Dear Editor,Metastasis leads to a poor prognosis of patients with esophageal squamous cell carcinoma(ESCC).1-3 but the study on cancer metastasis has been hampered by a lack of reliable cell and animal models.Systemat...Dear Editor,Metastasis leads to a poor prognosis of patients with esophageal squamous cell carcinoma(ESCC).1-3 but the study on cancer metastasis has been hampered by a lack of reliable cell and animal models.Systematic identification and functional validation of metastasis-associated long non-coding RNAs(lncRNAs)and microRNAs(miRNAs),as well as-their interactions in ESCC are urgently needed.展开更多
Esophageal cancer(EC)is one of the most lethal cancers in the world,and its morbidity and mortality rates rank among the top ten in China.Currently,surgical resection,radiotherapy and chemotherapy are the primary clin...Esophageal cancer(EC)is one of the most lethal cancers in the world,and its morbidity and mortality rates rank among the top ten in China.Currently,surgical resection,radiotherapy and chemotherapy are the primary clinical treatments for esophageal cancer.However,outcomes are still unsatisfactory due to the limited efficacy and severe adverse effects of conventional treatments.As a new type of approach,targeted therapies have been confirmed to play an important role in the treatment of esophageal cancer;these include cetuximab and bevacizumab,which target epidermal growth factor receptor(EGFR)and vascular endothelial growth factor(VEGF),respectively.In addition,other drugs targeting surface antigens and signaling pathways or acting on immune checkpoints have been continuously developed.For example,trastuzumab,a monoclonal antibody targeting human epidermal growth factor receptor 2(HER-2),has been approved by the Food and Drug Administration(FDA)as a first-line treatment of HER-2-positive cancer.Moreover,the PD-L1 inhibitor pembrolizumab has been approved as a highly efficient drug for patients with PD-L1-positive or advanced esophageal squamous cell carcinoma(ESCC).These novel drugs can be used alone or in combination with other treatment strategies to further improve the treatment efficacy and prognosis of cancer patients.Nevertheless,adverse events,optimal dosages and effective combinations still need further investigation.In this review,we expound an outline of the latest advances in targeted therapies of esophageal cancer and the mechanisms of relevant drugs,discuss their efficacy and safety,and provide a clinical rationale for precision medicine in esophageal cancer.展开更多
The latent infection by herpes virus type 1(HSV-1)may be lifelong in trigeminal ganglia and a suspected cause of Alzheimer's Disease(AD)and Amyotrophic lateral sclerosis(ALS).Whether and how N6-methyladenosine(m6A...The latent infection by herpes virus type 1(HSV-1)may be lifelong in trigeminal ganglia and a suspected cause of Alzheimer's Disease(AD)and Amyotrophic lateral sclerosis(ALS).Whether and how N6-methyladenosine(m6A)modification of viral RNAs affects virus infection are poorly understood.Here,we report that HSV-1 infection enhanced the expression of m6A writers(METTL3,METTL14)and readers(YTHDF1/2/3)at the early infection stage and decreased their expression later on,while suppressed the erasers'(FTO,ALBKH5)expression immediately upon infection to facilitate viral replication.Inhibiting m6A modification by 3-deazaadenosine(DAA)significantly decreased viral replication and reduced viral reproduction over 1000 folds.More interestingly,depleting the writers and readers by siRNAs inhibited virus replication and reproduction;whereas depleting the erasers promoted viral replication and reproduction.Silencing YTHDF3 strikingly decreased viral replication by up to 90%,leading to reduction of up to 10-fold viral replication and over 100-fold virus reproduction,respectively.Depletion of m6A initiator METTL3(by 60%–70%)by siRNA correlatedly decreased viral replication 60%–70%,and reduced virus yield over 30-fold.Consistently,ectopic expression of METTL3 largely increased virus yield.METTL3 knockdown suppressed the HSV-1 intermediate early and early genes(ICP0,ICP8 and UL23)and late genes(VP16,UL44,UL49 and ICP47);while ectopic expression of METTL3 upregulated these gene expression.Results from our study shed the lights on the importance for m6A modification to initiate HSV-1 early replication.The components of m6A modification machinery,particularly m6A initiator METTL3 and reader YTHDF3,would be potential important targets for combating HSV-1 infections.展开更多
