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Hepatocellular carcinoma (HCC) is a prevalent malignant tumor requiring effective treatments. Oncolytic viruses induce anti-tumor responses but have limited efficacy. Apolipoprotein A1 (ApoA1) inhibits inflammation, modulates immunity, and promotes anti-oxidation. This study aims to construct an oncolytic adenovirus (Ad5)-ApoA1 for superior anti-tumor effects. We analyzed ApoA1 expression in tumors and its prognostic significance using public databases. Subsequently, we engineered a recombinant oncolytic adenovirus Ad5-ApoA1 and assessed its replication and oncolytic efficacy in vitro and in nude mice. The impact of Ad5-ApoA1 on the tumor microenvironment of HCC was evaluated through flow cytometry, transcriptome sequencing, single-cell sequencing, and other methodologies. Additionally, mechanisms of immune microenvironment modulation by Ad5-ApoA1 were explored. ApoA1 expression was down-regulated with HCC progression and significantly positively correlated with the prognosis of HCC patients. Ad5-ApoA1 exhibited robust oncolytic activity but showed no therapeutic effect on nude mice. However, it significantly inhibited HCC growth and prolonged the survival period of both healthy-immune and humanized immune-reconstituted NCG mice. Furthermore, Ad5-ApoA1 significantly promoted the expression of IFN-γ and GzmB in CD8 + T cells while inhibiting the expression of PD-1 and LAG-3. Notably, the cholesterol content in the CD8 + T cells studied was significantly correlated with the expression of PD-1 and LAG-3, with ApoA1 promoting cholesterol efflux and reducing cholesterol levels. Ad5-ApoA1 activates CD8 + T cells by promoting large-scale viral replication. High levels of ApoA1 protein expression promote cholesterol efflux, inhibit CD8 + T cell depletion, and reduce inflammatory factors, ultimately leading to superior therapeutic effects on hepatocellular carcinoma., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Brain metastases (BM) of lung adenocarcinoma (LUAD) are the most common intracranial malignancy leading to death. However, the cellular origins and drivers of BM from LUAD have not been clarified. Cellular composition was characterized by single-cell sequencing analysis of primary lung adenocarcinoma (pLUAD), BM and lymph node metastasis (LNM) samples in GSE131907. Our study briefly analyzed the tumor microenvironment (TME), focusing on the role of epithelial cells (ECs) in BM. We have discovered a population of brain metastasis-associated epithelial cells (BMAECs) expressing SPP1, SAA1, and CDKN2A, and it has been observed that this population is mainly composed of aneuploid cells from pLUAD, playing a crucial role in brain metastasis. Our study concluded that both LNM and BM in LUAD originated from pLUAD lesions, but there is currently insufficient evidence to prove a direct association between BM lesions and LNM lesions, which provides inspiration for further investigation of the TME in BM., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Background and Aims: Molecular classification is a promising tool for prognosis prediction and optimizing precision therapy for HCC. Here, we aimed to develop a molecular classification of HCC based on the fatty acid degradation (FAD) pathway, fully characterize it, and evaluate its ability in guiding personalized therapy., Approach and Results: We performed RNA sequencing (RNA-seq), PCR-array, lipidomics, metabolomics, and proteomics analysis of 41 patients with HCC, in which 17 patients received anti-programmed cell death-1 (PD-1) therapy. Single-cell RNA sequencing (scRNA-seq) was performed to explore the tumor microenvironment. Nearly, 60 publicly available multiomics data sets were analyzed. The associations between FAD subtypes and response to sorafenib, transarterial chemoembolization (TACE), immune checkpoint inhibitor (ICI) were assessed in patient cohorts, patient-derived xenograft (PDX), and spontaneous mouse model ls. A novel molecular classification named F subtype (F1, F2, and F3) was identified based on the FAD pathway, distinguished by clinical, mutational, epigenetic, metabolic, and immunological characteristics. F1 subtypes exhibited high infiltration with immunosuppressive microenvironment. Subtype-specific therapeutic strategies were identified, in which F1 subtypes with the lowest FAD activities represent responders to compounds YM-155 and Alisertib, sorafenib, anti-PD1, anti-PD-L1, and atezolizumab plus bevacizumab (T + A) treatment, while F3 subtypes with the highest FAD activities are responders to TACE. F2 subtypes, the intermediate status between F1 and F3, are potential responders to T + A combinations. We provide preliminary evidence that the FAD subtypes can be diagnosed based on liquid biopsies., Conclusions: We identified 3 FAD subtypes with unique clinical and biological characteristics, which could optimize individual cancer patient therapy and help clinical decision-making., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Lung cancer is the second most common malignancy in the world, and lung adenocarcinoma (LUAD) in particular is the leading cause of cancer death worldwide. Endothelin converting enzyme 1 (ECE1) is a membrane-bound metalloprotease involved in endothelin-1 (ET-1) processing and regulates vasoconstriction. However, very few studies have reported the involvement of ECE1 in regulating tumor cell proliferation, and the mechanism remains poorly understood. Therefore, we aimed to determine the role of ECE1 in lung cancer development., Methods: The Cancer Genome Atlas database and Kaplan-Meier plotter were used to assess the association between ECE1 and lung cancer. The expression of ECE1 was detected using immunohistochemistry staining and western blotting. A variety of in vitro assays were performed to evaluate the effects of ECE1 on the colony formation, proliferation, migration and invasion using ECE1 knockdown lung cancer cells. The gene expression profiles regulated by ECE1 were investigated by RNA sequencing. An immunoprecipitation assay and immunofluorescence assay were used to evaluate the mechanism underlying the regulatory effect of ECE1 on protein kinase B (AKT). The effect of ECE1 on tumor development was assessed by xenografted lung cancer cells in either C57BL/6 mice or nude mice., Results: ECE1 was upregulated in LUAD and correlated with the poor prognosis of patients with LUAD. Functional studies showed that knockdown of ECE1 retarded the progression of tumors formed by lung cancer cells at least partly by inhibiting tumor cell proliferation. Moreover, ECE1 accelerated tumor cell proliferation through promoting AKT activation dispensable of its canonical target ET-1. Mechanically, ECE1 interacted with the pleckstrin homology (PH) domain of AKT and facilitated its translocation to the plasma membrane for activation. Furthermore, the inhibition of AKT activity counteracted the lung cancer cell growth inhibition observed both in vitro and in xenografts caused by ECE1 suppression., Conclusions: The present study reveals a non-canonical function of ECE1 in regulating AKT activation and cell proliferation, which provides the basis for the development of a novel strategy for the intervention of cancer including LUAD by abrogating ECE1-AKT signaling., (© 2023 John Wiley & Sons Ltd.)

