Siglec-9 acts as an immune-checkpoint molecule on macrophages in glioblastoma, restricting T-cell priming and immunotherapy response.

Neoadjuvant immune-checkpoint blockade therapy only benefits a limited fraction of patients with glioblastoma multiforme (GBM). Thus, targeting other immunomodulators on myeloid cells is an attractive therapeutic option. Here, we performed single-cell RNA sequencing and spatial transcriptomics of patients with GBM treated with neoadjuvant anti-PD-1 therapy. We identified unique monocyte-derived tumor-associated macrophage subpopulations with functional plasticity that highly expressed the immunosuppressive SIGLEC9 gene and preferentially accumulated in the nonresponders to anti-PD-1 treatment. Deletion of Siglece (murine homolog) resulted in dramatically restrained tumor development and prolonged survival in mouse models. Mechanistically, targeting Siglece directly activated both CD4+ T cells and CD8+ T cells through antigen presentation, secreted chemokines and co-stimulatory factor interactions. Furthermore, Siglece deletion synergized with anti-PD-1/PD-L1 treatment to improve antitumor efficacy. Our data demonstrated that Siglec-9 is an immune-checkpoint molecule on macrophages that can be targeted to enhance anti-PD-1/PD-L1 therapeutic efficacy for GBM treatment.

Long noncoding RNA HITT coordinates with RGS2 to inhibit PD-L1 translation in T cell immunity.

Programmed cell death ligand 1 (PD-L1) is an immune checkpoint protein frequently expressed in human cancers that contributes to immune evasion through its binding to PD-1 on activated T cells. Unveiling the mechanisms underlying PD-L1 expression is essential for understanding the impact of the immunosuppressive microenvironment and is also crucial for the purpose of reboosting antitumor immunity. However, how PD-L1 is regulated, particularly at translational levels, remains largely unknown. Here, we discovered that a long noncoding RNA (lncRNA), HIF-1α inhibitor at translation level (HITT), was transactivated by E2F transcription factor 1 (E2F1) under IFN-γ stimulation. It coordinated with regulator of G protein signaling 2 (RGS2) in binding to the 5' UTR of PD-L1, resulting in reduced PD-L1 translation. HITT expression enhanced T cell-mediated cytotoxicity both in vitro and in vivo in a PD-L1-dependent manner. The clinical correlation between HITT/PD-L1 and RGS2/PD-L1 expression was also detected in breast cancer tissues. Together, these findings demonstrate the role of HITT in antitumor T cell immunity, highlighting activation of HITT as a potential therapeutic strategy for enhancing cancer immunotherapy.

Pro-prion, as a membrane adaptor protein for E3 ligase c-Cbl, facilitates the ubiquitination of IGF-1R, promoting melanoma metastasis.

Aberrant activation of receptor tyrosine kinase (RTK) is usually a result of mutation and plays important roles in tumorigenesis. How RTK without mutation affects tumorigenesis remains incompletely understood. Here we show that in human melanomas pro-prion (pro-PrP) is an adaptor protein for an E3 ligase c-Cbl, enabling it to polyubiquitinate activated insulin-like growth factor-1 receptor (IGF-1R), leading to enhanced melanoma metastasis. All human melanoma cell lines studied here express pro-PrP, retaining its glycosylphosphatidylinositol-peptide signal sequence (GPI-PSS). The sequence, PVILLISFLI in the GPI-PSS of pro-PrP, binds c-Cbl, docking c-Cbl to the inner cell membrane, forming a pro-PrP/c-Cbl/IGF-1R trimeric complex. Subsequently, IGF-1R polyubiquitination and degradation are augmented, which increases autophagy and tumor metastasis. Importantly, the synthetic peptide PVILLISFLI disrupts the pro-PrP/c-Cbl/IGF-1R complex, reducing cancer cell autophagy and mitigating tumor aggressiveness in vitro and in vivo. Targeting cancer-associated GPI-PSS may provide a therapeutic approach for treating human cancers expressing pro-PrP.

