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Histone deacetylases (HDACs) are epigenetic regulators and additionally control the activity of non-histone substrates. We recently demonstrated that inhibition of HDAC8 overexpressed in various of cancers reduces hepatocellular carcinoma tumorigenicity in a T cell-dependent manner. Here, we present alkylated hydrazide-based class I HDAC inhibitors in which the

Obesity is a major risk factor for cancers including hepatocellular carcinoma (HCC) that develops from a background of non-alcoholic fatty liver disease (NAFLD). Hypercholesterolemia is a common comorbidity of obesity. Although cholesterol biosynthesis mainly occurs in the liver, its role in HCC development of obese people remains obscure. Using high-fat high-carbohydrate diet-associated orthotopic and spontaneous NAFLD-HCC mouse models, we found that hepatic cholesterol accumulation in obesity selectively suppressed natural killer T (NKT) cell-mediated antitumor immunosurveillance. Transcriptome analysis of human liver revealed aberrant cholesterol metabolism and NKT cell dysfunction in NAFLD patients. Notably, cholesterol-lowering rosuvastatin restored NKT expansion and cytotoxicity to prevent obesogenic diet-promoted HCC development. Moreover, suppression of hepatic cholesterol biosynthesis by a mammalian target of rapamycin (mTOR) inhibitor vistusertib preceded tumor regression, which was abolished by NKT inactivation but not CD8(+) T cell depletion. Mechanistically, sterol regulatory element-binding protein 2 (SREBP2)-driven excessive cholesterol production from hepatocytes induced lipid peroxide accumulation and deficient cytotoxicity in NKT cells, which were supported by findings in people with obesity, NAFLD and NAFLD-HCC. This study highlights mTORC1/SREBP2/cholesterol-mediated NKT dysfunction in the tumor-promoting NAFLD liver microenvironment, providing intervention strategies that invigorating NKT cells to control HCC in the obesity epidemic.

Legend for Supplemental Figures S1-S8.

HDAC8 expression positively correlates with its signaling components in primary human NAFLD-associated HCCs.

Description of additional methods and procedures used in the study.

Clinicopathological information of the NAFLD-associated HCC patients.

The growing epidemic of obesity, which causes nonalcoholic fatty liver disease (NAFLD) and the more severe phenotype nonalcoholic steatohepatitis (NASH), has paralleled the increasing incidence of hepatocellular carcinoma (HCC). Accumulating evidence demonstrates that overnutrition and metabolic pathways can trigger modifications of DNA and histones via deregulation of chromatin modifiers, resulting in aberrant transcriptional activity. However, the epigenetic regulation of HCC development in NAFLD remains obscure. Here, we uncover key epigenetic regulators using both dietary and genetic obesity-promoted HCC models through quantitative expression profiling and characterize the oncogenic activities of histone deacetylase HDAC8 in NAFLD-associated hepatocarcinogenesis. HDAC8 is directly upregulated by the lipogenic transcription factor SREBP-1 where they are coexpressed in dietary obesity models of NASH and HCC. Lentiviral-mediated HDAC8 attenuation in vivo reversed insulin resistance and reduced NAFLD-associated tumorigenicity. HDAC8 modulation by genetic and pharmacologic approaches inhibited p53/p21-mediated apoptosis and G2–M phase cell-cycle arrest and stimulated β-catenin–dependent cell proliferation. Mechanistically, HDAC8 physically interacted with the chromatin modifier EZH2 to concordantly repress Wnt antagonists via histone H4 deacetylation and H3 lysine 27 trimethylation. In human NAFLD-associated HCC, levels of SREBP-1, HDAC8, EZH2, H4 deacetylation, H3K27me3, and active β-catenin were all correlated positively in tumors compared with nontumor tissues. Overall, our findings show how HDAC8 drives NAFLD-associated hepatocarcinogenesis, offering a novel epigenetic target to prevent or treat HCC in obese patients. Cancer Res; 75(22); 4803–16. ©2015 AACR.

Supplementary Figure S5: Attenuation of tumor-suppressing effects of miR-490-3p by SMARCD1 overexpression.

Supplementary Table S1: Absolute expression levels of miR-490-3p, miR-375 and let-7b in non-cancerous gastric mucosa.