Background: The treatment of stage III non-small cell lung cancer (NSCLC) is very challenging because it is a heterogeneous group of diseases. This study was to investigative whether concurrent immunotherapy with chemoradiotherapy was associated with improved outcomes compared to consolidative immunotherapy following chemoradiotherapy in patients with unresectable stage III NSCLC, which may provide evidence-based medical evidence for the treatment of stage III NSCLC., Methods: A total of 78 epidermal growth factor receptor or anaplastic lymphoma kinase (EGFR/ALK) negative patients from the clinical database of the shanghai pulmonary hospital with locally advanced unresectable NSCLC and we evaluated them for baseline clinical factors, follow-up. Patients underwent concurrent immunotherapy with chemoradiotherapy or consolidative immunotherapy after chemoradiotherapy. Patients were classified based on initial site of progression (primary versus non-primary site). The study endpoints were progression-free survival (PFS) and time to death or distant metastasis (TDDM). Cox proportional hazards analysis was used to assess the factors affecting PFS and TDDM., Results: The median follow-up time for both groups was 26 months, and there was no significant difference in baseline clinical characteristics (P>0.05). The patients receiving concurrent immunotherapy (n=36) had a longer PFS than those receiving consolidative immunotherapy (n=42) (median 32.4 vs. 15.5 months; P<0.01). The TDDM was also longer in patients with concurrent immunotherapy than those with consolidative immunotherapy (median 57.3 vs. 31.0 months; P=0.01). Furthermore, in a subset of patients with initial site of progression at a non-primary-site, patients undergoing concurrent immunotherapy had longer PFS than those undergoing consolidative immunotherapy (median 22.7 vs. 11.9 months; P=0.03)., Conclusions: Concurrent immunotherapy with chemoradiotherapy may be associated with improved disease progression outcomes as compared to consolidative immunotherapy following chemoradiotherapy., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-575/coif). C.G. received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events for MSD, BMS, Amgen, Novartis, Astra Zeneca, Roche, Sanofi, Pfizer, Eli Lilly, Takeda, Boehringer. C.G. reports participation on a Data Safety Monitoring Board or Advisory Board for MSD, BMS, Amgen, Novartis, Astra Zeneca, Roche, Sanofi, Pfizer, Eli Lilly, Takeda, Boehringer, Karyopharm, GSK and received consulting fees for Menarini. H.S.P. has received institutional grants from RefleXion and Merck, and personal fees from AstraZeneca (consulting, advisory board), Bristol Myers Squibb (honoraria), Daiichi Sankyo (honoraria), G1 Therapeutics (honoraria), Galera (advisory board), and RefleXion (consulting). The other authors have no conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)

