Objective:Cisplatin-based chemotherapy is a cornerstone for bladder cancer treatment,but the development of resistance remains a major clinical challenge.Curcumol,a bioactive sesquiterpenoid derived from Curcumae Rhiz...Objective:Cisplatin-based chemotherapy is a cornerstone for bladder cancer treatment,but the development of resistance remains a major clinical challenge.Curcumol,a bioactive sesquiterpenoid derived from Curcumae Rhizoma,has shown anti-tumor potential.This study investigated the efficacy of curcumol in overcoming cisplatin resistance and elucidated its underlying molecular mechanisms in bladder cancer progression.Methods:Clinical correlation was assessed in patients receiving neoadjuvant chemotherapy with or without Curcumae Rhizoma.The anti-tumor effects of curcumol were evaluated in both cisplatin-sensitive and cisplatinresistant bladder cancer cells.Multi-omics approaches,including RNA sequencing,proteomics and metabolomics,were employed.Key mechanisms involving H3K9 lactylation(H3K9la)were explored via Western blotting,immunohistochemistry,and cleavage under targets and tagmentation(CUT&Tag)assays.The role of the identified target ORC6 was validated through genetic knockout and overexpression.Finally,ferroptosis was confirmed by measuring lipid peroxidation[malondialdehyde(MDA)],total iron levels,and ferroptosis-related protein markers in vitro.Results:Clinical data indicated that patients administered Curcumae Rhizoma exhibited enhanced responses to neoadjuvant chemotherapy.In addition,curcumol suppressed the proliferation,migration,and invasion of both bladder cancer cells and cisplatin-resistant cells.Mechanistically,proteomic analysis and non-targeted metabolomics revealed that curcumol suppresses glycolysis and lactate production.Subsequently,Western blotting analysis demonstrated a marked reduction in H3K9la levels in both T24 and 5637 cells following curcumol treatment.This decrease in H3K9la was also observed in patient tumor tissues via immunohistochemistry staining.CUT&Tag analysis identified that H3K9la is enriched with the highest number of reads at the ORC6 promoter region.Combined in vitro and in vivo experiments indicated that OCR6 exerted a tumor-promoting effect on bladder cancer.Its knockout induced G0/G1 phase arrest and enhanced apoptosis,while its expression contributed to cancer progression by enhancing invasive and migratory capabilities.Furthermore,ORC6 overexpression correlated with ferroptosis scores and ferroptosis-related genes.In vitro,OCR6 knockout promoted ferroptosis via DNA damage,characterized by elevated MDA content,decreased expression of core ferroptosis-related proteins(GPX4 and SLC7A11),increased percentage ofγH2AX-positive cells and longer DNA tails.Finally,we performed rescue experiments using a ferroptosis inhibitor in ORC6 knockout cells,which indicated that ferroptosis inhibitor could weaken the effect of ORC6 knockout on the invasive,migratory,and proliferative capacities.Conclusions:Our findings demonstrated that curcumol effectively counteracted cisplatin resistance and inhibited bladder cancer progression by targeting the glycolysis-H3K9la-ORC6 axis to induce ferroptosis.This study established a critical link between metabolic reprogramming,histone lactylation,and ferroptosis,providing a novel therapeutic avenue for treating chemoresistant bladder cancer.展开更多
Prostate cancer is the most prevalent malignant tumor among men,ranking first in incidence and second in mortality globally.Novel hormone therapies(NHT)targeting the androgen receptor(AR)pathway have become the standa...Prostate cancer is the most prevalent malignant tumor among men,ranking first in incidence and second in mortality globally.Novel hormone therapies(NHT)targeting the androgen receptor(AR)pathway have become the standard of care for metastatic prostate cancer.This review offers a comprehensive overview of NHT,including abiraterone,enzalutamide,apalutamide,darolutamide,and rezvilutamide,which have demonstrated efficacy in delaying disease progression and improving patient survival and quality of life.Nevertheless,resistance to NHT remains a critical challenge.The mechanisms underlying resistance are complex,involving AR gene amplification,mutations,splice variants,increased intratumoral androgens,and AR-independent pathways such as the glucocorticoid receptor,neuroendocrine differentiation,DNA repair defects,autophagy,immune evasion,and activation of alternative