Precise tumor immune rewiring via synthetic CRISPRa circuits gated by concurrent gain/loss of transcription factors.

Reinvigoration of antitumor immunity has recently become the central theme for the development of cancer therapies. Nevertheless, the precise delivery of immunotherapeutic activities to the tumors remains challenging. Here, we explore a synthetic gene circuit-based strategy for specific tumor identification, and for subsequently engaging immune activation. By design, these circuits are assembled from two interactive modules, i.e., an oncogenic TF-driven CRISPRa effector, and a corresponding p53-inducible off-switch (NOT gate), which jointly execute an AND-NOT logic for accurate tumor targeting. In particular, two forms of the NOT gate are developed, via the use of an inhibitory sgRNA or an anti-CRISPR protein, with the second form showing a superior performance in gating CRISPRa by p53 loss. Functionally, the optimized AND-NOT logic circuit can empower a highly specific and effective tumor recognition/immune rewiring axis, leading to therapeutic effects in vivo. Taken together, our work presents an adaptable strategy for the development of precisely delivered immunotherapy.

Single-Cell Analyses Reveal Mechanisms of Cancer Stem Cell Maintenance and Epithelial-Mesenchymal Transition in Recurrent Bladder Cancer.

PURPOSE: Bladder cancer treatment remains a major clinical challenge due to therapy resistance and a high recurrence rate. Profiling intratumor heterogeneity can reveal the molecular mechanism of bladder cancer recurrence. EXPERIMENTAL DESIGN: Here, we performed single-cell RNA sequencing and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) on tumors from 13 patients with low recurrence risk, high recurrence risk, and recurrent bladder cancer. RESULTS: Our study generated a comprehensive cancer-cell atlas consisting of 54,971 single cells and identified distinct cell subpopulations. We found that the cancer stem-cell subpopulation is enriched during bladder cancer recurrence with elevated expression of EZH2. We further defined a subpopulation-specific molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of the NCAM1 gene, thereby inactivating the cell invasive and stemness transcriptional program. Furthermore, taking advantage of this large single-cell dataset, we elucidated the spectrum of epithelial-mesenchymal transition (EMT) in clinical samples and revealed distinct EMT features associated with bladder cancer subtypes. We identified that TCF7 promotes EMT in corroboration with single-cell ATAC with high-throughput sequencing (scATAC-seq) analysis. Additionally, we constructed regulatory networks specific to recurrent bladder cancer. CONCLUSIONS: Our study and analytic approaches herein provide a rich resource for the further study of cancer stem cells and EMT in the bladder cancer research field.

Single-cell analyses reveal suppressive tumor microenvironment of human colorectal cancer.

Profiling heterologous cell types within tumors is essential to decipher tumor microenvironment that shapes tumor progress and determines the outcome of therapeutic response. Here, we comprehensively characterized transcriptomes of 34,037 single cells obtained from 12 treatment-naïve patients with colorectal cancer. Our comprehensive evaluation revealed attenuated B-cell antigen presentation, distinct regulatory T-cell clusters with different origin and novel polyfunctional tumor associated macrophages associated with CRC. Moreover, we identified expanded XCL1+ T-cell clusters associated with tumor mutational burden high status. We further explored the underlying molecular mechanisms by profiling epigenetic landscape and inferring transcription factor motifs using single-cell ATAC-seq. Our dataset and analysis approaches herein provide a rich resource for further study of the impact of immune cells and translational research for human colorectal cancer.

Single-cell expression profiles of ACE2 and TMPRSS2 reveals potential vertical transmission and fetus infection of SARS-CoV-2.