Purpose: The pathological diagnosis and prognosis prediction of hepatocellular carcinoma (HCC) is challenging due to the lack of specific biomarkers. This study aimed to validate the diagnostic and prognostic efficiency of Kidney-type glutaminase (GLS1) for HCC in prospective cohorts with a large sample size., Methods: A total of 1140 HCC patients were enrolled in our prospective clinical trials. Control cases included 114 nontumour tissues. The registered clinical trial (ChiCTR-DDT-14,005,102, chictr.org.cn) was referred to for the exact protocol. GLS1 immunohistochemistry was performed on the whole tumour section. The diagnostic and prognostic performances of GLS1 was evaluated by the receiver operating characteristic curve and Cox regression model., Results: The sensitivity, specificity, positive predictive value, negative predictive value, Youden index, and area under the curve of GLS1 for the diagnosis of HCC were 0.746, 0.842, 0.979, 0.249, 0.588, and 0.814, respectively, which could be increased to 0.846, 0.886, 0.987,0.366, 0.732, and 0.921 when combined with glypican 3 (GPC3) and alpha-fetoprotein (AFP), indicating better diagnostic performance. Further, we developed a nomogram with GPC3 and GLS1 for identifying HCC which showed good discrimination and calibration. GLS1 expression was also related with age, T stage, TNM stage, Edmondson-Steiner grade, microvascular invasion, Ki67, VEGFR2, GPC3, and AFP expression in HCC. GLS1 expression was negatively correlated with disease-free survival (P < 0.001) probability of patients with HCC., Conclusions: It was validated that GLS1 was a sensitive and specific biomarker for pathological diagnosis of HCC and had prognostic value, thus having practical value for clinical application., (© 2023. The Author(s).)

In the context of cancer expansion, epithelial-mesenchymal transition (EMT) plays an essential role in driving invasion and metastasis potential of cancer cells. Tumor-associated macrophages (TAMs)-derived factors involved in the initiation and progression of EMT. We assess the role of M2 macrophage in suppressing lung tumors of a natural compound (-)-Guaiol by using macrophage depleted model. Bone marrow-derived monocytes (BMDMs) were extracted and induced to M2-like phenotype in vitro. The co-culture of M2 macrophage and lung cancer cells was established to observe that inhibition of lung tumor growth by (-)-Guaiol requires presence of macrophages. This suppressed effect of (-)-Guaiol was alleviated when mice macrophage was depleted. The expression of M2-like macrophages was strongly reduced by (-)-Guaiol treated mice, but not the changes of M1-like macrophages. In vitro studies, we demonstrated that (-)-Guaiol suppressed M2 polarization of BMDMs, as well as migration, invasion, and EMT of lung cancer cells in co-culture. M2 macrophage-derived interleukin 10 (IL-10) was investigated as a critical signaling molecule between M2 macrophage and lung cancer cells. We have also verified that the mechanism of (-)-Guaiol inhibiting the EMT process of lung cancer is related to the activation of IL-10-mediated signal transducer and activator of transcription 3 (STAT3). These results suggested that the suppressive effect role of (-)-Guaiol in M2 macrophage promoting EMT of lung cancer, which was associated with inhibition of IL-10 mediated STAT3 signaling pathway., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Enhancing chemosensitivity is one of the largest unmet medical needs in cancer therapy. Cyclic GMP-AMP synthase (cGAS) connects genome instability caused by platinum-based chemotherapeutics to type I interferon (IFN) response. Here, by using a high-throughput small-molecule microarray-based screening of cGAS interacting compounds, we identify brivanib, known as a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor, as a cGAS modulator. Brivanib markedly enhances cGAS-mediated type I IFN response in tumor cells treated with platinum. Mechanistically, brivanib directly targets cGAS and enhances its DNA binding affinity. Importantly, brivanib synergizes with cisplatin in tumor control by boosting CD8 + T cell response in a tumor-intrinsic cGAS-dependent manner, which is further validated by a patient-derived tumor-like cell clusters model. Taken together, our findings identify cGAS as an unprecedented target of brivanib and provide a rationale for the combination of brivanib with platinum-based chemotherapeutics in cancer treatment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To develop a prediction model for estimating the expression of vascular endothelial growth factor receptor 2 (VEGFR2) in hepatocellular carcinoma (HCC) patients using clinical features and the contrast-enhanced MRI Liver Imaging Reporting and Data System (LI-RADS)., Methods: A total of 206 HCC patients were subjected to preoperative contrast-enhanced MRI, radical resection, and VEGFR2 immunohistochemistry labeling. The intensity of VEGFR2 expression was used to split patients into either the positive group or the negative group. For continuous data, the Mann-Whitney U test was employed, and for categorical variables, the χ2 test was utilized., Results: VEGFR2-positivity was identified in 41.7% (86/206) of the patients. VEGFR2-positive HCCs were confirmed by higher serum alpha-fetoprotein (AFP) levels, larger tumor dimensions (either on MRI or upon final pathology), and a higher LI-RADS score (all p < 0.001). LI-RADS scores and AFP levels were independent predictors for high VEGFR2 expression. These two parameters were used to establish a VEGFR2-positive risk nomogram, which was validated to possess both good discrimination and calibration. The area under the curve was 0.830 (sensitivity 83.6%, specificity 72.5%) and the mean absolute error was 0.021. The threshold probabilities ranged between 0.07 and 0.95, and usage of the model contributed net benefits., Conclusion: A nomogram including clinical features and contrast-enhanced MRI parameters was developed and was demonstrably effective at predicting VEGFR2 expression in HCC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Cheng, Li, Chen, Peng, Cao, Yue, Mai and Yu.)