The phosphatidylinositol 3-kinase(PI3K)/Akt pathway plays a crucial role in various cellular processes and is aberrantly activated in cancers,contributing to the occurrenee and progression of tumors.Examining the upst...The phosphatidylinositol 3-kinase(PI3K)/Akt pathway plays a crucial role in various cellular processes and is aberrantly activated in cancers,contributing to the occurrenee and progression of tumors.Examining the upstream and downstream nodes of this pathway could allow full elucidation of its function.Based on accumulating evidenee,strategies targeting major components of the pathway might provide new in sights for can cer drug discovery.Researchers have explored the use of some in hibitors targeti ng this pathway to block survival pathways.However,because oncogenic PI3K pathway activation occurs through various mechanisms,the clinical efficacies of these inhibitors are limited.Moreover,pathway activation is accompanied by the development of therapeutic resista nee.Therefore,strategies involvi ng pathway in hibitors and other can cer treatments in combinati on might solve the therapeutic dilemma.In this review,we discuss the roles of the PI3K/Akt pathway in various cancer phenotypes,review the current statuses of different PI3K/Akt in hibitors,and in troduce combi nation therapies con sisti ng of signaling in hibitors and conven tional cancer therapies.The information presented herein suggests that cascading inhibitors of the PI3K/Akt signaling pathway,either alone or in combi nation with other therapies,are the most effective treatment strategy for can cer.展开更多
基金supported by National Natural Science Foundation of China(Project Nos.82073196,81773085,31961160727,81803551,81973339)Guangdong Natural Science Research Grant(2021 Al 31157080)+4 种基金Guangdong Innovative and Entrepreneurial Research Team Program(Project No.2013Y113)Guangzhou Science and Technology Project(201904010061)Zhuhai Innovative and Entrepreneurial Research Team Program(Project No.ZH01110405160015PWC)National Key R&D Program of China(2017YFA0505100)the Fundamental Research Funds for the Central Universities(21620429).
文摘Dear Editor,Metastasis leads to a poor prognosis of patients with esophageal squamous cell carcinoma(ESCC).1-3 but the study on cancer metastasis has been hampered by a lack of reliable cell and animal models.Systematic identification and functional validation of metastasis-associated long non-coding RNAs(lncRNAs)and microRNAs(miRNAs),as well as-their interactions in ESCC are urgently needed.
基金supported by the National Key Research and Development Program of China(2017YFA0505100)the National Natural Science Foundation of China(81973339,31961160727,81803551,31770888,81773085,81672953,31570828)the Fundamental Research Funds for the Central Universities(21620429).
文摘Esophageal cancer(EC)is one of the most lethal cancers in the world,and its morbidity and mortality rates rank among the top ten in China.Currently,surgical resection,radiotherapy and chemotherapy are the primary clinical treatments for esophageal cancer.However,outcomes are still unsatisfactory due to the limited efficacy and severe adverse effects of conventional treatments.As a new type of approach,targeted therapies have been confirmed to play an important role in the treatment of esophageal cancer;these include cetuximab and bevacizumab,which target epidermal growth factor receptor(EGFR)and vascular endothelial growth factor(VEGF),respectively.In addition,other drugs targeting surface antigens and signaling pathways or acting on immune checkpoints have been continuously developed.For example,trastuzumab,a monoclonal antibody targeting human epidermal growth factor receptor 2(HER-2),has been approved by the Food and Drug Administration(FDA)as a first-line treatment of HER-2-positive cancer.Moreover,the PD-L1 inhibitor pembrolizumab has been approved as a highly efficient drug for patients with PD-L1-positive or advanced esophageal squamous cell carcinoma(ESCC).These novel drugs can be used alone or in combination with other treatment strategies to further improve the treatment efficacy and prognosis of cancer patients.Nevertheless,adverse events,optimal dosages and effective combinations still need further investigation.In this review,we expound an outline of the latest advances in targeted therapies of esophageal cancer and the mechanisms of relevant drugs,discuss their efficacy and safety,and provide a clinical rationale for precision medicine in esophageal cancer.