signaling pathways.This review discusses these resistance mechanisms and examines strategies to counteract them,including sequential treatment with novel AR-targeted drugs,chemotherapy,poly ADP-ribose polymerase inhibitors,radionuclide therapy,bipolar androgen therapy,and approaches targeting specific resistance pathways.Future research should prioritize elucidating the molecular basis of NHT resistance,optimizing existing therapeutic strategies,and developing more effective combination regimens.Additionally,advanced sequencing technologies and resistance research models should be leveraged to identify novel therapeutic targets and improve drug delivery efficiencies.These advancements hold the potential to overcome NHT resistance and significantly enhance the management and prognosis of patients with advanced prostate cancer.展开更多
Aging and circadian rhythms have been connected for decades,but their molecular interaction has remained unknown,especially for cancers.In this situation,we summarized the current research actuality and problems in th...Aging and circadian rhythms have been connected for decades,but their molecular interaction has remained unknown,especially for cancers.In this situation,we summarized the current research actuality and problems in this field using the bibliometric analysis.Publications in the PubMed and Web of Science databases were retrieved.Overall,there is a rising trend in the publication volume regarding aging and circadian rhythms in the field of cancer.Researchers from USA,Germany,Italy,China and England have greater studies than others.Top three publication institutions are University of California System,UDICE-French Research Universities and University of Texas System.Current research hotspots include oxidative stress,breast cancer,melatonin,cell cycle,calorie restriction,prostate cancer and NF-κB.In conclusion,results generated by bibliometric analysis indicate that many approaches involve in the complex interactions between aging and circadian rhythm in cancer.These established and emerging research directions guide our exploration of the regulatory mechanisms of aging and circadian rhythms in cancer and provide a reference for developing new research avenues.展开更多
Due to its lower risk of consequences when compared to a radical approach, focal treatment is a viable and minimally invasive option for treating specific localized prostate cancer. Although several recent good nonran...Due to its lower risk of consequences when compared to a radical approach, focal treatment is a viable and minimally invasive option for treating specific localized prostate cancer. Although several recent good nonrandomized trials have suggested that focused therapy may be an alternative choice for some patients, additional high-quality evidence is needed before it can be made widely available as a conventional treatment. As a result, we have summarized the most recent findings from the 38th Annual European Association of Urology Congress, one of the most renowned annual conferences in the area of urology, regarding focal ablation therapy for patients with localized prostate cancer. Additionally, we also provided clinical trials in progress for researchers to better understand the current research status of this field.展开更多
The incre asing interest in RNA modifications has signifcantly advanced epigenomic and epitranscriptomic technologies.This study focuses on the immuno oncological impact of ALYREF in human cancer through a pan-cancer ...The incre asing interest in RNA modifications has signifcantly advanced epigenomic and epitranscriptomic technologies.This study focuses on the immuno oncological impact of ALYREF in human cancer through a pan-cancer analysis,enhancing understanding of this gene's role in cancer.We observed differential ALYREF expression between tumor and normal samples,correl ating strongly with prognosis in various cancers,particularly kidney renal papillary cell carcinoma(KIRP)and liver hepatocellular carcinoma(LIHC).ALYREF showed a negative correlation with most tumor-infitrating cells in lung squamous cell carcinoma(LUSC)and lymphoid neoplasm difuse large B-cell lymphoma(DLBC),while positive correlations were noted in IIHC,kidney chromophobe(KICH),mesothelioma(MESO),KIRP,pheochromocytoma and paraganglioma(PARD),and glioma(GBMLGG).Aditionally,ALYREF expression was closely associated with tumor heterogeneity,stemness indices,and a high mutation rate in TP53 across these cancers.In conclusion,ALYREF may serve as an oncogenic biomarker in numerous cancers,meriting further research attention.展开更多
