies , Coronavirus Infections/pathology , Coronavirus Infections/therapy , Datasets as Topic , Humans , Lung/pathology , Models, Biological , Pandemics , Pilot Projects , Pneumonia, Viral/pathology , Pneumonia, Viral/therapy , Prognosis , Radiologists , Respiratory Insufficiency/diagnosis
3.
Cell Commun Signal ; 22(1): 274, 2024 May 16.
Article in English | MEDLINE | ID: mdl-38755598

ABSTRACT

BACKGROUND: Extracellular ATP-AMP-adenosine metabolism plays a pivotal role in modulating tumor immune responses. Previous studies have shown that the conversion of ATP to AMP is primarily catalysed by Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1/CD39), a widely studied ATPase, which is expressed in tumor-associated immune cells. However, the function of ATPases derived from tumor cells themselves remains poorly understood. The purpose of this study was to investigate the role of colon cancer cell-derived ATPases in the development and progression of colon cancer. METHODS: Bioinformatic and tissue microarray analyses were performed to investigate the expression of ATPase family members in colon cancer. An ATP hydrolysis assay, high-performance liquid chromatography (HPLC), and CCK8 and colony formation assays were used to determine the effects of ENTPD2 on the biological functions of colon cancer cells. Flow cytometric and RNA-seq analyses were used to explore the function of CD8+ T cells. Immunoelectron microscopy and western blotting were used to evaluate the expression of ENTPD2 in exosomes. Double-labelling immunofluorescence and western blotting were used to examine the expression of ENTPD2 in serum exosomes and colon cancer tissues. RESULTS: We found that ENTPD2, rather than the well-known ATPase CD39, is highly expressed in cancer cells and is significantly positively associated with poor patient prognosis in patients with colon cancer. The overexpression of ENTPD2 in cancer cells augmented tumor progression in immunocompetent mice by inhibiting the function of CD8+ T cells. Moreover, ENTPD2 is localized primarily within exosomes. On the one hand, exosomal ENTPD2 reduces extracellular ATP levels, thereby inhibiting P2X7R-mediated NFATc1 nuclear transcription; on the other hand, it facilitates the increased conversion of ATP to adenosine, hence promoting adenosine-A2AR pathway activity. In patients with colon cancer, the serum level of exosomal ENTPD2 is positively associated with advanced TNM stage and high tumor invasion depth. Moreover, the level of ENTPD2 in the serum exosomes of colon cancer patients is positively correlated with the ENTPD2 expression level in paired colon cancer tissues, and the ENTPD2 level in both serum exosomes and tissues is significantly negatively correlated with the ENTPD2 expression level in tumor-infiltrating CD8+ T cells. CONCLUSION: Our study suggests that exosomal ENTPD2, originated from colon cancer cells, contributes to the immunosuppressive microenvironment by promoting ATP-adenosine metabolism. These findings highlight the importance of exosome-derived hydrolytic enzymes as independent entities in shaping the tumor immune microenvironment.


Subject(s)
Adenosine Triphosphate , Adenosine , Apyrase , CD8-Positive T-Lymphocytes , Colonic Neoplasms , Exosomes , Humans , Exosomes/metabolism , Adenosine/metabolism , Adenosine Triphosphate/metabolism , Colonic Neoplasms/pathology , Colonic Neoplasms/metabolism , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , Apyrase/metabolism , Apyrase/genetics , Animals , Mice , Cell Line, Tumor , Male , Female , Metabolic Reprogramming , Receptor, Adenosine A2A
4.
J Hepatol ; 79(6): 1418-1434, 2023 12.
Article in English | MEDLINE | ID: mdl-37604269