Pattern recognition receptors are critical for the sensing of pathogen-associated molecular patterns or danger-associated molecular patterns and subsequent mounting of innate immunity and shaping of adaptive immunity. The identification of 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) as a major cytosolic DNA receptor is a milestone in the field of DNA sensing. The engagement of cGAS by double-stranded DNA from different origins, including invading pathogens, damaged mitochondria, ruptured micronuclei, and genomic DNA results in the generation of cGAMP and activation of stimulator of interferon genes, which thereby activates innate immunity mainly characterized by the activation of type I interferon response. In recent years, great progress has been made in understanding the subcellular localization and novel functions of cGAS. In this review, we particularly focus on summarizing the multifaceted roles of cGAS in regulating senescence, autophagy, cell stemness, apoptosis, angiogenesis, cell proliferation, antitumor effect, DNA replication, DNA damage repair, micronucleophagy, as well as cell metabolism., (© The Author(s) (2022). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS.)

Virus infection modulates both host immunity and host genomic stability. Poly(ADP-ribose) polymerase 1 (PARP1) is a key nuclear sensor of DNA damage, which maintains genomic integrity, and the successful application of PARP1 inhibitors for clinical anti-cancer therapy has lasted for decades. However, precisely how PARP1 gains access to cytoplasm and regulates antiviral immunity remains unknown. Here, we report that DNA virus induces a reactive nitrogen species (RNS)-dependent DNA damage and activates DNA-dependent protein kinase (DNA-PK). Activated DNA-PK phosphorylates PARP1 on Thr 594 , thus facilitating the cytoplasmic translocation of PARP1 to inhibit the antiviral immunity both in vitro and in vivo. Mechanistically, cytoplasmic PARP1 interacts with and directly PARylates cyclic GMP-AMP synthase (cGAS) on Asp 191 to inhibit its DNA-binding ability. Together, our findings uncover an essential role of PARP1 in linking virus-induced genome instability with inhibition of host immunity, which is of relevance to cancer, autoinflammation, and other diseases., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Micronuclei are constantly considered as a marker of genome instability and very recently found to be a trigger of innate immune responses. An increased frequency of micronuclei is associated with many diseases, but the mechanism underlying the regulation of micronuclei homeostasis remains largely unknown. Here, we report that CGAS (cyclic GMP-AMP synthase), a known regulator of DNA sensing and DNA repair, reduces the abundance of micronuclei under genotoxic stress in an autophagy-dependent manner. CGAS accumulates in the autophagic machinery and directly interacts with MAP1LC3B/LC3B in a manner dependent upon its MAP1LC3-interacting region (LIR). Importantly, the interaction is essential for MAP1LC3 recruitment to micronuclei and subsequent clearance of micronuclei via autophagy (micronucleophagy) in response to genotoxic stress. Moreover, in contrast to its DNA sensing function to activate micronuclei-driven inflammation, CGAS-mediated micronucleophagy blunts the production of cyclic GMP-AMP (cGAMP) induced by genotoxic stress. We therefore conclude that CGAS is a receptor for the selective autophagic clearance of micronuclei and uncovered an unprecedented role of CGAS in micronuclei homeostasis to dampen innate immune surveillance. Abbreviations: ATG: autophagy-related; CGAS: cyclic GMP-AMP synthase; CQ: chloroquine; GABARAP: GABA type A receptor-associated protein; GFP: green fluorescent protein; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; LIR, MAP1LC3-interacting region; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; NDZ: nocodazole; STING1: stimulator of interferon response cGAMP interactor 1.

APOBEC3 (A3) cytidine deaminases inhibit hepatitis B virus (HBV) infection and play vital roles in maintaining a variety of biochemical processes, including the regulation of protein expression and innate immunity. Emerging evidence indicates that the deaminated deoxycytidine biochemical activity of A3 proteins in single-stranded DNA makes them a double-edged sword. These enzymes can cause cellular genetic mutations at replication forks or within transcription bubbles, depending on the physiological state of the cell and the phase of the cell cycle. Under pathological conditions, aberrant expression of A3 genes with improper deaminase activity regulation may threaten genomic stability and eventually lead to cancer development. This review attempted to summarize the antiviral activities and underlying mechanisms of A3 editing enzymes in HBV infections. Moreover, the correlations between A3 genes and hepatocarcinogenesis were also elucidated.