基金This work was supported by grants from National Science Foundation of China(No.81671995)The Science Technology and Innovation Committee of Shenzhen Municipality(No.JCYJ20180507181627057)and Strategic funds from City University of Hong Kong.
文摘The latent infection by herpes virus type 1(HSV-1)may be lifelong in trigeminal ganglia and a suspected cause of Alzheimer's Disease(AD)and Amyotrophic lateral sclerosis(ALS).Whether and how N6-methyladenosine(m6A)modification of viral RNAs affects virus infection are poorly understood.Here,we report that HSV-1 infection enhanced the expression of m6A writers(METTL3,METTL14)and readers(YTHDF1/2/3)at the early infection stage and decreased their expression later on,while suppressed the erasers'(FTO,ALBKH5)expression immediately upon infection to facilitate viral replication.Inhibiting m6A modification by 3-deazaadenosine(DAA)significantly decreased viral replication and reduced viral reproduction over 1000 folds.More interestingly,depleting the writers and readers by siRNAs inhibited virus replication and reproduction;whereas depleting the erasers promoted viral replication and reproduction.Silencing YTHDF3 strikingly decreased viral replication by up to 90%,leading to reduction of up to 10-fold viral replication and over 100-fold virus reproduction,respectively.Depletion of m6A initiator METTL3(by 60%–70%)by siRNA correlatedly decreased viral replication 60%–70%,and reduced virus yield over 30-fold.Consistently,ectopic expression of METTL3 largely increased virus yield.METTL3 knockdown suppressed the HSV-1 intermediate early and early genes(ICP0,ICP8 and UL23)and late genes(VP16,UL44,UL49 and ICP47);while ectopic expression of METTL3 upregulated these gene expression.Results from our study shed the lights on the importance for m6A modification to initiate HSV-1 early replication.The components of m6A modification machinery,particularly m6A initiator METTL3 and reader YTHDF3,would be potential important targets for combating HSV-1 infections.
基金The current work was supported by the National Natural Science Foundation of China(Project nos.31961160727,81773085,82073196,81973339,81873455 and 81803551)the Guangdong Natural Science Research Grant(No.2021A1515011158)the Fundamental Research Funds for the Central Universities(No.21620429).
文摘The phosphatidylinositol 3-kinase(PI3K)/Akt pathway plays a crucial role in various cellular processes and is aberrantly activated in cancers,contributing to the occurrenee and progression of tumors.Examining the upstream and downstream nodes of this pathway could allow full elucidation of its function.Based on accumulating evidenee,strategies targeting major components of the pathway might provide new in sights for can cer drug discovery.Researchers have explored the use of some in hibitors targeti ng this pathway to block survival pathways.However,because oncogenic PI3K pathway activation occurs through various mechanisms,the clinical efficacies of these inhibitors are limited.Moreover,pathway activation is accompanied by the development of therapeutic resista nee.Therefore,strategies involvi ng pathway in hibitors and other can cer treatments in combinati on might solve the therapeutic dilemma.In this review,we discuss the roles of the PI3K/Akt pathway in various cancer phenotypes,review the current statuses of different PI3K/Akt in hibitors,and in troduce combi nation therapies con sisti ng of signaling in hibitors and conven tional cancer therapies.The information presented herein suggests that cascading inhibitors of the PI3K/Akt signaling pathway,either alone or in combi nation with other therapies,are the most effective treatment strategy for can cer.