ABSTRACT

BACKGROUND & AIMS: Integrin αv (ITGAV, CD51) is regarded as a key component in multiple stages of tumor progression. However, the clinical failure of cilengitide, a specific inhibitor targeting surface CD51, suggests the importance of yet-unknown mechanisms by which CD51 promotes tumor progression. METHODS: In this study, we used several hepatocellular carcinoma (HCC) cell lines and murine hepatoma cell lines. To investigate the role of CD51 on HCC progression, we used a 3D invasion assay and in vivo bioluminescence imaging. We used periostin-knockout transgenic mice to uncover the role of the tumor microenvironment on CD51 cleavage. Moreover, we used several clinically relevant HCC models, including patient-derived organoids and patient-derived xenografts, to evaluate the therapeutic efficacy of cilengitide in combination with the γ-secretase inhibitor LY3039478. RESULTS: We found that CD51 could undergo transmembrane cleavage by γ-secretase to produce a functional intracellular domain (CD51-ICD). The cleaved CD51-ICD facilitated HCC invasion and metastasis by promoting the transcription of oxidative phosphorylation-related genes. Furthermore, we identified cancer-associated fibroblast-derived periostin as the major driver of CD51 cleavage. Lastly, we showed that cilengitide-based therapy led to a dramatic therapeutic effect when supplemented with LY3039478 in both patient-derived organoid and xenograft models. CONCLUSIONS: In summary, we revealed previously unrecognized mechanisms by which CD51 is involved in HCC progression and uncovered the underlying cause of cilengitide treatment failure, as well as providing evidence supporting the translational prospects of combined CD51-targeted therapy in the clinic. IMPACT AND IMPLICATIONS: Integrin αv (CD51) is a widely recognized pro-tumoral molecule that plays a crucial role in various stages of tumor progression, making it a promising therapeutic target. However, despite early promising results, cilengitide, a specific antagonist of CD51, failed in a phase III clinical trial. This prompted further investigation into the underlying mechanisms of CD51's effects. This study reveals that the γ-secretase complex directly cleaves CD51 to produce an intracellular domain (CD51-ICD), which functions as a pro-tumoral transcriptional regulator and can bypass the inhibitory effects of cilengitide by entering the nucleus. Furthermore, the localization of CD51 in the nucleus is significantly associated with the prognosis of patients with HCC. These findings provide a theoretical basis for re-evaluating cilengitide in clinical settings and highlight the importance of identifying a more precise patient subpopulation for future clinical trials targeting CD51.


Subject(s)
Carcinoma, Hepatocellular , Integrin alphaV , Liver Neoplasms, Experimental , Liver Neoplasms , Animals , Humans , Mice , Amyloid Precursor Protein Secretases , Carcinoma, Hepatocellular/genetics , Cell Line, Tumor , Integrin alphaV/genetics , Integrin alphaV/metabolism , Liver Neoplasms/genetics , Tumor Microenvironment
5.
Proc Natl Acad Sci U S A ; 116(13): 6286-6291, 2019 03 26.
Article in English | MEDLINE | ID: mdl-30862736

ABSTRACT

Disruption of mucosal immunity plays a critical role in the pathogenesis of inflammatory bowel disease, yet its mechanism remains not fully elucidated. Here, we found that activating transcription factor 3 (ATF3) protects against colitis by regulating follicular helper T (TFH) cells in the gut. The expression of ATF3 in CD4+ T cells was negatively correlated with the severity of ulcerative colitis in clinical patients. Mice with ATF3 deficiency in CD4+ T cells (CD4creAtf3fl/fl ) were much more susceptible to dextran sulfate sodium-induced colitis. The frequencies of TFH cells, not other T cell subsets, were dramatically decreased in Peyer's patches from CD4creAtf3fl/fl mice compared with Atf3fl/fl littermate controls. The defective TFH cells significantly diminished germinal center formation and IgA production in the gut. Importantly, adoptive transfer of TFH or IgA+ B cells caused significant remission of colitis in CD4creAtf3fl/fl mice, indicating the TFH-IgA axis mediated the effect of ATF3 on gut homeostasis. Mechanistically, B cell lymphoma 6 was identified as a direct transcriptional target of ATF3 in CD4+ T cells. In summary, we demonstrated ATF3 as a regulator of TFH cells in the gut, which may represent a potential immunotherapeutic target in colitis.