Introduction Newborns typically acquire microbiota from both their mothers and the surrounding environment,which can eventually reach around 500 g in adulthood(1).Microbiota serves as a historical record of an individ...Introduction Newborns typically acquire microbiota from both their mothers and the surrounding environment,which can eventually reach around 500 g in adulthood(1).Microbiota serves as a historical record of an individual’s life and may also hold a predictive value for their future health(2).Human microbiota is involved in disease occurrence and progression(3,4).展开更多
The intricate relationship between cancer,circadian rhythms,and aging is increasingly recognized as a critical factor in understanding the mechanisms underlying tumorigenesis and cancer progression.Aging is a well-est...The intricate relationship between cancer,circadian rhythms,and aging is increasingly recognized as a critical factor in understanding the mechanisms underlying tumorigenesis and cancer progression.Aging is a well-established primary risk factor for cancer,while disruptions in circadian rhythms are intricately associated with the tumorigenesis and progression of various tumors.Moreover,aging itself disrupts circadian rhythms,leading to physiological changes that may accelerate cancer development.Despite these connections,the specific interplay between these processes and their collective impact on cancer remains inadequately explored in the literature.In this review,we systematically explore the physiological mechanisms of circadian rhythms and their influence on cancer development.We discuss how core circadian genes impact tumor risk and prognosis,highlighting the shared hallmarks of cancer and aging such as genomic instability,cellular senescence,and chronic inflammation.Furthermore,we examine the interplay between circadian rhythms and aging,focusing on how this crosstalk contributes to tumorigenesis,tumor proliferation,and apoptosis,as well as the impact on cellular metabolism and genomic stability.By elucidating the common pathways linking aging,circadian rhythms,and cancer,this review provides new insights into the pathophysiology of cancer and identifies potential therapeutic strategies.We propose that targeting the circadian regulation of cancer hallmarks could pave the way for novel treatments,including chronotherapy and antiaging interventions,which may offer important benefits in the clinical management of cancer.展开更多
Prostate cancer(PCa)is considered as an age-related disease and accounts for the most prevalence of urinary malignancies in men.1 We previously analyzed the cellular landscape of tumor microenvironment in PCa patients...Prostate cancer(PCa)is considered as an age-related disease and accounts for the most prevalence of urinary malignancies in men.1 We previously analyzed the cellular landscape of tumor microenvironment in PCa patients,where we found that cancer-related fibroblasts might play an important role in tumorigenesis and the development of PCa and tumor-associated macrophage(TAM)could function synergistically with them.2 Thus,we further integrated single-cell and bulk RNA sequencing with meta-analysis to specify the prognostic effect of TAM on PCa and construct molecular subgroups and predictive index to guide clinical practice.展开更多
基金supports of Science and Technology Plan Basic Project of Guizhou Province(No.ZK[2022]General 446)the Natural Science Fundation of Zhejiang Province(No.Q24H160134)+4 种基金Science and Technology Project of Zhejiang Health Commission(No.2024660542)Clinical Research Plan for TCM of Administration of Traditional Chinese Medicine of Zhejiang Province(No.2025075369)Bijie City Science and Technology Plan Project(No.[2025]No.60)National Health Commission of the People’s Republic of China-Zhejiang Province Jointly Constructed ProjectZhejiang Province Medical and Health Science and Technology Plan(No.WKJ-ZJ-2517)。
