Objective:Lung cancer is the most common cause of cancer-related deaths worldwide.Somatic copy number alterations(SCNAs)have been used to predict responses to therapies in many cancers,including lung cancer.However,li...Objective:Lung cancer is the most common cause of cancer-related deaths worldwide.Somatic copy number alterations(SCNAs)have been used to predict responses to therapies in many cancers,including lung cancer.However,little is known about whether they are predictive of radiotherapy outcomes.We aimed to understand the prognostic value and biological functions of SCNAs.Methods:We analyzed the correlation between SCNAs and clinical outcomes in The Cancer Genome Atlas data for 486 patients with non-small cell lung cancer who received radiotherapy.Gene set enrichment analyses were performed to investigate the potential mechanisms underlying the roles of SCNAs in the radiotherapy response.Our results were validated in 20 patients with lung adenocarcinoma(LUAD)receiving radiotherapy.Results:SCNAs were a better predictor of progression-free survival(PFS)in LUAD(P=0.024)than in lung squamous carcinoma(P=0.18)in patients treated with radiotherapy.Univariate and multivariate regression analyses revealed the superiority of SCNAs in predicting PFS in patients with LUAD.Patients with stage I cancer and low SCNA levels had longer PFS than those with high SCNA levels(P=0.022).Our prognostic nomogram also showed that combining SCNAs and tumor/node/metastasis provided a better model for predicting long-term PFS.Additionally,high SCNA may activate the cell cycle pathway and induce tumorigenesis.Conclusions:SCNAs may be used to predict PFS in patients with early-stage LUAD with radiotherapy,in combination with TNM,with the aim of predicting long-term PFS.Therefore,SCNAs are a novel predictive biomarker for radiotherapy in patients with LUAD.展开更多
Cancer stem cells(CSCs)play a pivotal role in tumor initiation,proliferation,metastasis,drug resistance,and recurrence.Consequently,targeting CSCs has emerged as a promising avenue for cancer therapy.Recently,3-phosph...Cancer stem cells(CSCs)play a pivotal role in tumor initiation,proliferation,metastasis,drug resistance,and recurrence.Consequently,targeting CSCs has emerged as a promising avenue for cancer therapy.Recently,3-phosphoglycerate dehydrogenase(PHGDH)has been identified as being intricately associated with the regulation of numerous cancer stem cells.Yet,reports detailing the functional regulators of PHGDH that can mitigate the stemness across cancer types are limited.In this study,the novel“molecular glue”LXH-3-71 was identified,and it robustly induced degradation of PHGDH,thereby modulating the stemness of colorectal cancer cells(CRCs)both in vitro and in vivo.Remarkably,LXH-3-71 was observed to form a dynamic chimera,between PHGDH and the DDB1-CRL E3 ligase.These insights not only elucidate the anti-CSCs mechanism of the lead compound but also suggest that degradation of PHGDH may be a more viable therapeutic strategy than the development of PHGDH inhibitors.Additionally,compound LXH-3-71 was leveraged as a novel ligand for the DDB1-CRL E3 ligase,facilitating the development of new PROTAC molecules targeting EGFR and CDK4 degradation.展开更多
Platinum-based chemotherapy resistance is a key factor of poor prognosis and recurrence in hepatocellular carcinoma(HCC).Herein,RNAseq analysis revealed that elevated tubulin folding cofactor E(TBCE)expression is asso...Platinum-based chemotherapy resistance is a key factor of poor prognosis and recurrence in hepatocellular carcinoma(HCC).Herein,RNAseq analysis revealed that elevated tubulin folding cofactor E(TBCE)expression is associated with platinum-based chemotherapy resistance.High expression of TBCE contributes to worse prognoses and earlier recurrence among liver cancer patients.Mechanistically,TBCE silencing significantly affects cytoskeleton rearrangement,which in turn increases cisplatin-induced cycle arrest and apoptosis.To develop these findings into potential therapeutic drugs,endosomal pH-responsive nanoparticles(NPs)were developed to simultaneously encapsulate TBCE siRNA and cisplatin(DDP)to reverse this phenomena.NPs(siTBCE+DDP)concurrently silenced TBCE expression,increased cell sensitivity to platinum treatment,and subsequently resulted in superior anti-tumor effects both in vitro and in vivo in orthotopic and patient-derived xenograft(PDX)models.Taken together,NP-mediated delivery and the co-treatment of siTBCE+DDP proved to be effective in reversing chemotherapy resistance of DDP in multiple tumor models.展开更多
基金This work was supported by grants from the National Key Technology R&D Program(Grant No.2018YFC1313400)National Natural Science Foundation of China(Grant No.81974246)+1 种基金Scientific Research Program of Tianjin Education Commission(Grant No.2019KJ185)Tianjin Research Innovation Project(Grant No.2020YJSB164)for postgraduate students.
