N6-methyladenosine methylation regulates the tumor microenvironment of Epstein-Barr virus-associated gastric cancer

BACKGROUND N6-methyladenosine(m6A)methylation modification exists in Epstein-Barr virus(EBV)primary infection,latency,and lytic reactivation.It also modifies EBV latent genes and lytic genes.EBV-associated gastric cancer(EBVaGC)is a distinctive molecular subtype of GC.We hypothesized EBV and m6A methylation regulators interact with each other in EBVaGC to differentiate it from other types of GC.AIM To investigate the mechanisms of m6A methylation regulators in EBVaGC to determine the differentiating factors from other types of GC.METHODS First,The Cancer Gene Atlas and Gene Expression Omnibus databases were used to analyze the expression pattern of m6A methylation regulators between EBVaGC and EBV-negative GC(EBVnGC).Second,we identified Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)functional enrichment of m6A-related differentially expressed genes.We quantified the relative abundance of immune cells and inflammatory factors in the tumor microenvironment(TME).Finally,cell counting kit-8 cell proliferation test,transwell test,and flow cytometry were used to verify the effect of insulin-like growth factor binding protein 1(IGFBP1)in EBVaGC cell lines.RESULTS m6A methylation regulators were involved in the occurrence and development of EBVaGC.Compared with EBVnGC,the expression levels of m6A methylation regulators Wilms tumor 1-associated protein,RNA binding motif protein 15B,CBL proto-oncogene like 1,leucine rich pentatricopeptide repeat containing,heterogeneous nuclear ribonucleoprotein A2B1,IGFBP1,and insulin-like growth factor 2 binding protein 1 were significantly downregulated in EBVaGC(P<0.05).The overall survival rate of EBVaGC patients with a lower expression level of IGFBP1 was significantly higher(P=0.046).GO and KEGG functional enrichment analyses showed that the immunity pathways were significantly activated and rich in immune cell infiltration in EBVaGC.Compared with EBVnGC,the infiltration of activated CD4+T cells,activated CD8+T cells,monocytes,activated dendritic cells,and plasmacytoid dendritic cells were significantly upregulated in EBVaGC(P<0.001).In EBVaGC,the expression level of proinflammatory factors interleukin(IL)-17,IL-21,and interferon-γ and immunosuppressive factor IL-10 were significantly increased(P<0.05).In vitro experiments demonstrated that the expression level of IGFBP1 was significantly lower in an EBVaGC cell line(SNU719)than in an EBVnGC cell line(AGS)(P<0.05).IGFBP1 overexpression significantly attenuated proliferation and migration and promoted the apoptosis levels in SNU719.Interfering IGFBP1 significantly promoted proliferation and migration and attenuated the apoptosis levels in AGS.CONCLUSION m6A regulators could remodel the TME of EBVaGC,which is classified as an immune-inflamed phenotype and referred to as a“hot”tumor.Among these regulators,we demonstrated that IGFBP1 affected proliferation,migration,and apoptosis.

Role of chemokines in the hepatocellular carcinoma microenvironment and their translational value in immunotherapy

The difficulty of early diagnosis,high tumor heterogeneity,and high recurrence and metastasis rates lead to an unsatisfactory treatment status for hepatocellular carcinoma(HCC).HCC is a typical inflammation-driven tumor.Chronic inflammation allows nascent tumors to escape immunosurveillance.Chemokines are small,soluble,secreted proteins that can regulate the activation and trafficking of immune cells during inflammation.Several studies have shown that various chemokines with overarching functions disrupt the immune microenvironment during the initiation and progression of HCC.The dysregulated chemokine network in HCC contributes to multiple malignant processes,including angiogenesis,tumor proliferation,migration,invasion,tumor low response,and resistance to immune therapy.Here,we summarize the current studies focusing on the role of chemokines and their receptors in the HCC immune microenvironment,highlighting potential translational therapeutic uses for modulating the chemokine system in HCC.

Infliximab stopped severe gastrointestinal bleeding in Crohn's disease

To report the result of rapid ulcer healing by infliximab in Crohn's patients with severe enterocolic bleeding. During 2005 and 2010, inflammatory bowel disease database of King Chulalongkorn Memorial and Samitivej hospitals were reviewed. There were seven Crohn's disease (CD) patients (4 women and 3 men; mean age 52 ± 10.4 years; range: 11-86 years). Two of the seven patients developed severe gastrointestinal bleeding (GIB) as a flare up of CD whereas the other five patients presented with GIB as their first symptom for CD. Their mean hemoglobin level dropped from 12 ± 1.3 g/ dL to 8.7 ± 1.3 g/dL in a 3-d period. Median packed red blood cells units needed for resuscitation was 4 units. Because of uncontrolled bleeding, surgical resection was considered. However, due to the poor surgical candidacy of these patients (n = 3) and /or possible development of short bowel syndrome (n = 6), surgery was not pursued. Likewise angiographic embolization was not considered in any due to the risk of large infarction. All severe GIBs successfully stopped by one or two doses of intravenous infliximab. Our data suggests that infliximab is an alternative therapy for CD with severe GIB when surgery has limitation or patient is a high risk.

The switch triggering the invasion process:Lipid metabolism in the metastasis of hepatocellular carcinoma

In humans,the liver is a central metabolic organ with a complex and unique histological microenvironment.Hepatocellular carcinoma(HCC),which is a highly aggressive disease with a poor prognosis,accounts for most cases of primary liver cancer.As an emerging hallmark of cancers,metabolic reprogramming acts as a runaway mechanism that disrupts homeostasis of the affected organs,including the liver.Specifically,rewiring of the liver metabolic microenvironment,including lipid metabolism,is driven by HCC cells,propelling the phenotypes of HCC cells,including dissemination,invasion,and even metastasis in return.The resulting formation of this vicious loop facilitates various malignant behaviors of HCC further.However,few articles have comprehensively summarized lipid reprogramming in HCC metastasis.Here,we have reviewed the general situation of the liver microenvironment and the physiological lipid metabolism in the liver,and highlighted the effects of different aspects of lipid metabolism on HCC metastasis to explore the underlying mechanisms.In addition,we have recapitulated promising therapeutic strategies targeting lipid metabolism and the effects of lipid metabolic reprogramming on the efficacy of HCC systematical therapy,aiming to offer new perspectives for targeted therapy.

Targeting lysosomes in human disease:from basic research to clinical applications

In recent years,accumulating evidence has elucidated the role of lysosomes in dynamically regulating cellular and organismal homeostasis.Lysosomal changes and dysfunction have been correlated with the development of numerous diseases.In this review,we interpreted the key biological functions of lysosomes in four areas:cellular metabolism,cell proliferation and differentiation,immunity,and cell death.More importantly,we actively sought to determine the characteristic changes and dysfunction of lysosomes in cells affected by these diseases,the causes of these changes and dysfunction,and their significance to the development and treatment of human disease.Furthermore,we outlined currently available targeting strategies:(1)targeting lysosomal acidification;(2)targeting lysosomal cathepsins;(3)targeting lysosomal membrane permeability and integrity;(4)targeting lysosomal calcium signaling;(5)targeting mTOR signaling;and(6)emerging potential targeting strategies.Moreover,we systematically summarized the corresponding drugs and their application in clinical trials.By integrating basic research with clinical findings,we discussed the current opportunities and challenges of targeting lysosomes in human disease.