Chromatin remodeling has emerged as a hallmark of gastric cancer, but the regulation of chromatin regulators other than genetic change is unknown. Helicobacter pylori causes epigenetic dysregulation to promote gastric carcinogenesis, but the roles and functions of microRNAs (miRNA) in this multistage cascade are not fully explored. In this study, miRNA expression in preneoplastic and neoplastic lesions in murine stomachs induced by H. pylori and N-methyl-N-nitrosourea (MNU) was profiled by miRNA expression array. miR-490-3p exhibited progressive downregulation in gastritis, intestinal metaplasia, and adenocarcinoma during H. pylori and MNU-induced gastric carcinogenesis. Significant downregulation of miR-490-3p was confirmed in human gastric cancer tissues in which its regulatory region was found to be hypermethylated. miR-490-3p exerted growth- and metastasis-suppressive effects on gastric cancer cells through directly targeting SMARCD1, a SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex subunit. Knockdown of SMARCD1 significantly attenuated the protumorigenic effects of miR-490-3p inhibitor, whereas enforced expression of SMARCD1 promoted in vitro and in vivo oncogenic phenotypes of gastric cancer cells. SMARCD1 was markedly upregulated in gastric cancer in which its high expression was associated with shortened patients' survival independent of TNM staging. In conclusion, hypermethylation-mediated silencing of miR-490-3p reactivates SMARCD1 to confer malignant phenotypes, mechanistically linking H. pylori, chromatin remodeling, and gastric carcinogenesis. Cancer Res; 75(4); 754–65. ©2014 AACR.

Supplementary Materials and Methods

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Hepatocellular carcinoma (HCC) is a major cancer burden worldwide with increasing incidence in many developed countries. Super-enhancers (SEs) drive gene expressions required for cell type-specificity and tumor cell identity. However, their roles in HCC remain unclear because of data scarcity from primary tumors. Herein, chromatin profiling of non-alcoholic fatty liver disease (NAFLD)-associated HCCs and matched liver tissues uncovered an average of ∼500 somatically-acquired SEs per patient. The identified SE-target genes were functionally enriched for aberrant metabolism and cancer phenotypes, especially chromatin regulators including deacetylases and Polycomb repressive complexes. Notably, all examined tumors exhibited SE activation of Sirtuin 7 (SIRT7), genome-wide promoter H3K18 deacetylation and concurrent H3K27me3, as well as tumor-suppressor gene silencing. Depletion of SIRT7 SE in hepatoma cells induced global H3K18 acetylation and reactivated key metabolic and immune regulators, leading to marked suppression of tumorigenicity in vitro and in vivo. In concordance, SIRT7 physically interacted with the methyltransferase EZH2, and they were co-expressed in primary HCCs. In summary, our integrative analysis establishes a compendium of SEs in NAFLD-associated HCCs and uncovers SIRT7-driven chromatin regulatory network as potential druggable vulnerability of this increasingly prevalent cancer.

MotivationIn metabolic engineering and synthetic biology applications, promoters with appropriate strengths are critical. However, it is time-consuming and laborious to annotate promoter strength by experiments. Nowadays many machine learning (ML) methods are applied to synthetic promoter strength prediction, but existing models are limited by the excessive proximity between synthetic promoters.ResultsIn order to enhance ML models to better predict the synthetic promoter strength, we propose EVMP(Extended Vision Mutant Priority), a universal framework which utilize mutation information more effectively. In EVMP, synthetic promoters are equivalently transformed into base promoter and correspondingk-mer mutations, which are input into BaseEncoder and VarEncoder respectively. In Trc synthetic promoter library, EVMP was applied to multiple ML models and the model effect was enhanced to varying extents, up to 61.30%, while the SOTA(state-of-the-art) record was improved by 15.25%. EVMP also provides optional data augmentation based on multiple base promoters, which further improved the model performance by 17.95% compared with non-EVMP SOTA record. In further study, extended vision is shown to be essential for EVMP. We also found that EVMP can alleviate the over-smoothing phenomenon, which may contributes to its effectiveness. Our work suggests that EVMP can highlight the mutation information of synthetic promoters and significantly improve the prediction accuracy of strength.Availability and implementationThe source code is publicly available on github:https://github.com/Tiny-Snow/EVMP.Contacthuangrr@sdu.edu.cnSupplementary informationAppendix is available atbioRxivonline.