文摘Objective:Cisplatin-based chemotherapy is a cornerstone for bladder cancer treatment,but the development of resistance remains a major clinical challenge.Curcumol,a bioactive sesquiterpenoid derived from Curcumae Rhizoma,has shown anti-tumor potential.This study investigated the efficacy of curcumol in overcoming cisplatin resistance and elucidated its underlying molecular mechanisms in bladder cancer progression.Methods:Clinical correlation was assessed in patients receiving neoadjuvant chemotherapy with or without Curcumae Rhizoma.The anti-tumor effects of curcumol were evaluated in both cisplatin-sensitive and cisplatinresistant bladder cancer cells.Multi-omics approaches,including RNA sequencing,proteomics and metabolomics,were employed.Key mechanisms involving H3K9 lactylation(H3K9la)were explored via Western blotting,immunohistochemistry,and cleavage under targets and tagmentation(CUT&Tag)assays.The role of the identified target ORC6 was validated through genetic knockout and overexpression.Finally,ferroptosis was confirmed by measuring lipid peroxidation[malondialdehyde(MDA)],total iron levels,and ferroptosis-related protein markers in vitro.Results:Clinical data indicated that patients administered Curcumae Rhizoma exhibited enhanced responses to neoadjuvant chemotherapy.In addition,curcumol suppressed the proliferation,migration,and invasion of both bladder cancer cells and cisplatin-resistant cells.Mechanistically,proteomic analysis and non-targeted metabolomics revealed that curcumol suppresses glycolysis and lactate production.Subsequently,Western blotting analysis demonstrated a marked reduction in H3K9la levels in both T24 and 5637 cells following curcumol treatment.This decrease in H3K9la was also observed in patient tumor tissues via immunohistochemistry staining.CUT&Tag analysis identified that H3K9la is enriched with the highest number of reads at the ORC6 promoter region.Combined in vitro and in vivo experiments indicated that OCR6 exerted a tumor-promoting effect on bladder cancer.Its knockout induced G0/G1 phase arrest and enhanced apoptosis,while its expression contributed to cancer progression by enhancing invasive and migratory capabilities.Furthermore,ORC6 overexpression correlated with ferroptosis scores and ferroptosis-related genes.In vitro,OCR6 knockout promoted ferroptosis via DNA damage,characterized by elevated MDA content,decreased expression of core ferroptosis-related proteins(GPX4 and SLC7A11),increased percentage ofγH2AX-positive cells and longer DNA tails.Finally,we performed rescue experiments using a ferroptosis inhibitor in ORC6 knockout cells,which indicated that ferroptosis inhibitor could weaken the effect of ORC6 knockout on the invasive,migratory,and proliferative capacities.Conclusions:Our findings demonstrated that curcumol effectively counteracted cisplatin resistance and inhibited bladder cancer progression by targeting the glycolysis-H3K9la-ORC6 axis to induce ferroptosis.This study established a critical link between metabolic reprogramming,histone lactylation,and ferroptosis,providing a novel therapeutic avenue for treating chemoresistant bladder cancer.
文摘Prostate cancer is the most prevalent malignant tumor among men,ranking first in incidence and second in mortality globally.Novel hormone therapies(NHT)targeting the androgen receptor(AR)pathway have become the standard of care for metastatic prostate cancer.This review offers a comprehensive overview of NHT,including abiraterone,enzalutamide,apalutamide,darolutamide,and rezvilutamide,which have demonstrated efficacy in delaying disease progression and improving patient survival and quality of life.Nevertheless,resistance to NHT remains a critical challenge.The mechanisms underlying resistance are complex,involving AR gene amplification,mutations,splice variants,increased intratumoral androgens,and AR-independent pathways such as the glucocorticoid receptor,neuroendocrine differentiation,DNA repair defects,autophagy,immune evasion,and activation of alternative signaling pathways.This review discusses these resistance mechanisms and examines strategies to counteract them,including sequential treatment with novel AR-targeted drugs,chemotherapy,poly ADP-ribose polymerase inhibitors,radionuclide therapy,bipolar androgen therapy,and approaches targeting specific resistance pathways.Future research should prioritize elucidating the molecular basis of NHT resistance,optimizing existing therapeutic strategies,and developing more effective combination regimens.Additionally,advanced sequencing technologies and resistance research models should be leveraged to identify novel therapeutic targets and improve drug delivery efficiencies.These advancements hold the potential to overcome NHT resistance and significantly enhance the management and prognosis of patients with advanced prostate cancer.