Background: The Warburg effect, also termed "aerobic glycolysis", is one of the most remarkable and ubiquitous metabolic characteristics exhibited by cancer cells, representing a potential vulnerability that might be targeted for tumor therapy. Ketogenic diets (KDs), composed of high-fat, moderate-protein and low carbohydrates, are aimed at targeting the Warburg effect for cancer treatment, which have recently gained considerable attention. However, the efficiency of KDs was inconsistent, and the genotypic contribution is still largely unknown., Methods: The bulk RNA-seq data from The Cancer Genome Atlas (TCGA), single cell RNA sequencing (scRNA-seq), and microarray data from Gene Expression Omnibus (GEO) and Cancer Cell Line Encyclopedia (CCLE) were collected. A joint analysis of glycolysis and ketone bodies metabolism (KBM) pathway was performed across over 10,000 tumor samples and nearly 1,000 cancer cell lines. A series of bioinformatic approaches were combined to identify a metabolic subtype that may predict the response to ketogenic dietary therapy (KDT). Mouse xenografts were established to validate the predictive utility of our subtypes in response to KDT., Results: We first provided a system-level view of the expression pattern and prognosis of the signature genes from glycolysis and KBM pathway across 33 cancer types. Analysis by joint stratification of glycolysis and KBM revealed four metabolic subtypes, which correlated extensively but diversely with clinical outcomes across cancers. The glycolytic subtypes may be driven by TP53 mutations, whereas the KB-metabolic subtypes may be mediated by CTNNB1 (β-catenin) mutations. The glycolytic subtypes may have a better response to KDs compared to the other three subtypes. We preliminarily confirmed the idea by literature review and further performed a proof-of-concept experiment to validate the predictive value of the metabolic subtype in liver cancer xenografts., Conclusions: Our findings identified a metabolic subtype based on glycolysis and KBM that may serve as a promising biomarker to predict the clinical outcomes and therapeutic responses to KDT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Qian, Li, Cao, Meng, Peng, Li, Wang, Xu, Zhang, Sun, Li and Yu.)

Mycobacterial arabinogalactan (AG) is an essential cell wall component of mycobacteria and a frequent structural and bio-synthetical target for anti-tuberculosis (TB) drug development. Here, we report that mycobacterial AG is recognized by galectin-9 and exacerbates mycobacterial infection. Administration of AG-specific aptamers inhibits cellular infiltration caused by Mycobacterium tuberculosis (Mtb) or Mycobacterium bovis BCG, and moderately increases survival of Mtb-infected mice or Mycobacterium marinum-infected zebrafish. AG interacts with carbohydrate recognition domain (CRD) 2 of galectin-9 with high affinity, and galectin-9 associates with transforming growth factor β-activated kinase 1 (TAK1) via CRD2 to trigger subsequent activation of extracellular signal-regulated kinase (ERK) as well as induction of the expression of matrix metalloproteinases (MMPs). Moreover, deletion of galectin-9 or inhibition of MMPs blocks AG-induced pathological impairments in the lung, and the AG-galectin-9 axis aggravates the process of Mtb infection in mice. These results demonstrate that AG is an important virulence factor of mycobacteria and galectin-9 is a novel receptor for Mtb and other mycobacteria, paving the way for the development of novel effective TB immune modulators., (© 2021 The Authors.)

Background: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death in the worldwide. A great number of reports manifested that circular RNA hsa-circRNA-103809 (circRNA-103809) could work in several cancers., Aims: This study aimed to explore the function and mechanism of circRNA-103809 in HCC., Methods: Gene expressions were detected by quantitative real-time polymerase chain reaction. Colony formation, cell counting kit-8, transwell and wound healing assays were implemented to check the role of circRNA-103809 in HCC. Subcellular fractionation analysis was designed to figure out the cellular location of circRNA-103809. Luciferase reporter assay and RNA pull down assay were employed to verify the relationships among RNAs., Results: CircRNA-103809 was highly expressed in HCC cell lines. After interfering circRNA-103809, the proliferation, migration, invasion and epithelial-to-mesenchymal transition process were all hindered in HCC cells. Significantly, circRNA-103809 competed with PLAG1 like zinc finger 2 (PLAGL2) for binding with microRNA-1270 (miR-1270), which formulated a competing endogenous RNA network in HCC. Thereafter, we verified the tumor-facilitating effect of circRNA-103809/miR-1270/PLAGL2 axis on biological behaviors of HCC cells., Conclusion: Hsa-circRNA-103809 promoted development of HCC via sequestering miR-1270 and up-regulating PLAGL2.

Objective: The role of the complement and coagulation cascades signaling pathway in the pathogenesis of cancers remains uncertain. This study aimed to investigate the associations between enriched differentially expressed genes (DEGs) in this pathway and hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients., Materials and Methods: Clinical and gene expression data of the Gene Expression Omnibus (GEO) series profile GSE14520 were downloaded. The "Limma" package was used to screen the DEGs and the "clusterProfiler" package was used to identify the complement and coagulation cascades pathway and enriched significant genes. Cox regression analysis, the Kaplan-Meier method, and the nomogram model were used to address the correlations between significantly enriched DEGs in the complement and coagulation cascades pathway and HCC survival., Results: A total of 220 HBV-related HCC patients were enrolled in this study. The complement and coagulation cascades pathway was significantly enriched by 37 DEGs (p-value < 0.05 and adjusted p-value < 0.05). Complement 8 beta chain (C8B) expression levels had protective effects on overall survival (OS) and recurrence-free survival (RFS) in HBV-related HCC patients. High levels of C8B contributed to favorable OS and RFS in this population (both p < 0.01), even after adjustment of clinicopathological characteristics including tumor node metastasis (TNM) staging, Barcelona Clinic liver cancer (BCLC) staging, gender, and fibrinogen beta chain (FGB) expression (all p < 0.05)., Conclusion: C8B in the complement and coagulation cascades signaling pathway serves as a predictive candidate for survival in HBV-related HCC patients., Competing Interests: The authors declare no conflicts of interest in this work., (© 2021 Zhang et al.)