Breast cancer is the most frequent malignancy in females worldwide, causing more than 680,000 deaths in 2020. Dysregulated microRNAs have been linked etiologically with breast cancer, controlling a wide range of cellular pathways. Dual luciferase reporter assay was used to confirm the link between miR-499a-5p and SOX6. Studies including proliferation, migration and invasion assay were carried out to investigated functional roles. Animal model was introduced for in vivo investigation. We found high expression level of miR-499a-5p in breast cancer tissues which associated with worse survival. Overexpression of miR-499a-5p played oncogenic role by promoting cell growth and invasiveness in breast cancer cells. SOX6 was identified as the potential target of miR-499a-5p by silico prediction, which was confirmed by dual luciferase reporter assay. Further study confirmed a tumor suppressive role of SOX6 in breast cancer. Subcutaneous administration of breast cancer cells with ectopic miR-499a-5p expression led to larger tumor volume in mice. Taken together, for the first time, we identified a direct link between miR-499a-5p and its down-stream target SOX6, revealing their functionality, which would provide novel insight into the mechanism of breast cancer. Our finding indicating a promising diagnostic and therapeutic op-tion towards this malignant disease.

As a noninvasive method, circulating tumor cell (CTC) provides ideal liquid biopsy specimens for early cancer screening and diagnosis. CTCs detection in breast cancer is correlated with patient prognosis such as disease-free survival (DFS) and overall survival (OS). Besides, accumulating evidence supported that CTCs count may be indicator for chemotherapy response as well. The functional roles of microRNA (miRNA) in breast cancer have been well-recognized for the last few years. Due to its stability in circulation, numerous studies have proven that circulating miRNA may serve as promising diagnostic and prognostic biomarkers in breast cancer. The potential ability of miRNAs in disease screening, staging or even molecular subtype classification makes them valuable tools for early breast cancer patients. It would be of great significance to characterize the miRNA expression profile in CTCs, which could provide reliable biological information originated from tumor. However, some issues need to be addressed before the utility of CTC-specific miRNAs in clinical setting. Taken together, we believe that CTC-specific miRNA detection will be trend for early breast cancer screening, diagnosis and treatment monitor in near future.

Histone deacetylases (HDACs) are modulators of epigenetic gene regulation and additionally control the activity of non-histone protein substrates by removing acyl or acetyl groups from modified lysine residues. We recently demonstrated that pharmacological inhibition of the HDAC8 enzyme belonging to class I of HDACs and overexpressed in a variety of human cancers controls histone H3 lysine 27 (H3K27)-acetylation and reduces hepatocellular carcinoma tumorigenicity in a T cell-dependent manner. Here, we present a new chemotype of alkylated hydrazide-based class I HDAC inhibitors in which the n-hexyl side chain attached to the hydrazide moiety show HDAC8 selectivity in vitro. An enzymatic assay provided important structure-activity relationships for this new series of alkyl hydrazides. Analysis of the mode of inhibition of the alkyl hydrazides against HDAC8 revealed a substrate-competitive binding mode. The most promising compound 7d marked induced acetylation of the HDAC8 substrates H3K27 and SMC3 at 10 μM but not tubulin in CD4+ T lymphocytes, and significantly upregulated gene expressions for memory and effector functions. Furthermore, intraperitoneal injection administration of 7d (10 mg/kg) in C57BL/6 mice increased interleukin-2 expression in CD4+ T cells and CD8+ T cell proportion with no apparent toxicity. This study expands a novel chemotype of highly potent class I HDAC inhibitors with T cell modulatory properties for future therapeutic applications.

Mesenchymal stem or stromal cells (MSCs) are nonhematopoietic postnatal stem cells with self-renewal, multipotent differentiation, and potent immunomodulatory and anti-inflammatory capabilities, thus playing an important role in tissue repair and regeneration. Numerous clinical and preclinical studies have demonstrated the potential application of MSCs in the treatment of tissue inflammation and immune diseases, including inflammatory skin diseases. Therefore, understanding the biological and immunological characteristics of MSCs is important to standardize and optimize MSC-based regenerative therapy. In this review, we highlight the mechanisms underlying MSC-mediated immunomodulation and tissue repair/regeneration and present the latest development of MSC-based clinical trials on cutaneous diseases.

Intestinal metaplasia (IM) refers to the replacement of gastric epithelial cells by intestinal epithelial cells. This is often accompanied by chronic atrophic gastritis (CAG), which is a precancerous lesion of gastric cancer. The incidence rates of CAG and IM are increasing gradually, which generates an enormous economic burden to individuals and society. To explore the pathogenesis of CAG with IM, we screened out the differentially expressed gene olfactomedin 4 (OLFM4) by bioinformatics and constructed OLFM4-shRNA plasmid chitosan magnetic nanoparticles to knockdown this gene. This caused a downregulation of caudal type homeobox 2 (CDX2), a marker of IM, suggesting that knocking down OLFM4 may slow the pathological process of IM, thus providing putative relevant targets for the treatment of CAG with IM.

