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.

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.

Surgical treatments of recurrent small intestine metastatic melanoma manifesting with gastrointestinal hemorrhage and intussusception:A case report

BACKGROUND Melanoma is the most aggressive form of skin cancer,with a tendency to metastasize to any organ.Malignant melanoma is the most frequent cause of skin cancer-related deaths worldwide.Small intestine cancers especially small intestine metastases are relatively rare.Small intestine metastases are seldom described and likely underdiagnosed.Intussusception is most common in pediatric age,and in adults are almost 5%of all cases.CASE SUMMARY A 75-year-old man with a history of acral malignant melanoma was admitted to the Gastroenterology Department of our hospital,complaining of intermittent melena for 1 mo.Magnetic resonance enterography showed partial thickening of the jejunal wall and formation of a soft tissue mass,indicating a neoplastic lesion with jejunojejunal intussusception.The patient underwent partial small bowel resection.Pathological findings and immunohistochemical staining indicated small intestine metastatic melanoma.The patient refused further anti-tumor treatment after the surgery.Ten months after the first surgery,the patient presented with melena again.Computed tomography enterography showed the anastomotic stoma was normal without thickening of the intestinal wall,and routine conservative treatment was given.Three months later,the patient developed melena again.The patient underwent a second surgery,and multiple metastatic melanoma lesions were found.The patient refused adjuvant anti-tumor treatment and was alive at the latest follow-up.CONCLUSION Small intestine metastatic melanoma should be suspected in any patient with a history of malignant melanoma and gastrointestinal symptoms.

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.

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.

Combination Therapies for Advanced Biliary Tract Cancer

Biliary tract cancers(BTCs)are a group of malignant neoplasms that have recently increased in incidence and have a poor prognosis.Surgery is the only curative therapy.However,most patients are only indicated for palliative therapy because of advanced-stage disease at diagnosis and rapid progression.The current first-line treatment for advanced BTC is gemcitabine and cisplatin chemotherapy.Nonetheless,many patients develop resistance to this regimen.Over the years,few chemotherapy regimens have managed to improve the overall survival of patients.Accordingly,novel therapies such as targeted therapy have been introduced to treat this patient population.Extensive research on tumorigenesis and the genetic profiling of BTC have revealed the heterogenicity and potential target pathways,such as EGFR,VEGF,MEK/ERK,PI3K and mTOR.Moreover,mutational analysis has documented the presence of IDH1,FGFR2,HER2,PRKACA,PRKACB,BRAF,and KRAS gene aberrations.The emergence of immunotherapy in recent years has expanded the treatment landscape for this group of malignancies.Cancer vaccines,adoptive cell transfer,and immune checkpoint inhibitors have been extensively investigated in trials of BTC.Therefore,patient stratification and a combination of various therapies have become a reasonable and important clinical strategy to improve patient outcomes.This review elaborates the literature on combined treatment strategies for advanced BTC from the past few years and ongoing clinical trials to provide new inspiration for the treatment of advanced BTC.

p53 positively regulates the proliferation of hepatic progenitor cells promoted by laminin-521

Hepatic progenitor cells(HPCs)hold tremendous potential for liver regeneration,but their well-known limitation of proliferation hampers their broader use.There is evidence that laminin is required for the proliferation of HPCs,but the laminin isoform that plays the dominant role and the key intracellular downstream targets that mediate the regulation of HPC proliferation have yet to be determined.Here we showed that p53 expression increased gradually and reached maximal levels around 8 days when lamininα4,α5,β2,β1,andγ1 subunit levels also reached a maximum during HPC activation and expansion.Laminin-521(LN-521)promoted greater proliferation of HPCs than do laminin,matrigel or other laminin isoforms.Inactivation of p53 by PFT-αor Ad-p53^(V143A) inhibited the promotion of proliferation by LN-521.Further complementary MRI and bioluminescence imaging analysis showed that p53 inactivation decreased the proliferation of transplanted HPCs in vivo.p53 was activated by LN-521 through the Integrinα6β1/FAK-Src-Paxillin/Akt axis.Activated p53 was involved in the nuclear translocation of CDK4 and inactivation of Rb by inducing p27^(Kip1).Taken together,this study identifies LN-521 as an ideal candidate substrate for HPC culture and uncovers an unexpected positive role for p53 in regulating proliferation of HPCs,which makes it a potential target for HPC-based regenerative medicine.

Conversion therapy for advanced cholangiocarcinoma in the era of molecular targeted therapy and immune therapy

Cholangiocarcinoma(CCA)encompasses a range of neoplasms,namely intrahepatic CCA,perihilar CCA,and distal CCA,which are distinguished by their anatomical origin.In cases where radical resection of CCA is feasible and the patient’s physical condition permits surgical intervention,it is advisable to proceed with surgical treatment(1).However,the insidious onset of the disease restricts surgical candidacy to only 20-30%of patients(2,3).For those with unresectable CCAs,the recommended initial treatment is gemcitabine plus cisplatin(GemCis)chemotherapy(4).