Objective: This study is aimed at investigating the enriched functions of polymeric immunoglobulin receptor (PIGR) and its correlations with liver fibrosis stage., Methods: PIGR mRNA expression in normal liver, liver fibrosis, hepatic stellate cells (HSCs), and hepatitis virus infection samples was calculated in Gene Expression Omnibus (GEO) and Oncomine databases. Enrichment analysis of PIGR-related genes was conducted in Metascape and Gene Set Enrichment Analysis (GSEA). Logistic model and ROC curve were performed to evaluate the correlations between pIgR and liver fibrosis., Results: PIGR mRNA was upregulated in advanced liver fibrosis, cirrhosis compared to normal liver (all p < 0.05). PIGR mRNA was also overexpressed in activated HSCs compared to senescent HSCs, liver stem/progenitor cells, and reverted HSCs (all p < 0.05). Enrichment analysis revealed that PIGR-related genes involved in the defense response to virus and interferon (IFN) signaling. In GEO series, PIGR mRNA was also upregulated by hepatitis virus B, C, D, and E infection (all p < 0.05). After adjusting age and gender, multivariate logistic regression models revealed that high PIGR in the liver was a risk factor for liver fibrosis (OR = 82.2, p < 0.001). The area under curve (AUC), positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity of PIGR for liver fibrosis stage >2 were 0.84, 0.86, 0.7, 0.61, and 0.90., Conclusion: PIGR was correlated with liver fibrosis and might involve in hepatitis virus infection and HSC transdifferentiation., Competing Interests: The authors declared no conflicts of interest in this work., (Copyright © 2021 Yuan Zhang et al.)

Background: Hepatocellular carcinoma (HCC) is understood to be an immunogenic tumor caused by chronic liver disease. Emerging research has indicated close interaction between various immune cells and tumor cells. Immunophenotyping, which has shown potential predictive value for the prognosis of various human malignancies, might allow responsive and non-responsive patients to be identified based on the extent and distribution of immune cell infiltration. Several novel immunotherapeutic approaches have been trialed and have shown promising efficacy. However, the efficacy of immunotherapies in HCC is limited by several factors. This study aimed to investigate tumor-infiltrating immune cells in HCC., Methods: Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) allows immune cell profiling analysis by deconvolution of gene expression microarray data. In this study, we analyzed the proportions of immune cells in 14 paired samples of HCC tissues obtained from GSE84402 in Gene Expression Omnibus (GEO) database., Results: In the 14 paired samples, HCC tissues showed significant infiltration by regulatory T cells (Tregs), activated natural killer (NK) cells, and M0 macrophages (P<0.001, P=0.007 and P=0.001, respectively), which were validated in CIBERSORT with the P value set at ≤0.05. In four paired samples identified from those selected by CIBERSORT, HCC tissues were found to have significant Treg and activated NK cell infiltration compared to non-tumor tissues (P=0.007 and P=0.015, respectively). Additionally, Pearson correlation analysis revealed Tregs to be positively correlated with activated NK cells (Correlation coefficient =0.41)., Conclusions: HCC tumor tissues were markedly infiltrated by Tregs and activated NK cells, which should be considered as candidate therapeutic targets in HCC multidisciplinary treatments., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-5830). The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

Recently, reactive oxygen species (ROS), a class of highly bioactive molecules, have been extensively studied in cancers. Cancer cells typically exhibit higher levels of basal ROS than normal cells, primarily due to their increased metabolism, oncogene activation, and mitochondrial dysfunction. This moderate increase in ROS levels facilitates cancer initiation, development, and progression; however, excessive ROS concentrations can lead to various types of cell death. Therefore, therapeutic strategies that either increase intracellular ROS to toxic levels or, conversely, decrease the levels of ROS may be effective in treating cancers via ROS regulation. Chinese herbal medicine (CHM) is a major type of natural medicine and has greatly contributed to human health. CHMs have been increasingly used for adjuvant clinical treatment of tumors. Although their mechanism of action is unclear, CHMs can execute a variety of anticancer effects by regulating intracellular ROS. In this review, we summarize the dual roles of ROS in cancers, present a comprehensive analysis of and update the role of CHM-especially its active compounds and ingredients-in the prevention and treatment of cancers via ROS regulation and emphasize precautions and strategies for the use of CHM in future research and clinical trials., Competing Interests: All the authors declare that there are no potential conflicts of interest regarding this article., (Copyright © 2019 Qiaohong Qian et al.)