Epidermolysis bullosa (EB) is a heritable blistering disorder. We performed a next-generation sequencing-based multigene panel test and successfully predicted 100% of the EB types, including, 36 EB simplex (EBS), 13 junctional EB (JEB), 86 dystrophic EB (DEB), and 3 Kindler EB. Chinese JEB and recessive DEB (RDEB) patients have relatively mild phenotypes; for severe type separately accounts for 45.5% and 23.8%, respectively. We identified 96 novel and 49 recurrent pathogenic variants in 11 genes, although we failed to detect the second mutation in one JEB and five RDEB patients. We identified one novel p.E475K mosaic mutation in the clinically normal mother of one out of 13 EBS patients with KRT5 mutations, one recurrent p.G2034R mosaic mutation, and one novel p.G2043R mosaic mutation in the clinically normal relatives of two out of 19 dominant DEB patients. This study shows that next-generation technology could be an effective tool in diagnosing EB.

Weighted gene co-expression network analysis (WGCNA) identified a cell-cycle module that is associated with poor prognosis and aggressiveness of glioma. One of the core members, Regulator of chromatin condensation 2 (RCC2) is a component of the chromosome passenger complex. Accumulating evidence suggests that RCC2 plays a vital role in the mitotic process and that abnormal RCC2 expression is involved in cancer development. Gene silencing experiments show that RCC2 is required for glioma cell proliferation and migration. RNA-Sequencing analysis reveals a dual role of RCC2 in both the cell cycle and metabolism. Specifically, RCC2 regulates G2/M progression via CDC2 phosphorylation at Tyrosine 15. Metabolomic analysis identifies a role for RCC2 in promoting the glycolysis and pentose phosphate pathway. RCC2 exerts effects on metabolism by stabilizing the transcription factor BACH1 at its C-terminus leading to the transcriptional upregulation of hexokinase 2 (HK2). These findings elucidate a novel PTEN/RCC2/BACH1/HK2 signaling axis that drives glioma progression through the dual regulation of mitotic cell cycle and glycolytic events.

Breast cancer is one the most common malignancies and leading cause of cancer-related mortality in women. Recent studies suggested that hypercholesterolemia may be the potential modifiable risk factors for breast cancer. Cholesterol was well-known for its strong association with cardiovascular disease for long. Moreover, solid evidence has been provided by different studies to illustrate the correlation between lipid and incidence in multiple cancers. Although the conclusion remains controversial or sometimes contrary, which may be due to the multifactorial nature of the disease and the disparity of ethnic population, it is critical to elucidate the relationship between specific cholesterol components in certain population and the exact underlying mechanism of the lipid-associated signaling pathway in breast cancer. The implications of dysregulated lipoproteins as therapeutic targets or options for breast cancer provide novel strategies for us in combating with this malignant disease, which may be achieved by manipulating lipid levels with pharmacological compounds.

Background Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) as a distinct variant of HCC displayed immunologically hot tumor features with prominent tumor-infiltrating CD8+T lymphocytes (TILs). Our whole exosome sequencing data found an increased prevalence of chromosome 11q13.3 amplification in LEL-HCC, in which contains fas-associated death domain (FADD) that displayed a strongest positive correlation with differentially expressed genes function in TIL migration. We hence aim to elucidate the functional roles and molecular mechanisms of hepatoma-intrinsic FADD in regulating TIL abundance in general HCC patients. Methods FADD-overexpressed HepG2 (FADD-oe) and FADD-knockdown huh7 cells (FADD-kd) were constructed to investigate cell growth rate by colony formation and MTS assay in vitro, subcutaneous tumor in immunodeficient nude and NOD/SCID mice in vivo. A co-culture model of human peripheral blood-derived- CD8+T cells and HepG2-oe or Huh7-kd in vitro, T cell adoptive transfer and humanized mice models in vivo were used to detect T migration preference. The downstream functional chemokines and molecular pathways controlled by FADD were determined by RT-qPCR, ELISA, western blot as well as gene modulation assays. Finally, the associations among FADD (Fadd) expression, TIL proportion and patient prognosis or tumor development were evaluated by NanoString/immunohistochemistry analysis in HCC patients or RT-qPCR/flow cytometry in orthotopic HCC mouse models. Results CD8+T cell migration rate was significantly enhanced in FADD-oe tumors, but reduced in FADD-kd tumors in both HCC cells-T cell co-culture system in vitro and subcutaneous tumor models in vivo. Mechanistically, FADD activated NF-κB, which in turn promoted T cell trafficking chemokine CCL5 production. Furthermore, Fadd expression was positively correlated with Ccl5 and TIL proportions, but negatively correlated with orthotopic HCC tumor weights. As we showed that FADD was positively correlated with CD8+T cells in HCC patients, our data pinpointed that FADD controls TIL abundance in HCC. Conclusions Our findings reveal an underlying mechanism of TIL accumulation in HCC, which provides a novel strategy of FADD activation in turning immunologically cold tumors into hot ones for better prognosis and immunotherapeutic responses.