Morbidity and mortality of coronavirus disease 2019 (COVID-19) is age-dependent. It remains unclear whether vertical severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurs during pregnancy and how such infection will affect fetal development. Here, we performed single-cell transcriptomic analysis of placenta and other tissues from fetuses in comparison with those from adults using public-available datasets. Our analysis revealed that a very small proportion of trophoblast cells expressed the Angiotensin I Converting Enzyme 2 (ACE2) gene, suggesting a low possibility of vertical transmission of SARS-CoV-2 from mother to fetus during pregnancy. We found that the fetal adrenal gland, heart, kidney and stomach were susceptible to SARS-CoV-2 infection, because these organs contained cell clusters that expressed high levels of the ACE2 gene. In particular, a higher proportion of ACE2-expressing cell clusters in the adrenal gland and kidney also expressed the Transmembrane Serine Protease 2 (TMPRSS2) gene compared with other organs. Surprisingly, ACE2-expressing type II alveolar (AT2) equivalent cells were absent in fetal lungs. This is in sharp contrast to adult lungs. As ACE2 expression is regulated by various conditions, including oxygen concentration, inflammation and smoking, caution is warranted to avoid triggering potential ACE2 expression in fetal and placental tissue.

Immunomodulatory and Antiviral Activity of Metformin and Its Potential Implications in Treating Coronavirus Disease 2019 and Lung Injury.

The pandemic of coronavirus disease 2019 (COVID-19), a disease which causes severe lung injury and multiple organ damage, presents an urgent need for new drugs. The case severity and fatality of COVID-19 are associated with excessive inflammation, namely, a cytokine storm. Metformin, a widely used drug to treat type 2 diabetes (T2D) mellitus and metabolic syndrome, has immunomodulatory activity that reduces the production of proinflammatory cytokines using macrophages and causes the formation of neutrophil extracellular traps (NETs). Metformin also inhibits the cytokine production of pathogenic Th1 and Th17 cells. Importantly, treatment with metformin alleviates various lung injuries in preclinical animal models. In addition, a recent proteomic study revealed that metformin has the potential to directly inhibit SARS-CoV-2 infection. Furthermore, retrospective clinical studies have revealed that metformin treatment reduces the mortality of T2D with COVID-19. Therefore, metformin has the potential to be repurposed to treat patients with COVID-19 at risk of developing severe illness. This review summarizes the immune pathogenesis of SARS-CoV-2 and addresses the effects of metformin on inhibiting cytokine storms and preventing SARS-CoV-2 infection, as well as its side effects.

Interleukin-8 as a candidate for thymoma identification and recurrence surveillance.

Thymoma is the most common tumor of the anterior mediastinum. Routine imaging methods such as computed tomography or magnetic resonance imaging often lead to misdiagnosis between thymoma and other thymic abnormalities. Therefore, urgently needed is to develop a new diagnostic strategy. Here we identify interleukin-8 (IL-8) as a biomarker for auxiliary diagnosis of thymoma. We find that IL-8 levels in naïve T cells are markedly elevated in patients with thymoma compared to those with other thymic tumors. IL-8 levels in naive T cells are significantly decreased after surgical resection in thymoma patients, and rise again when thymoma recurs. A receiver operating characteristic curve analysis shows that IL-8 evaluation performs well in thymoma identification, with high specificities and sensitivities. We also observe significant clinical relevance between IL-8 levels in naïve T cells and clinicopathological features. In conclusion, our study suggests that IL-8 is a biomarker for thymoma identification and recurrence surveillance.

Macrophage NCOR1 Deficiency Ameliorates Myocardial Infarction and Neointimal Hyperplasia in Mice.