Objective: This study was aimed at investigating the prognostic significance of Baculoviral IAP repeat containing 5 (BIRC5) in lung adenocarcinoma (LAD) lacking EGFR, KRAS, and ALK mutations (triple-negative (TN) adenocarcinomas)., Methods: The gene expression profiles were obtained from Gene Expression Omnibus (GEO). The identification of the differentially expressed genes (DEGs) was performed by GeneSpring GX. Gene set enrichment analysis (GSEA) was used to execute gene ontology function and pathway enrichment analysis. The protein interaction network was constructed by Cytoscape. The hub genes were extracted by MCODE and cytoHubba plugin from the network. Then, using BIRC5 as a candidate, the prognostic value in LAD and TN adenocarcinomas was verified by the Kaplan-Meier plotter and The Cancer Genome Atlas (TCGA) database, respectively. Finally, the mechanism of BIRC5 was predicted by a coexpressed network and enrichment analysis., Results: A total of 38 upregulated genes and 121 downregulated genes were identified. 9 hub genes were extracted. Among them, the mRNA expression of 5 genes, namely, BIRC5, MCM4, CDC20, KIAA0101, and TRIP13, were significantly upregulated among TN adenocarcinomas (all P < 0.05). Notably, only the overexpression of BIRC5 was associated with unfavorable overall survival (OS) in TN adenocarcinomas (log rank P = 0.0037). TN adenocarcinoma patients in the BIRC5 high-expression group suffered from a significantly high risk of distant metastasis ( P = 0.046), advanced N stage ( P = 0.033), and tumor-bearing ( P = 0.031) and deceased status ( P = 0.003). The mechanism of BIRC5 and coexpressed genes may be linked closely with the cell cycle., Conclusion: Overexpressed in tumors, BIRC5 is associated with unfavorable overall survival in TN adenocarcinomas. BIRC5 is a potential predictor and therapeutic target in TN adenocarcinomas.

Background: Hepatocellular carcinoma (HCC) is an aggressive malignant disease with poor prognosis. Recent advances suggest the existence of cancer stem cells (CSCs) within liver cancer, which are considered to be responsible for tumor relapse, metastasis, and chemoresistance. However, novel therapeutic approaches for eradicating CSCs are yet to be established. Here, we aimed to identify the role of glutaminase 1 (GLS1) in stemness, and the feasibility that GLS1 serves as a therapeutic target for elimination CSCs as well as the possible mechanism., Methods: Publicly-available data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) was mined to unearth the association between GLS1 and stemness phenotype. Using big data, human tissues and multiple cell lines, we gained a general picture of GLS1 expression in HCC progression. We generated stable cell lines by lentiviral-mediated overexpression or CRISPR/Cas9-based knockout. Sphere formation assays and colony formation assays were employed to analyze the relationship between GLS1 and stemness. A series of bioinformatics analyses and molecular experiments including qRT-PCR, immunoblotting, flow cytometry, and immunofluorescence were employed to investigate the role of GLS1 in regulating stemness in vitro and in vivo., Findings: We observed GLS1 (both KGA and GAC isoform) is highly expressed in HCC, and that high expression of GAC predicts a poor prognosis. GLS1 is exclusively expressed in the mitochondrial matrix. Upregulation of GLS1 is positively associated with advanced clinicopathological features and stemness phenotype. Targeting GLS1 reduced the expression of stemness-related genes and suppressed CSC properties in vitro. We further found GLS1 regulates stemness properties via ROS/Wnt/β-catenin signaling and that GLS1 knockout inhibits tumorigenicity in vivo., Interpretation: Targeting GLS1 attenuates stemness properties in HCC by increasing ROS accumulation and suppressing Wnt/β-catenin pathway, which implied that GLS1 could serve as a therapeutic target for elimination of CSCs., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Cd-induced stress response of Phanerochaete chrysosporium during the biodegradation of BDE-47 was investigated in this study, with the goal of elucidating the tolerance behavior and the detoxification mechanisms of P. chrysosporium to resist the Cd stress in the course of BDE-47 biodegradation, which has implications for expanding the application of P. chrysosporium in the bioremediation of Cd and BDE-47 combined pollution. The results suggested that single BDE-47 exposure did not induce obvious oxidative stress in P. chrysosporium, but coexistent Cd significantly triggered ROS generation, both intracellular ROS level and H 2 O 2 content showed positive correlation with Cd concentration. The activities of SOD and CAT were enhanced by low level of Cd (≤ 1 mg/L), but Cd of higher doses (＞1 mg/L) depressed the expression of these two antioxidant enzymes at the later exposure period (3-5 days). The intracellular content of GSH along with GSH/GSSG ratio also exhibited a bell-shaped response with a maximum value at Cd of 1 mg/L. Furthermore, Cd-induced ROS generation resulted in the lipid peroxidation, as indicated by a noticeable increment of MDA content found after 3 days. Moreover, the study also indicated that Cd less than 1 mg/L promoted the production of extracellular protein and quickened the decrease of pH value in the medium, while excessive Cd (＞1 mg/L) would lead to inhibition. These findings obtained demonstrated that P. chrysosporium had a certain degree of tolerance to Cd within a specific concentration range via regulating the antioxidant levels, inducing the synthesis of extracellular protein as well as stimulating the production of organic acids, and 1 mg/L is suggested to be the tolerance threshold of this strains under Cd stress during BDE-47 biodegradation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide, because recurrence often occurs in most HCC patients undergoing hepatectomy. It is necessary to identify patients with high risk for recurrence and adopt effective therapies. An obstacle to monitor patients at high risk for poor prognosis has been the lack of useful predictive biomarkers. Fortunately, recent progress in system biology allows to screen the biomarkers for HCC prognosis in a high-throughput manner. In this study, we performed systematic Kaplan-Meier survival analysis of the whole mRNA transcriptomics based on the Cancer Genome Atlas project (TCGA) and developed a three-gene prognostic signature composing of three genes UPB1, SOCS2 and RTN3. The model was validated in two independent microarray data sets retrieved from Gene Expression Omnibus (GEO) and the expression pattern of these three predictive genes in HCC was confirmed by western blot and immunohistochemistry with our HCC samples. In conclusion, our results showed that this three-gene signature has prognostic value for HCC patients.