Subject(s)
Activating Transcription Factor 3/immunology , Activating Transcription Factor 3/pharmacology , Colitis/drug therapy , Colitis/immunology , T-Lymphocytes, Helper-Inducer/drug effects , T-Lymphocytes, Helper-Inducer/immunology , Activating Transcription Factor 3/genetics , Activating Transcription Factor 3/metabolism , Adoptive Transfer , Animals , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , Colitis/pathology , Colitis, Ulcerative , Colon/pathology , Dextran Sulfate/adverse effects , Disease Models, Animal , Gene Expression Profiling , Homeostasis , Immunity, Mucosal/immunology , Immunoglobulin A , Immunotherapy , Mice , Peyer's Patches/immunology , T-Lymphocyte Subsets
6.
Hepatobiliary Pancreat Dis Int ; 21(2): 106-112, 2022 Apr.
Article in English | MEDLINE | ID: mdl-34583911

ABSTRACT

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.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Liver Transplantation , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/surgery , Humans , Immunosuppressive Agents/adverse effects , Liver Neoplasms/drug therapy , Liver Neoplasms/surgery , Liver Transplantation/methods , Multicenter Studies as Topic , Neoplasm Recurrence, Local/drug therapy , Prospective Studies , Quality of Life , Sirolimus/adverse effects , Treatment Outcome
7.
J Ultrasound Med ; 38(3): 597-604, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30378156

ABSTRACT

OBJECTIVES: To investigate hemodynamic changes in the hepatic artery after hepatic ischemia-reperfusion injury (IRI) in rats via ultrasound (US) imaging and to discuss the protective effect of phentolamine (PHT) pretreatment on hepatic IRI. METHODS: Fifty rats were randomly divided into 3 groups: a sham operation group (n = 10), a control ischemia-reperfusion group (n = 20), and a PHT pretreatment group (n = 20). Color Doppler flow imaging and contrast-enhanced US examinations were performed in each group at 30 minutes (n = 10) and 90 minutes (n = 10) after reperfusion. Blood samples were obtained to analyze serum alanine aminotransferase and aspartate aminotransferase levels, and liver tissue specimens were collected for pathologic analysis. RESULTS: Using US, we found that hepatic artery resistance at 30 minutes after reperfusion in the control group was higher than that in the sham group (mean resistive index [RI] ± SD, 0.65 ± 0.09 versus 0.50 ± 0.09; P < .01), which was higher at 30 than 90 minutes (RI, 0.65 ± 0.09 versus 0.50 ± 0.08; P < .01) after reperfusion in the control group. However, the hepatic artery resistance and liver microcirculation in the PHT group were better than those in the control group at 30 minutes after reperfusion (RI, 0.54 ± 0.09 versus 0.65 ± 0.09; P < .05; time to peak, 31.94 ± 2.02 versus 48.34 ± 4.74 seconds; P < .01). Compared to the control group, the aspartate aminotransferase and alanine aminotransferase levels were significantly lower at 30 minutes after reperfusion in the PHT group (P < .05). A pathologic examination revealed a smaller hepatic artery diameter and a depressed vessel wall in the control group. CONCLUSIONS: The hepatic artery can undergo a transient spasm during the hepatic IRI process, which can exacerbate liver damage. Phentolamine treatment can alleviate hepatic artery spasms, improve liver perfusion, and reduce liver injury by ameliorating the hepatic microcirculation.


Subject(s)
Hepatic Artery/diagnostic imaging , Hepatic Artery/physiopathology , Reperfusion Injury/diagnosis , Reperfusion Injury/pathology , Animals , Disease Models, Animal , Liver/diagnostic imaging , Liver/physiopathology , Male , Rats , Rats, Sprague-Dawley , Ultrasonography/methods
8.
Cell Physiol Biochem ; 51(6): 2746-2759, 2018.
Article in English | MEDLINE | ID: mdl-30562736