Background NCOR1 (nuclear receptor corepressor 1) is an essential coregulator of gene transcription. It has been shown that NCOR1 in macrophages plays important roles in metabolic regulation. However, the function of macrophage NCOR1 in response to myocardial infarction (MI) or vascular wire injury has not been elucidated. Methods and Results Here, using macrophage Ncor1 knockout mouse in combination with a mouse model of MI, we demonstrated that macrophage NCOR1 deficiency significantly reduced infarct size and improved cardiac function after MI. In addition, macrophage NCOR1 deficiency markedly inhibited neointimal hyperplasia and vascular remodeling in a mouse model of arterial wire injury. Inflammation and macrophage proliferation were substantially attenuated in hearts and arteries of macrophage Ncor1 knockout mice after MI and arterial wire injury, respectively. Cultured primary macrophages from macrophage Ncor1 knockout mice manifested lower expression of inflammatory genes upon stimulation by interleukin-1ß, interleukin-6, or lipopolysaccharide, together with much less activation of inflammatory signaling cascades including signal transducer and activator of transcription 1 and nuclear factor-κB. Furthermore, macrophage Ncor1 knockout macrophages were much less proliferative in culture, with inhibited cell cycle progression compared with control cells. Conclusions Collectively, our data have demonstrated that NCOR1 is a critical regulator of macrophage inflammation and proliferation and that deficiency of NCOR1 in macrophages attenuates MI and neointimal hyperplasia. Therefore, macrophage NCOR1 may serve as a potential therapeutic target for MI and restenosis.

ProGeo-neo: a customized proteogenomic workflow for neoantigen prediction and selection.

BACKGROUND: Neoantigens can be differentially recognized by T cell receptor (TCR) as these sequences are derived from mutant proteins and are unique to the tumor. The discovery of neoantigens is the first key step for tumor-specific antigen (TSA) based immunotherapy. Based on high-throughput tumor genomic analysis, each missense mutation can potentially give rise to multiple neopeptides, resulting in a vast total number, but only a small percentage of these peptides may achieve immune-dominant status with a given major histocompatibility complex (MHC) class I allele. Specific identification of immunogenic candidate neoantigens is consequently a major challenge. Currently almost all neoantigen prediction tools are based on genomics data. RESULTS: Here we report the construction of proteogenomics prediction of neoantigen (ProGeo-neo) pipeline, which incorporates the following modules: mining tumor specific antigens from next-generation sequencing genomic and mRNA expression data, predicting the binding mutant peptides to class I MHC molecules by latest netMHCpan (v.4.0), verifying MHC-peptides by MaxQuant with mass spectrometry proteomics data searched against customized protein database, and checking potential immunogenicity of T-cell-recognization by additional screening methods. ProGeo-neo pipeline achieves proteogenomics strategy and the neopeptides identified were of much higher quality as compared to those identified using genomic data only. CONCLUSIONS: The pipeline was constructed based on the genomics and proteomics data of Jurkat leukemia cell line but is generally applicable to other solid cancer research. With massively parallel sequencing and proteomics profiling increasing, this proteogenomics workflow should be useful for neoantigen oriented research and immunotherapy.

Transfer of cGAMP into Bystander Cells via LRRC8 Volume-Regulated Anion Channels Augments STING-Mediated Interferon Responses and Anti-viral Immunity.

The enzyme cyclic GMP-AMP synthase (cGAS) senses cytosolic DNA in infected and malignant cells and catalyzes the formation of 2'3'cGMP-AMP (cGAMP), which in turn triggers interferon (IFN) production via the STING pathway. Here, we examined the contribution of anion channels to cGAMP transfer and anti-viral defense. A candidate screen revealed that inhibition of volume-regulated anion channels (VRACs) increased propagation of the DNA virus HSV-1 but not the RNA virus VSV. Chemical blockade or genetic ablation of LRRC8A/SWELL1, a VRAC subunit, resulted in defective IFN responses to HSV-1. Biochemical and electrophysiological analyses revealed that LRRC8A/LRRC8E-containing VRACs transport cGAMP and cyclic dinucleotides across the plasma membrane. Enhancing VRAC activity by hypotonic cell swelling, cisplatin, GTPγS, or the cytokines TNF or interleukin-1 increased STING-dependent IFN response to extracellular but not intracellular cGAMP. Lrrc8e-/- mice exhibited impaired IFN responses and compromised immunity to HSV-1. Our findings suggest that cell-to-cell transmission of cGAMP via LRRC8/VRAC channels is central to effective anti-viral immunity.