文摘Objective:Lung cancer is the most common cause of cancer-related deaths worldwide.Somatic copy number alterations(SCNAs)have been used to predict responses to therapies in many cancers,including lung cancer.However,little is known about whether they are predictive of radiotherapy outcomes.We aimed to understand the prognostic value and biological functions of SCNAs.Methods:We analyzed the correlation between SCNAs and clinical outcomes in The Cancer Genome Atlas data for 486 patients with non-small cell lung cancer who received radiotherapy.Gene set enrichment analyses were performed to investigate the potential mechanisms underlying the roles of SCNAs in the radiotherapy response.Our results were validated in 20 patients with lung adenocarcinoma(LUAD)receiving radiotherapy.Results:SCNAs were a better predictor of progression-free survival(PFS)in LUAD(P=0.024)than in lung squamous carcinoma(P=0.18)in patients treated with radiotherapy.Univariate and multivariate regression analyses revealed the superiority of SCNAs in predicting PFS in patients with LUAD.Patients with stage I cancer and low SCNA levels had longer PFS than those with high SCNA levels(P=0.022).Our prognostic nomogram also showed that combining SCNAs and tumor/node/metastasis provided a better model for predicting long-term PFS.Additionally,high SCNA may activate the cell cycle pathway and induce tumorigenesis.Conclusions:SCNAs may be used to predict PFS in patients with early-stage LUAD with radiotherapy,in combination with TNM,with the aim of predicting long-term PFS.Therefore,SCNAs are a novel predictive biomarker for radiotherapy in patients with LUAD.
基金the National Natural Science Foundation of China(NSFC,No.82003186,82073691 and 82373134)the International Science and Technology Cooperation Project of China(No.2022YFE0133300)+3 种基金Ningbo Science and Technology Bureau under CM2025 Programme(2020Z092,China)Shenzhen Science and Technology Foundation(JCYJ20210324122006017,China)Tianjin Natural Science Fund(21JCQNJC01910,China)China Postdoctoral Science Foundation e Tianjin Joint Support Program(No.2023T029TJ).
文摘Cancer stem cells(CSCs)play a pivotal role in tumor initiation,proliferation,metastasis,drug resistance,and recurrence.Consequently,targeting CSCs has emerged as a promising avenue for cancer therapy.Recently,3-phosphoglycerate dehydrogenase(PHGDH)has been identified as being intricately associated with the regulation of numerous cancer stem cells.Yet,reports detailing the functional regulators of PHGDH that can mitigate the stemness across cancer types are limited.In this study,the novel“molecular glue”LXH-3-71 was identified,and it robustly induced degradation of PHGDH,thereby modulating the stemness of colorectal cancer cells(CRCs)both in vitro and in vivo.Remarkably,LXH-3-71 was observed to form a dynamic chimera,between PHGDH and the DDB1-CRL E3 ligase.These insights not only elucidate the anti-CSCs mechanism of the lead compound but also suggest that degradation of PHGDH may be a more viable therapeutic strategy than the development of PHGDH inhibitors.Additionally,compound LXH-3-71 was leveraged as a novel ligand for the DDB1-CRL E3 ligase,facilitating the development of new PROTAC molecules targeting EGFR and CDK4 degradation.
基金supported by grants from the National Natural Science Foundation of China (81874226 and 81803020)the “Three Million for Three Years” Project of the High-Level Talent Special Funding Scheme of Sun Yat-sen Memorial Hospitalthe Guangdong Natural Science Foundation (2016A030313834and 2017A030313871,China)
文摘Platinum-based chemotherapy resistance is a key factor of poor prognosis and recurrence in hepatocellular carcinoma(HCC).Herein,RNAseq analysis revealed that elevated tubulin folding cofactor E(TBCE)expression is associated with platinum-based chemotherapy resistance.High expression of TBCE contributes to worse prognoses and earlier recurrence among liver cancer patients.Mechanistically,TBCE silencing significantly affects cytoskeleton rearrangement,which in turn increases cisplatin-induced cycle arrest and apoptosis.To develop these findings into potential therapeutic drugs,endosomal pH-responsive nanoparticles(NPs)were developed to simultaneously encapsulate TBCE siRNA and cisplatin(DDP)to reverse this phenomena.NPs(siTBCE+DDP)concurrently silenced TBCE expression,increased cell sensitivity to platinum treatment,and subsequently resulted in superior anti-tumor effects both in vitro and in vivo in orthotopic and patient-derived xenograft(PDX)models.Taken together,NP-mediated delivery and the co-treatment of siTBCE+DDP proved to be effective in reversing chemotherapy resistance of DDP in multiple tumor models.