ABSTRACT

BACKGROUND/AIMS: Numerous studies have shown that NIMA-related kinase 2 (NEK2) expression in hepatocellular carcinoma (HCC) tissue is associated with survival and clinicopathological features; however, the evidence remains inconclusive. Thus, we aimed to further explore the prognostic and clinicopathological significance of NEK2 expression in HCC using a two-part study consisting of a retrospective cohort study and a meta-analysis. METHODS: In the cohort study, NEK2 expression in 206 HCC samples and adjacent normal liver tissues was detected by immunohistochemistry (IHC). Patients were divided into a high NEK2 expression group and a low NEK2 expression group by the median value of the immunohistochemical scores. The Kaplan-Meier method with the log-rank test was used to analyze survival outcomes in the two groups, and multivariate analysis based on Cox proportional hazard regression models was applied to identify independent prognostic factors. In the meta-analysis, eligible studies were searched in PubMed, EMBASE, Web of Science, and CNKI databases. STATA version 12.0 (Stata Corporation, College Station, TX) was used for statistical analyses. RESULTS: The IHC results of our cohort study showed higher NEK2 expression in HCC tissues compared with adjacent normal liver tissues. Multivariate analysis revealed that high NEK2 expression was an independent risk factor for poor overall survival (OS) [hazard ratio (HR) = 1.763; 95% CI, 1.060-2.935; P = 0.029] and disease-free survival (DFS) [hazard ratio (HR) = 1.687; 95% CI, 1.102-2.584; P = 0.016] in HCC patients. A total of 11 studies with 1,698 patients were enrolled in the meta-analysis, consisting of 10 studies from the database search and our cohort study. The pooled results revealed that high NEK2 expression correlated closely with poor OS among HCC patients (HR = 1.47; 95% CI, 1.21-1.80; P < 0.01), and DFS/recurrence-free survival (RFS) (HR = 1.92; 95% CI, 1.41-2.63; P < 0.01). Additionally, our meta-analysis also showed that the proportion of HCC patients with high NEK2 expression was greater in the group with larger tumors (> 5 cm) than in the group with smaller tumors (≤ 5 cm) [odds ratio (OR) = 2.02; 95% CI, 1.13-3.64; P < 0.01). CONCLUSION: Our study demonstrated that high NEK2 expression is a risk factor for poor survival in HCC patients. More prospective, homogeneous, and multiethnic studies are required to validate our findings.


Subject(s)
Carcinoma, Hepatocellular/diagnosis , Liver Neoplasms/diagnosis , NIMA-Related Kinases/analysis , Biomarkers, Tumor/analysis , Carcinoma, Hepatocellular/pathology , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Liver Neoplasms/pathology , Male , Middle Aged , Prognosis , Retrospective Studies
10.
Biomol Biomed ; 2024 Mar 16.
Article in English | MEDLINE | ID: mdl-38498315

ABSTRACT

Identifying the precise moment before the onset of hepatocellular carcinoma (HCC) remains a significant challenge in the medical field. The existing biomarkers fall short of pinpointing the critical point preceding HCC formation. This study aimed to determine the exact tipping point for the transition from cirrhosis to HCC, identify the core Dynamic Network Biomarker (DNB), and elucidate its regulatory effects on HCC. A spontaneous HCC mouse model was established to mimic HCC formation in patients with chronic hepatitis. Using the DNB method, C1q and tumor necrosis factor (TNF) related 1 (C1QTNF1) protein was identified as the key DNB at the crucial tipping time of spontaneous HCC development. Both in vitro and in vivo studies showed that C1QTNF1 could inhibit tumor growth. Overexpression of C1QTNF1 before the tipping point effectively prevented HCC occurrence. Patients with elevated C1QTNF1 expression demonstrated improved overall survival (OS) (P = 0.03) and disease-free survival (DFS) (P = 0.03). The diagnostic value of C1QTNF1 was comparable to that of alpha-fetoprotein (AFP) (area under the curve [AUC] = 0.84; sensitivity 85%; specificity 80%). Furthermore, our research indicated that platelet-expressed C1QTNF1 is involved in cancer-associated signaling pathways. Our findings introduce a novel perspective by highlighting C1QTNF1 as the pivotal biomarker at the tipping point of primary HCC formation using DNB. We propose C1QTNF1 as a prognostic biomarker for HCC, potentially influencing tumor development through a platelet-related cancer signaling pathway.