The treatment of recessive dystrophic epidermolysis bullosa (RDEB) remains challenging. Elevated IgE levels have previously been reported in several RDEB patients. In this prospective, single-centre, open intervention study, elevated IgE levels were seen in 11 out of 12 patients with intense pruritus, and the patients with elevated IgE levels received anti-IgE therapy every 4 weeks for at least 3 cycles. Compared with the baseline, 10 patients with RDEB had good clinical outcomes with enhanced wound healing, a reduction in Birmingham (epidermolysis bullosa) EB severity score by 15%, a reduction in affected body surface area by 23.3%, amelioration of skin inflammation, and an increase in type VII collagen deposition by 13.1-fold. All the patients had a good tolerance to anti-IgE therapy. Furthermore, patients with higher IgE levels tended to have higher disease severity and more favourable clinical outcomes. Our report also suggested the potential role of IgE in the pathogenesis of inflammatory conditions associated with RDEB. (ChiCTR1900021437). This article is protected by copyright. All rights reserved.

ObjectiveHepatocellular carcinoma (HCC), mostly developed in fibrotic/cirrhotic liver, exhibits relatively low responsiveness to immune checkpoint blockade (ICB) therapy. As myeloid-derived suppressor cell (MDSC) is pivotal for immunosuppression, we investigated its role and regulation in the fibrotic microenvironment with an aim of developing mechanism-based combination immunotherapy.DesignFunctional significance of MDSCs was evaluated by flow cytometry using two orthotopic HCC models in fibrotic liver setting via carbon tetrachloride or high-fat high-carbohydrate diet and verified by clinical specimens. Mechanistic studies were conducted in human hepatic stellate cell (HSC)-peripheral blood mononuclear cell culture systems and fibrotic-HCC patient-derived MDSCs. The efficacy of single or combined therapy with anti-programmed death-1-ligand-1 (anti-PD-L1) and a clinically trialled BET bromodomain inhibitor i-BET762 was determined.ResultsAccumulation of monocytic MDSCs (M-MDSCs), but not polymorphonuclear MDSCs, in fibrotic livers significantly correlated with reduced tumour-infiltrating lymphocytes (TILs) and increased tumorigenicity in both mouse models. In human HCCs, the tumour-surrounding fibrotic livers were markedly enriched with M-MDSC, with its surrogate marker CD33 significantly associated with aggressive tumour phenotypes and poor survival rates. Mechanistically, activated HSCs induced monocyte-intrinsic p38 MAPK signalling to trigger enhancer reprogramming for M-MDSC development and immunosuppression. Treatment with p38 MAPK inhibitor abrogated HSC-M-MDSC crosstalk to prevent HCC growth. Concomitant with patient-derived M-MDSC suppression by i-BET762, combined treatment with anti-PD-L1 synergistically enhanced TILs, resulting in tumour eradication and prolonged survival in the fibrotic-HCC mouse model.ConclusionOur results signify how non-tumour-intrinsic properties in the desmoplastic microenvironment can be exploited to reinstate immunosurveillance, providing readily translatable combination strategies to empower HCC immunotherapy.