Pre-existing heterologous T-cell immunity and neoantigen immunogenicity.

Neoantigens are tumor-specific mutated proteins that are exempt from central tolerance and are therefore capable of efficiently eliciting effective T-cell responses. The identification of immunogenic neoantigens in tumor-specific mutated proteins has promising clinical implications for cancer immunotherapy. However, the factors that may contribute to neoantigen immunogenicity are not yet fully understood. Through molecular mimicry of antigens arising during cancer progression, the gut microbiota and previously encountered pathogens potentially have profound impacts on T-cell responses to previously unencountered tumor neoantigens. Here, we review the characteristics of immunogenic neoantigens and how host exposure to microbes may affect T-cell responses to neoantigens. We address the hypothesis that pre-existing heterologous memory T-cell immunity is a major factor that influences neoantigen immunogenicity in individual cancer patients. Accumulating data suggest that differences in individual histories of microbial exposure should be taken into account during the optimisation of algorithms that predict neoantigen immunogenicity.

Gut epithelial TSC1/mTOR controls RIPK3-dependent necroptosis in intestinal inflammation and cancer.

Although Western diet and dysbiosis are the most prominent environmental factors associated with inflammatory bowel diseases (IBDs), the corresponding host factors and cellular mechanisms remain poorly defined. Here we report that the TSC1/mTOR pathway in the gut epithelium represents a metabolic and innate immune checkpoint for intestinal dysfunction and inflammation. mTOR hyperactivation triggered by Western diet or Tsc1 ablation led to epithelium necroptosis, barrier disruption, and predisposition to dextran sulfate sodium-induced colitis and inflammation-associated colon cancer. Mechanistically, our results uncovered a critical role for TSC1/mTOR in restraining the expression and activation of RIPK3 in the gut epithelium through TRIM11-mediated ubiquitination and autophagy-dependent degradation. Notably, microbiota depletion by antibiotics or gnotobiotics attenuated RIPK3 expression and activation, thereby alleviating epithelial necroptosis and colitis driven by mTOR hyperactivation. mTOR primarily impinged on RIPK3 to potentiate necroptosis induced by TNF and by microbial pathogen-associated molecular patterns (PAMPs), and hyperactive mTOR and aberrant necroptosis were intertwined in human IBDs. Together, our data reveal a previously unsuspected link between the Western diet, microbiota, and necroptosis and identify the mTOR/RIPK3/necroptosis axis as a driving force for intestinal inflammation and cancer.

TSC1/mTOR-controlled metabolic-epigenetic cross talk underpins DC control of CD8+ T-cell homeostasis.

Dendritic cells (DCs) play pivotal roles in T-cell homeostasis and activation, and metabolic programing has been recently linked to DC development and function. However, the metabolic underpinnings corresponding to distinct DC functions remain largely unresolved. Here, we demonstrate a special metabolic-epigenetic coupling mechanism orchestrated by tuberous sclerosis complex subunit 1 (TSC1)-mechanistic target of rapamycin (mTOR) for homeostatic DC function. Specific ablation of Tsc1 in the DC compartment (Tsc1DC-KO) largely preserved DC development but led to pronounced reduction in naïve and memory-phenotype cluster of differentiation (CD)8+ T cells, a defect fully rescued by concomitant ablation of mTor or regulatory associated protein of MTOR, complex 1 (Rptor) in DCs. Moreover, Tsc1DC-KO mice were unable to launch efficient antigen-specific CD8+ T effector responses required for containing Listeria monocytogenes and B16 melanomas. Mechanistically, our data suggest that the steady-state DCs tend to tune down de novo fatty acid synthesis and divert acetyl-coenzyme A (acetyl-CoA) for histone acetylation, a process critically controlled by TSC1-mTOR. Correspondingly, TSC1 deficiency elevated acetyl-CoA carboxylase 1 (ACC1) expression and fatty acid synthesis, leading to impaired epigenetic imprinting on selective genes such as major histocompatibility complex (MHC)-I and interleukin (IL)-7. Remarkably, tempering ACC1 activity was able to divert cytosolic acetyl-CoA for histone acetylation and restore the gene expression program compromised by TSC1 deficiency. Taken together, our results uncover a crucial role for TSC1-mTOR in metabolic programing of the homeostatic DCs for T-cell homeostasis and implicate metabolic-coupled epigenetic imprinting as a paradigm for DC specification.