11.
Nat Commun ; 15(1): 2859, 2024 Apr 03.
Article in English | MEDLINE | ID: mdl-38570500

ABSTRACT

Cold-induced injuries severely limit opportunities and outcomes of hypothermic therapies and organ preservation, calling for better understanding of cold adaptation. Here, by surveying cold-altered chromatin accessibility and integrated CUT&Tag/RNA-seq analyses in human stem cells, we reveal forkhead box O1 (FOXO1) as a key transcription factor for autonomous cold adaptation. Accordingly, we find a nonconventional, temperature-sensitive FOXO1 transport mechanism involving the nuclear pore complex protein RANBP2, SUMO-modification of transporter proteins Importin-7 and Exportin-1, and a SUMO-interacting motif on FOXO1. Our conclusions are supported by cold survival experiments with human cell models and zebrafish larvae. Promoting FOXO1 nuclear entry by the Exportin-1 inhibitor KPT-330 enhances cold tolerance in pre-diabetic obese mice, and greatly prolongs the shelf-life of human and mouse pancreatic tissues and islets. Transplantation of mouse islets cold-stored for 14 days reestablishes normoglycemia in diabetic mice. Our findings uncover a regulatory network and potential therapeutic targets to boost spontaneous cold adaptation.


Subject(s)
Diabetes Mellitus, Experimental , Forkhead Transcription Factors , Mice , Humans , Animals , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Forkhead Box Protein O1/genetics , Forkhead Box Protein O1/metabolism , Active Transport, Cell Nucleus , Zebrafish/metabolism , Karyopherins/metabolism
12.
Heliyon ; 9(11): e22458, 2023 Nov.
Article in English | MEDLINE | ID: mdl-38034691

ABSTRACT

Background: Identifying patients with hepatocellular carcinoma (HCC) at high risk of recurrence after hepatectomy can help to implement timely interventional treatment. This study aimed to develop a machine learning (ML) model to predict the recurrence risk of HCC patients after hepatectomy. Methods: We retrospectively collected 315 HCC patients who underwent radical hepatectomy at the Third Affiliated Hospital of Sun Yat-sen University from April 2013 to October 2017, and randomly divided them into the training and validation sets at a ratio of 7:3. According to the postoperative recurrence of HCC patients, the patients were divided into recurrence group and non-recurrence group, and univariate and multivariate logistic regression were performed for the two groups. We applied six machine learning algorithms to construct the prediction models and performed internal validation by 10-fold cross-validation. Shapley additive explanations (SHAP) method was applied to interpret the machine learning model. We also built a web calculator based on the best machine learning model to personalize the assessment of the recurrence risk of HCC patients after hepatectomy. Results: A total of 13 variables were included in the machine learning models. The multilayer perceptron (MLP) machine learning model was proved to achieve optimal predictive value in test set (AUC = 0.680). The SHAP method displayed that γ-glutamyl transpeptidase (GGT), fibrinogen, neutrophil, aspartate aminotransferase (AST) and total bilirubin (TB) were the top 5 important factors for recurrence risk of HCC patients after hepatectomy. In addition, we further demonstrated the reliability of the model by analyzing two patients. Finally, we successfully constructed an online web prediction calculator based on the MLP machine learning model. Conclusion: MLP was an optimal machine learning model for predicting the recurrence risk of HCC patients after hepatectomy. This predictive model can help identify HCC patients at high recurrence risk after hepatectomy to provide early and personalized treatment.

13.
Nat Commun ; 14(1): 7709, 2023 Nov 24.
Article in English | MEDLINE | ID: mdl-38001101

ABSTRACT

Atezolizumab (anti-PD-L1) combined with bevacizumab (anti-VEGFA) is the first-line immunotherapy for advanced hepatocellular carcinoma (HCC), but the number of patients who benefit from this regimen remains limited. Here, we combine dual PD-L1 and VEGFA blockade (DPVB) with low-dose radiotherapy (LDRT), which rapidly inflames tumors, rendering them vulnerable to immunotherapy. The combinatorial therapy exhibits superior antitumor efficacy mediated by CD8+ T cells in various preclinical HCC models. Treatment efficacy relies upon mobilizing exhausted-like CD8+ T cells (CD8+ Tex) with effector function and cytolytic capacity. Mechanistically, LDRT sensitizes tumors to DPVB by recruiting stem-like CD8+ Tpex, the progenitor exhausted CD8+ T cells, from draining lymph nodes (dLNs) into the tumor via the CXCL10/CXCR3 axis. Together, these results further support the rationale for combining LDRT with atezolizumab and bevacizumab, and its clinical translation.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/radiotherapy , Carcinoma, Hepatocellular/drug therapy , CD8-Positive T-Lymphocytes/pathology , B7-H1 Antigen , Liver Neoplasms/therapy , Liver Neoplasms/pathology , Bevacizumab/pharmacology , Bevacizumab/therapeutic use , Cell Line, Tumor , Vascular Endothelial Growth Factor A
14.
World J Gastroenterol ; 28(42): 6034-6044, 2022 Nov 14.
Article in English | MEDLINE | ID: mdl-36405383