Emerging evidence suggests that long non-coding RNA (lncRNA) plays a critical role in human disease progression. Recently, a novel lncRNA ST8SIA6-AS1 was shown as an important driver in various cancer types. Nevertheless, its contribution to lung adenocarcinoma (LUAD) remains undocumented. Herein, we found that ST8SIA6-AS1 was frequently overexpressed in LUAD cell lines, tissues, and plasma. Depletion of ST8SIA6-AS1 significantly inhibited LUAD cell proliferation and invasion in vitro and tumor growth in vivo. In term of mechanism, ST8SIA6-AS1 was transcriptionally repressed by tumor suppressor p53, and ST8SIA6-AS1 was mainly located in the cytoplasm and could abundantly sponge miR-125a-3p to increase nicotinamide N-methyltransferase (NNMT) expression, thereby facilitating LUAD malignant progression. Clinically, high ST8SIA6-AS1 was positively correlated with larger tumor size, lymph node metastasis, and later TNM stage. Moreover, ST8SIA6-AS1 was identified as an excellent indicator for MM diagnosis and prognosis. Collectively, our data demonstrate that ST8SIA6-AS1 is a carcinogenic lncRNA in LUAD, and targeting the axis of ST8SIA6-AS1/miR-125a-3p/NNMT may be a promising treatment for LUAD patients.

Background The insufficient T cell infiltration into non-inflamed tumors such as hepatocellular carcinoma (HCC) restricts the effectiveness of immune-checkpoint blockade (ICB) to a minority of patients. Epigenetic therapy provides new opportunities to rewire cancer transcriptional programs, but whether and how selective epigenetic inhibition counteracts the immune-excluded phenotype to sensitize ICB therapy remain incompletely defined. Here, we aimed to investigate the therapeutic efficacy and mechanistic basis of histone deacetylase 8 (HDAC8), a histone H3 lysine 27 (H3K27)-specific isoform, in HCC development and ICB responsiveness. Methods The immune-modulatory and anti-tumor effects of HDAC8 inhibition via a HDAC8-selective inhibitor, PCI34051, were determined in orthotopic HCC mouse models. Molecular mechanisms and functional significance of HDAC8 inhibition were conducted by genome-wide H3K27ac ChIP-seq and RNAseq in HCC patient specimens, cancer cell lines, NOD-SCID and humanized mouse models. The efficacy of single or combined therapy with anti-programmed death-1-ligand-1 (anti-PD-L1) and PCI34051 was determined in orthotopic and spontaneous HCC mouse models. Results Pharmacological inhibition of HDAC8 thwarted HCC tumorigenicity in immunocompetent but not immunodeficient mice. The tumor-suppressive effect of PCI34051 was abrogated by CD8+T cell depletion or regulatory T cell adoptive transfer. Chromatin profiling of human HDAC8-expressing HCCs revealed genome-wide H3K27 deacetylation in 1,251 silenced enhancer-target gene pairs that were enriched in metabolic and immune regulators. Mechanistically, down-regulation of HDAC8 increased global and enhancer levels of H3K27 acetylation to reactivate T cell-trafficking chemokine production from HCC cells, thus relieving T cell exclusion in both NOD-SCID and humanized mouse models. In the HCC preclinical model, selective HDAC8 inhibition significantly increased tumor-infiltrating CD8+T cells and potentiated eradication of established hepatoma by anti-PD-L1 therapy without a sign of toxicity. Importantly, mice treated with HDAC8/PD-L1 co-blockade were protected against subsequent tumor re-challenge with the induction of memory T cells and remained tumor-free for ≥15 months. Conclusions Our study demonstrates that selective HDAC8 inhibition elicits effective and durable ICB responses by co-opting adaptive immunity via enhancer reprogramming, thereby providing a new strategy for effective combined epigenetic immunotherapy.

Background Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the second leading cause of cancer deaths worldwide. Driven by the epidemics of obesity and diabetes, it is anticipated that non-alcoholic fatty liver disease (NAFLD) will become the most important cause of HCC. Emerging evidence suggests that metabolic and immune dysfunction are key features of NAFLD-associated HCC, my research aim to investigate the metabolic-immune dysregulation underlying NAFLD-HCC development. Here we show that aberrant cholesterol accumulation in the liver predisposes cancer development by reprogramming the immunosurveillance microenvironment. Methods Comprehensive immune profiling in a high-fat high-carbohydrate diet-induced NAFLD murine model was performed. Results Our results revealed a specific reduction of cytolytic natural killer T (NKT) cells in the liver, which was negatively correlated with the elevated cholesterol level. Cholesterol-lowering drug Rosuvastatin reduced cholesterol level and restored NKT cell proportion and function, which subsequently suppressed the growth of orthotopically-implanted HCC tumor. Inhibition of cholesterol synthesis by an mTORC1/C2 dual kinase inhibitor Vistusertib (AZD2014), or lentiviral-mediated suppression of the mTOR pathway also showed similar effects. Notably, NKT inactivation by a specific CD1d receptor-targeting antibody abolished the anti-tumorigenic effects of both Rosuvastatin and Vistusertib, thus underscoring the casual role of NKT in cholesterol-mediated hepatocarcinogenesis. We also showed a reduction of NKT cells and its negative correlation with cholesterol elevation in obese patients undergone bariatric surgery. Conclusions Our study elucidates a new immunosuppressive role of cholesterol in establishing a pro-tumorigenic microenvironment. These findings explain why cholesterol-lowering drugs may reduce cancer incidence and provide new therapeutic strategies of revitalizing the immunosurveillant NKT cells for the intervention of NAFLD-associated HCC. This project is supported by the University Grants Committee through the Collaborative Research Fund (C4045-18W), General Research Fund (14108219, 14105419), the Li Ka Shing Foundation and the Terry Fox Foundation and the AstraZeneca Preclinical Oncology Research Program (2017).