The nuclear receptor corepressor NCoR1 regulates hematopoiesis and leukemogenesis in vivo.

Enhanced understanding of normal and malignant hematopoiesis pathways should facilitate the development of effective clinical treatment strategies for hematopoietic malignancies. Nuclear receptor corepressor 1 (NCoR1) has been implicated in transcriptional repression and embryonic organ development, but its role in hematopoiesis is yet to be fully elucidated. Here, we showed that hematopoietic-specific loss of NCoR1 leads to expansion of the hematopoietic stem cell (HSC) pool due to aberrant cell cycle entry of long-term HSCs under steady-state conditions. Moreover, NCoR1-deficient HSCs exhibited normal self-renewal capacity but severely impaired lymphoid-differentiation potential in competitive hematopoietic-reconstitution assays. Transcriptome analysis further revealed that several hematopoiesis-associated genes are regulated by NCoR1. In addition, NCoR1 deficiency in hematopoietic cells delayed the course of leukemia and promoted leukemia cell differentiation in an MLL-AF9-induced mouse model. NCoR1 and its partner, histone deacetylase 3, can modulate histone acetylation and gene transcription through binding the promoter regions of myeloid-differentiation genes. Our collective results support the critical involvement of NCoR1 in normal and malignant hematopoiesis in vivo.

BLT1 signaling in epithelial cells mediates allergic sensitization via promotion of IL-33 production.

BACKGROUND: Epithelial cells (ECs) play a crucial role in allergic sensitization to inhaled protease allergens by instructing type 2 innate lymphoid cells (ILC2) and dendritic cells (DCs) via release of pro-type 2 cytokines, particularly interleukin-33 (IL-33). Leukotriene B4 (LTB4) is a well-known leukocyte chemoattractant via engagement of its receptor 1 (BLT1). However, the role of LTB4-BLT1 axis in allergic sensitization via activation of ECs is still unknown. METHODS: We evaluated the effect of LTB4-BLT1 axis on IL-33 expression and ILC2 activation in vivo and in vitro. Chimeric mice were established to evaluate the contribution of BLT1 expression in nonimmune cell to allergic sensitization. RESULTS: Genetical or pharmacological interruption of LTB4-BLT1 axis during sensitization phase markedly reduced papain-induced IL-33 expression, decreased ILC2 activation and DC migration, thereby impairing the priming of allergic Th2 responses. Furthermore, papain inhalation induced a rapid release of LTB4 preceding IL-33, and intranasal administration of LTB4 to naïve WT mice significantly increased IL-33 expression and ILC2 activation in lung, which was absent in Il33-/- or Ltb4r1-/- mice. Furthermore, BLT1 was expressed in primary mouse ECs or normal human bronchial ECs (NHBE), and papain induced LTB4 release by NHBE, which in turn amplified IL-33 production dependent on Akt activation via BLT1. Consequently, bone marrow chimeric mice lacking BLT1 in radio-resistant structural cells failed to develop allergic lung inflammation to papain. CONCLUSION: Our study reveals a functional role of LTB4-BLT1 axis in nonimmune cells, most likely lung ECs, in controlling allergic sensitization as an upstream regulator of IL-33.