ABSTRACT

The disease burden related to hepatocellular carcinoma (HCC) is increasing. Most HCC patients are diagnosed at the advanced stage and multikinase inhibitors have been the only treatment choice for them. Recently, the approval of immune checkpoint inhibitors (ICIs) has provided a new therapeutic strategy for HCC. It is noteworthy that the positive outcomes of the phase III clinical trial IMBrave150 [atezolizumab (anti-programmed cell death ligand 1 antibody) combined with bevacizumab (anti-vascular endothelial growth factor monoclonal antibody)], showed that overall survival and progression-free survival were significantly better with sorafenib. This combination therapy has become the new standard therapy for advanced HCC and has also attracted more attention in the treatment of HCC with anti-angiogenesis-immune combination therapy. Currently, the synergistic antitumor efficacy of this combination has been shown in many preclinical and clinical studies. In this review, we discuss the mechanism and clinical application of anti-angiogenics and immunotherapy in HCC, outline the relevant mechanism and rationality of the combined application of anti-angiogenics and ICIs, and point out the existing challenges of the combination therapy.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Immunotherapy , Liver Neoplasms/drug therapy , Sorafenib/therapeutic use , Clinical Trials, Phase III as Topic
15.
J Clin Transl Hepatol ; 10(2): 308-320, 2022 Apr 28.
Article in English | MEDLINE | ID: mdl-35528973

ABSTRACT

Background and Aims: Numerous studies have explored the important role of N6-methyladenosine (m6A) in cancer. Nonetheless, the interaction between m6A and long noncoding RNAs (lncRNAs) is poorly investigated. Herein, we systematically analyzed the role and prognostic value of m6A-related lncRNAs in hepatocellular carcinoma (HCC). Methods: The m6A-related lncRNAs were identified based on the correlation coefficients with m6A-related genes in HCC from The Cancer Genome Atlas. Subsequently, a novel risk score model was determined using the least absolute shrinkage and selection operator Cox regression analyses. Univariate and multivariate Cox analyses were used to identify independent prognostic factors for overall survival (OS) of HCC; thereafter, a prognostic nomogram was constructed. Results: A total of 259 lncRNAs showed significant correlations with m6A in HCC, while 29 lncRNAs had prognostic significance. Further, six critical m6A-related lncRNAs (NRAV, SNHG3, KDM4A-AS1, AC074117.1, AC025176.1, and AL031985.3) were screened out to construct a novel risk score model which classified HCC patients into high- and low-risk groups. Survival analyses revealed that patients in the high-risk group exhibited worse OS, both in the training and validation groups. The risk score was also identified as an independent prognostic factor of OS, and a nomogram was established and verified with superior prediction capacity. Besides, the risk score significantly correlated with the expression of immune checkpoint genes and immune subtypes. Conclusions: These findings indicated the significant role of m6A-related lncRNAs in HCC and the potential application of the novel risk score model for prognostic prediction.