The liver is an immunologically tolerant organ and a common metastatic site of multiple cancer types. Although a role for cancer cell invasion programs has been well characterized, whether and how liver-intrinsic factors drive metastatic spread is incompletely understood. Here, we show that aberrantly activated hepatocyte-intrinsic cell cycle-related kinase (CCRK) signaling in chronic liver diseases is critical for cancer metastasis by reprogramming an immunosuppressive microenvironment. Using an inducible liver-specific transgenic model, we found that CCRK overexpression dramatically increased both B16F10 melanoma and MC38 colorectal cancer (CRC) metastasis to the liver, which was highly infiltrated by polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSCs) and lacking natural killer T (NKT) cells. Depletion of PMN-MDSCs in CCRK transgenic mice restored NKT cell levels and their interferon gamma production and reduced liver metastasis to 2.7% and 0.7% (metastatic tumor weights) in the melanoma and CRC models, respectively. Mechanistically, CCRK activated nuclear factor-kappa B (NF-κB) signaling to increase the PMN-MDSC-trafficking chemokine C-X-C motif ligand 1 (CXCL1), which was positively correlated with liver-infiltrating PMN-MDSC levels in CCRK transgenic mice. Accordingly, CRC liver metastasis patients exhibited hyperactivation of hepatic CCRK/NF-κB/CXCL1 signaling, which was associated with accumulation of PMN-MDSCs and paucity of NKT cells compared to healthy liver transplantation donors. In summary, this study demonstrates that immunosuppressive reprogramming by hepatic CCRK signaling undermines antimetastatic immunosurveillance. Our findings offer new mechanistic insights and therapeutic targets for liver metastasis intervention.

In the past 30 years, dengue has undergone dramatic changes in China every year. This study explores the epidemiological trend of dengue in China during this period to identify high-risk seasons, regions, ages, susceptible populations, and provide information for dengue prevention and control activities. Dengue data from 1990 to 2019 were derived from the Public Health Science Data Center, Web of Science, China National Knowledge Infrastructure, PubMed, and Centers for Disease Control and Prevention of the corresponding province. GraphPad Prism 7 was conducted to generate disease evolution maps, occupational heat maps, and monthly heat maps of dengue cases and deaths in mainland China and Guangdong Province. Excel 2016 was used to create a cyclone map of age and gender distribution. Powerpoint 2016 was performed to create geographic maps. From 1990 to 2019, the annual number of dengue cases showed an increasing trend and reaching a peak in 2014, with 46,864 dengue cases (incidence rate: 3.4582/100,000), mainly contributed by Guangdong Province (45,189 cases, accounting for 96.43%). Dengue pandemics occurred every 4 to 6 years. The prevalence of dengue fever was Autumn, which was generally prevalent from June to December and reached its peak from September to November. The provinces reporting dengue cases each year have expanded from the southeastern coastal region to the southwest, central, northeast, and northwest regions, and the provinces with a high incidence were Guangdong, Guangxi, Yunnan, Fujian, and Zhejiang. People aged 25 to 44 years were more susceptible to dengue virus infection. And most of them were male patients. Dengue mainly occurs in the following groups: students, business service staffs, workers, farmers, retired staffs, housewives, and the unemployed. Four provinces reported deaths from dengue, namely Guangdong Province, Zhejiang Province, Henan Province, and Hunan Province. The dengue fever epidemic occurred every 4 to 6 years, mostly in autumn. The endemic areas were Guangdong, Guangxi, Yunnan, Fujian, and Zhejiang provinces. People aged 25 to 44 years, men, students, business service staffs, workers, farmers, retired staffs, housewives, and the unemployed were more susceptible to dengue fever. These findings help to develop targeted public health prevention and control measures.