Insect cell-produced recombinant protein subunit vaccines protect against Zika virus infection.

Infection with Zika virus (ZIKV) may lead to severe neurologic disorders. It is of significant importance and urgency to develop safe and effective vaccines to prevent ZIKV infection. Here we report the development of ZIKV subunit vaccines based on insect cell-produced recombinant proteins. The N-terminal approximately 80% region (designated as E80) and the domain III (designated as EDIII) of ZIKV envelope (E) protein were efficiently produced as secreted proteins in a Drosophila S2 cell expression system. Both E80 and EDIII could inhibit ZIKV infection in vitro, suggesting that they may have folded properly to display native conformations. Immunization studies demonstrated that both E80 and EDIII vaccines were able to trigger antigen-specific antibody and T-cell responses in mice. The resulting anti-E80 and anti-EDIII sera could potently neutralize ZIKV infection in vitro. More importantly, passive transfer of either anti-E80 or anti-EDIII sera protected recipient mice against lethal ZIKV challenge. It is worth noting that the anti-EDIII sera possessed higher neutralizing titers and conferred more complete protection than the anti-E80 sera, indicating that the S2 cell-produced EDIII is a superior ZIKV vaccine candidate compared with the E80. These data support further preclinical and clinical development of a ZIKV subunit vaccine based on S2 cell-produced EDIII.

Elevated sodium chloride drives type I interferon signaling in macrophages and increases antiviral resistance.

Type I IFN production and signaling in macrophages play critical roles in innate immune responses. High salt (i.e. high concentrations of NaCl) has been proposed to be an important environmental factor that influences immune responses in multiple ways. However, it remains unknown whether high salt regulates type I IFN production and signaling in macrophages. Here, we demonstrated that high salt promoted IFNß production and its signaling in both human and mouse macrophages, and consequentially primed macrophages for strengthened immune sensing and signaling when challenged with viruses or viral nucleic acid analogues. Using both pharmacological inhibitors and RNA interference we showed that these effects of high salt on IFNß signaling were mediated by the p38 MAPK/ATF2/AP1 signaling pathway. Consistently, high salt increased resistance to vesicle stomatitis virus (VSV) infection in vitro. In vivo data indicated that a high-salt diet protected mice from lethal VSV infection. Taken together, these results identify high salt as a crucial regulator of type I IFN production and signaling, shedding important new light on the regulation of innate immune responses.

Distinct role of nuclear receptor corepressor 1 regulated de novo fatty acids synthesis in liver regeneration and hepatocarcinogenesis in mice.

It is urgent that the means to improve liver regeneration (LR) be found, while mitigating the concurrent risk of hepatocarcinogenesis (HCG). Nuclear receptor corepressor 1 (NCoR1) is a co-repressor of nuclear receptors, which regulates the expression level of metabolic genes; however, little is known about its potential contribution for LR and HCG. Here, we found that liver-specific NCoR1 knockout in mice (NCoR1Δhep ) dramatically enhances LR after partial hepatectomy and, surprisingly, blocks the process of diethylnitrosamine (DEN)-induced HCG. Both RNA-sequencing and metabolic assay results revealed improved expression of Fasn and Acc2 in NCoR1Δhep mice, suggesting the critical role of de novo fatty acid synthesis (FAS) in LR. Continual enhanced de novo FAS in NCoR1Δhep mice resulted in overwhelmed adenosine triphosphate ATP and nicotinamide adenine dinucleotide phosphate (NADPH) consumption and increased mitochondrial reactive oxygen species production, which subsequently attenuated HCG through inducing apoptosis of hepatocytes at an early stage after DEN administration. CONCLUSION: NCoR1 functions as a negative modulator for hepatic de novo FAS and mitochondria energy adaptation, playing distinct roles in regeneration or carcinogenesis. (Hepatology 2018;67:1071-1087).