16.
J Immunother Cancer ; 10(8)2022 08.
Article in English | MEDLINE | ID: mdl-36002188

ABSTRACT

BACKGROUND: Emerging evidence indicates that the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) axis plays a pivotal role in intrinsic antitumor immunity. Previous studies demonstrate that the conventional chemotherapy agent, teniposide, effectively promotes the therapeutic efficacy of programmed cell death protein-1 antibody (PD-1 Ab) through robust cGAS-STING activation. Unfortunately, the cGAS expression of tumor cells is reported to be severely suppressed by the hypoxic status in solid tumor. Clinically, enhancing chemotherapy-induced, DNA-activated tumor STING signaling by alleviating tumor hypoxia might be one possible direction for improving the currently poor response rates of patients with hepatocellular carcinoma (HCC) to PD-1 Ab. METHODS: Teniposide was first screened out from several chemotherapy drugs according to their potency in inducing cGAS-STING signaling in human HCC cells. Teniposide-treated HCC cells were then cultured under hypoxia, normoxia or reoxygenation condition to detect change in cGAS-STING signaling. Next, oxaliplatin/teniposide chemotherapy alone or combined with hyperbaric oxygen (HBO) therapy was administered on liver orthotopic mouse tumor models, after which the tumor microenvironment (TME) was surveyed. Lastly, teniposide alone or combined with HBO was performed on multiple mouse tumor models and the subsequent anti-PD-1 therapeutic responses were observed. RESULTS: Compared with the first-line oxaliplatin chemotherapy, teniposide chemotherapy induced stronger cGAS-STING signaling in human HCC cells. Teniposide-induced cGAS-STING activation was significantly inhibited by hypoxia inducible factor 1α in an oxygen-deficient environment in vitro and the inhibition was rapidly removed via effective reoxygenation. HBO remarkably enhanced the cGAS-STING-dependent tumor type Ⅰ interferon and nuclear factor kappa-B signaling induced by teniposide in vivo, both of which contributed to the activation of dendritic cells and subsequent cytotoxic T cells. Combined HBO with teniposide chemotherapy improved the therapeutic effect of PD-1 Ab in multiple tumor models. CONCLUSIONS: By combination of two therapies approved by the Food and Drug Administration, we safely stimulated an immunogenic, T cell-inflamed HCC TME, leading to further sensitization of tumors to anti-PD-1 immunotherapy. These findings might enrich therapeutic strategies for advanced HCC andwe can attempt to improve the response rates of patients with HCC to PD-1 Ab by enhancing DNA-activated STING signaling through effective tumor reoxygenation.


Subject(s)
Carcinoma, Hepatocellular , Hyperbaric Oxygenation , Liver Neoplasms , Animals , Antibodies , Carcinoma, Hepatocellular/drug therapy , Humans , Hypoxia , Liver Neoplasms/drug therapy , Membrane Proteins , Mice , Nucleotidyltransferases/genetics , Nucleotidyltransferases/metabolism , Oxaliplatin , Oxygen , Teniposide , Tumor Microenvironment , United States
17.
J Clin Transl Hepatol ; 10(5): 913-924, 2022 Oct 28.
Article in English | MEDLINE | ID: mdl-36304514

ABSTRACT

Background and Aims: TMCO3, a member of the monovalent cation:proton antiporter-2 family, has been annotated as a Na+/H+ antiporter, but its pathophysiological role is still unclear. We aimed to investigate the expression profile, prognostic significance, and oncogenic role of TMCO3 in hepatocellular carcinoma (HCC). Methods: Bioinformatic analyses were conducted using transcriptome data from public databases to determine the expression, prognosis, and functional enrichment of TMCO3 in HCC. TMCO3 expression was further validated in an independent HCC cohort from our institution. The oncogenic role of TMCO3 in HCC was evaluated using in vitro and in vivo experiments. Results: The upregulated expression of TMCO3 was identified and verified in multiple HCC cohorts, and worse overall survival and recurrence-free survival were observed in patients with high TMCO3 expression. The overexpression and knockdown of TMCO3 could affect the proliferation and metastasis of HCC cells, which might be associated with the p53-induced cell cycle regulation and epithelial-mesenchymal transition, respectively. Notably, significant correlations were found between dysregulated TMCO3 and various antitumor agents. Its role in sorafenib sensitivity was further identified by in vitro experiments and the potential mechanism might be related to the regulation of apoptosis. Positive correlations were also identified between upregulation of TMCO3 and the increased infiltration of various immune cells and the elevated expression of multiple immune checkpoint genes in HCC. Conclusions: Upregulated TMCO3 could act as an oncogenic mediator and promote sorafenib resistance in HCC, providing a potential therapeutic target for HCC treatment.