Ovarian cancer is the most lethal cancer of the female reproductive system. In that regard, several epidemiological studies suggest that long‐term exposure to estrogen could increase ovarian cancer risk, although its precise role remains controversial. To decipher a mechanism for this, we previously generated a mathematical model of how estrogen‐mediated upregulation of the transcription factor, E2F6, upregulates the ovarian cancer stem/initiating cell marker, c‐Kit, by epigenetic silencing the tumor suppressor miR‐193a, and a competing endogenous (ceRNA) mechanism. In this study, we tested that previous mathematical model, showing that estrogen treatment of immortalized ovarian surface epithelial cells upregulated both E2F6 and c‐KIT, but downregulated miR‐193a. Luciferase assays further confirmed that microRNA‐193a targets both E2F6 and c‐Kit. Interestingly, ChIP‐PCR and bisulphite pyrosequencing showed that E2F6 also epigenetically suppresses miR‐193a, through recruitment of EZH2, and by a complex ceRNA mechanism in ovarian cancer cell lines. Importantly, cell line and animal experiments both confirmed that E2F6 promotes ovarian cancer stemness, whereas E2F6 or EZH2 depletion derepressed miR‐193a, which opposes cancer stemness, by alleviating DNA methylation and repressive chromatin. Finally, 118 ovarian cancer patients with miR‐193a promoter hypermethylation had poorer survival than those without hypermethylation. These results suggest that an estrogen‐mediated E2F6 ceRNA network epigenetically and competitively inhibits microRNA‐193a activity, promoting ovarian cancer stemness and tumorigenesis.

Tuberculosis (TB) immunity is affected by complex immune regulation processes, which involve various immune cells, immune molecules, and cytokines. Here, we evaluated the expression of B12, CD272 and miR-16 in peripheral blood mononuclear cells (PBMC) of patients with active pulmonary tuberculosis. The results showed that monocytes expressing CD272 or B12 were down-regulated in patients with tuberculosis. The expression of B12 and CD272 in T cells and monocytes is related to tuberculosis. In TB patients, the up-regulation of miR-16 was negatively correlated with B12 mRNA expression, miR-16 was mainly expressed in CD14(+) monocytes, and CD272 mRNA was mainly expressed in CD19(+) B cells. It is worth noting that the overexpression of miR-16 inhibits the expression of CD272 and B12 in monocytes of TB patients. After BCG stimulation, miR-16 expression of CD14(+) monocytes was up-regulated and B12 mRNA and CD272 mRNA expressions were down-regulated in TB patients. Finally, we found that miR-16 may participate in the TB immunization process through targeted regulation of B12 expression. These studies indicate that the expression of B12, CD272 and miR-16 in PBMC may be related to tuberculosis.

Obesity increases the risk of hepatocellular carcinoma (HCC) especially in men, but the molecular mechanism remains obscure. Here, we show that an androgen receptor (AR)-driven oncogene, cell cycle-related kinase (CCRK), collaborates with obesity-induced pro-inflammatory signaling to promote non-alcoholic steatohepatitis (NASH)-related hepatocarcinogenesis. Lentivirus-mediated Ccrk ablation in liver of male mice fed with high-fat high-carbohydrate diet abrogates not only obesity-associated lipid accumulation, glucose intolerance and insulin resistance, but also HCC development. Mechanistically, CCRK fuels a feedforward loop by inducing STAT3-AR promoter co-occupancy and transcriptional up-regulation, which in turn activates mTORC1/4E-BP1/S6K/SREBP1 cascades via GSK3β phosphorylation. Moreover, hepatic CCRK induction in transgenic mice stimulates mTORC1-dependent G−csf expression to enhance polymorphonuclear myeloid-derived suppressor cell recruitment and tumorigenicity. Finally, the STAT3-AR-CCRK-mTORC1 pathway components are concordantly over-expressed in human NASH-associated HCCs. These findings unveil the dual roles of an inflammatory-CCRK circuitry in driving metabolic and immunosuppressive reprogramming through mTORC1 activation, thereby establishing a pro-tumorigenic microenvironment for HCC development., Obesity increases the risk of hepatocellular carcinoma (HCC) especially in men. Here the authors find a potential mechanistic explanation by showing that, in mice, obesity-induced STAT3 cooperates with the androgen receptor to activate the mTORC pathway through up regulation of CCRK, resulting in hepatic steatosis worsening and HCC development via metabolic and immune reprogramming.