Aerobic biodegradation of 2,2',4,4'-tetrabrominated diphenyl ether (BDE-47) by Phanerochaete chrysosporium in the presence of Cd 2+ was investigated in this study. The results showed that P. chrysosporium could effectively degrade BDE-47, and its extracellular enzyme played an important role in the process of decomposition. BDE-47 biodegradation by fungi was more tolerant than extracellular enzyme in the presence of Cd 2+ . Also, both of the activity of two typical enzymes, MnP and LiP, descended with ascended Cd 2+ concentration. Based on the four mono-hydroxylated PBDEs (5-OH-BDE-47, 4'-OH-BDE-17, 6-OH-BDE-47, and 2'-OH-BDE-28) and two bromophenols (2,4-DBP, 4-BP) detected, three possible degradation pathways were proposed, inferring that BDE-47 was more easily to transform via hydroxylation. With addition of Cd 2+ , the types of degradation products did not change, merely a variation of the content of these products observed. Meanwhile, the major metabolites of BDE-47, bromophenol compounds, have been found to be transformed or even mineralized by P. chrysosporium quickly, which also helped better explain why the amounts of BDE-47 decomposed did not match with that of the metabolites detected.

In the present study, we used a small series of highly defined patients, where we had matched timed peripheral blood samples (PBS), as well as paired liver biopsies obtained during collection of blood samples from patients with diagnosed hepatocellular carcinoma (HCC) and compared the correlation between the changes of telomere lengths in these defined samples. Patients included had either HCC alone or in conjunction with either pre-existing hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. PCR-based assay incorporating primers to the telomeric hexamer repeats to polymerize and detect telomeric DNA was used. The average telomere length for each independent assessment was measured by seeing the differences in the intensity of the sample's telomere signal (T) to the signal from a single-copy gene (S-, β-globin) to estimate the standard ratio. Our results provide the first convincing evidence that PBS may be utilized to assay telomere shortening as a predictor for disease persistence in HCC resulting after HBV or HCV infection, but not in non-infectious cause-stimulated HCC. These findings provide incipient opportunity to develop telomere length assessment as a biomarker tool for prediction of HCC in patients with HBV or HCV infection, as well as to gauge responses to chemotherapy and other treatment modalities., (© 2017 The Author(s).)

Homologs of the Yersinia virulence factor YopJ are found in both animal and plant bacterial pathogens, as well as in plant symbionts. The conservation of this effector family indicates that several pathogens may use YopJ-like proteins to regulate bacteria-host interactions during infection. YopJ and YopJ-like proteins share structural homology with cysteine proteases and are hypothesized to functionally mimic small ubiquitin-like modifier (SUMO) proteases in eukaryotic cells. Strains of the phytopathogenic bacterium Xanthomonas campestris pv. vesicatoria are known to possess four YopJ-like proteins, AvrXv4, AvrBsT, AvrRxv, and XopJ. In this work, we have characterized AvrXv4 to determine if AvrXv4 functions like a SUMO protease in planta during Xanthomonas-plant interactions. We provide evidence that X. campestris pv. vesicatoria secretes and translocates the AvrXv4 protein into plant cells during infection in a type III-dependent manner. Once inside the plant cell, AvrXv4 is localized to the plant cytoplasm. By performing AvrXv4 deletion and mutational analysis, we have identified amino acids required for type III delivery and for host recognition. We show that AvrXv4 recognition by resistant plants requires a functional protease catalytic core, the domain that is conserved in all of the putative YopJ-like cysteine proteases. We also show that AvrXv4 expression in planta leads to a reduction in SUMO-modified proteins, demonstrating that AvrXv4 possesses SUMO isopeptidase activity. Overall, our studies reveal that the YopJ-like effector AvrXv4 encodes a type III SUMO protease effector that is active in the cytoplasmic compartment of plant cells.