18.
Asian J Surg ; 45(1): 435-440, 2022 Jan.
Article in English | MEDLINE | ID: mdl-34426060

ABSTRACT

BACKGROUND: CTCs play a critical role in the diagnosis and prognosis of liver cancer. However, there are few studies on whether different types of CTCs can predict the prognosis in patients with HCC following LT. METHODS: Retrospective data including CTCs detected by the CanPatrolTM platform combined with RNA-ISH were collected and analyzed on 56 patients from December 2016 to December 2019 at the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China. RESULTS: During the study period, fifty-six patients (51 males, 5 females) were included with an mean age of 52 ± 9 years. The 1-, 2- and 3-year recurrence rates of postoperative interstitial CTC-positive and CTC-negative groups were 21.7% vs 10.8%, 37.5% vs 10.8% and 55.5% vs 10.8%, confirming a statistically significant difference between the 2 groups (p = 0.044). The 1-, 2- and 3-year recurrence rates of the increasing interstitial CTCs group were 25.2%, 36.9% and 66.9%, while 12.6%, 24.4% and 24.4% in the decreasing and unchanged group, indicating a significant difference (p = 0.038). CONCLUSION: CanPatrolTM platform presents a superior analytical sensitivity, and may be used as a dynamic monitoring tool for CTCs. And interstitial CTCs which are more aggressive and metastatic caused by EMT can be regarded as a predictor of post-transplant tumor recurrence after LT for HCC.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Liver Transplantation , Neoplastic Cells, Circulating , Adult , Biomarkers, Tumor , Carcinoma, Hepatocellular/surgery , Female , Humans , Liver Neoplasms/surgery , Male , Middle Aged , Neoplasm Recurrence, Local , Prognosis , Retrospective Studies
19.
Front Med (Lausanne) ; 8: 795849, 2021.
Article in English | MEDLINE | ID: mdl-34938753

ABSTRACT

Background: The potential role of Neurotrophic factor-3(NTF3) in liver cancer is unknown. Therefore, we aimed to explore the clinical value of NTF3 in hepatocellular carcinoma (HCC). Methods: We used a variety of databases to analyze the expression, relationship with prognosis and immune significance of NTF3 in liver cancer through bioinformatics. Results: NTF3 was low expressed in HCC and was an independent prognostic factor in patients with HCC. CIBERSORT analysis indicated that NTF3 expression was positively correlated with CD4+ cells, mast cells, NK cells, macrophages and B cells in the tumor microenvironment. Furthermore, we found that NTF3 expression was negatively correlated with the immune checkpoints PD-L1, TIGIT and TIM-3. Functional network analysis revealed that NTF3 regulates HCC progression through a variety of cancer-related kinases, transcription factors and signaling pathways. Conclusions: We demonstrate that NTF3 correlates with prognosis and immune infiltration in HCC.

20.
J Oncol ; 2021: 1379706, 2021.
Article in English | MEDLINE | ID: mdl-34484330

ABSTRACT

BACKGROUND: The role of ABL1 in hepatocellular carcinoma (HCC) is still unclear. Therefore, this study aims to explore the potential role of ABL1 in the progression of HCC using bioinformatics methods. METHODS: We analyzed the expression, prognostic potential, and immune cell effect of ABL1 in HCC by using a variety of datasets. RESULTS: ABL1 is highly expressed in HCC and associated with unfavorable overall survival (OS) and disease-free survival (DFS). Functional network analysis revealed that ABL1 plays an important role in mitochondrial activity, ATP metabolism, protein translation and metabolism, various neurological diseases, nonalcoholic fatty liver disease, and notch signaling pathway. In addition, we found that ABL1 expression was closely correlated with B cells, CD8 + T cells, CD4 + T cells, macrophages, neutrophils, and dendritic cells. Furthermore, ABL1 expression was positively associated with the expression levels of immune checkpoint genes, such as PD-1L, TIM3, TIGIT, and CTLA4. CONCLUSION: ABL1 is associated with immune infiltration and prognosis of HCC.

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