基金supported by the Chinese Scholarship Council(No.202206240086)Zhejiang Province Public Welfare Technology Application Research Project in China(No.TGY23H160090 and No.LGF21H160029)+1 种基金Taizhou Science and Technology Project,Zhejiang Province(No.20ywb12)Program for Talents of Chongqing University Three Gorges Hospital(No.2022YJKYXM-036).
文摘Aging and circadian rhythms have been connected for decades,but their molecular interaction has remained unknown,especially for cancers.In this situation,we summarized the current research actuality and problems in this field using the bibliometric analysis.Publications in the PubMed and Web of Science databases were retrieved.Overall,there is a rising trend in the publication volume regarding aging and circadian rhythms in the field of cancer.Researchers from USA,Germany,Italy,China and England have greater studies than others.Top three publication institutions are University of California System,UDICE-French Research Universities and University of Texas System.Current research hotspots include oxidative stress,breast cancer,melatonin,cell cycle,calorie restriction,prostate cancer and NF-κB.In conclusion,results generated by bibliometric analysis indicate that many approaches involve in the complex interactions between aging and circadian rhythm in cancer.These established and emerging research directions guide our exploration of the regulatory mechanisms of aging and circadian rhythms in cancer and provide a reference for developing new research avenues.
基金supported by the Luzhou City Science and Technology Bureau (No.2020LZXNYDJ10 and 2020LZXNYDJ14)Cooperation Project between the Second People’s Hospital of Deyang and Southwest Medical University (No.2022DYEXNYD002)。
文摘Due to its lower risk of consequences when compared to a radical approach, focal treatment is a viable and minimally invasive option for treating specific localized prostate cancer. Although several recent good nonrandomized trials have suggested that focused therapy may be an alternative choice for some patients, additional high-quality evidence is needed before it can be made widely available as a conventional treatment. As a result, we have summarized the most recent findings from the 38th Annual European Association of Urology Congress, one of the most renowned annual conferences in the area of urology, regarding focal ablation therapy for patients with localized prostate cancer. Additionally, we also provided clinical trials in progress for researchers to better understand the current research status of this field.
基金the Chinese Scholarship Council(Grant No.202206240086)the National Natural Science Foundation of China(Grant No.82170432)programs from Science and Technology Department of Sichuan Province(Grant No.2020YFSY0024).
文摘The incre asing interest in RNA modifications has signifcantly advanced epigenomic and epitranscriptomic technologies.This study focuses on the immuno oncological impact of ALYREF in human cancer through a pan-cancer analysis,enhancing understanding of this gene's role in cancer.We observed differential ALYREF expression between tumor and normal samples,correl ating strongly with prognosis in various cancers,particularly kidney renal papillary cell carcinoma(KIRP)and liver hepatocellular carcinoma(LIHC).ALYREF showed a negative correlation with most tumor-infitrating cells in lung squamous cell carcinoma(LUSC)and lymphoid neoplasm difuse large B-cell lymphoma(DLBC),while positive correlations were noted in IIHC,kidney chromophobe(KICH),mesothelioma(MESO),KIRP,pheochromocytoma and paraganglioma(PARD),and glioma(GBMLGG).Aditionally,ALYREF expression was closely associated with tumor heterogeneity,stemness indices,and a high mutation rate in TP53 across these cancers.In conclusion,ALYREF may serve as an oncogenic biomarker in numerous cancers,meriting further research attention.
基金supported by Chinese Scholarship Council(No.202206240086)。
文摘Introduction Newborns typically acquire microbiota from both their mothers and the surrounding environment,which can eventually reach around 500 g in adulthood(1).Microbiota serves as a historical record of an individual’s life and may also hold a predictive value for their future health(2).Human microbiota is involved in disease occurrence and progression(3,4).
基金supported by the Chinese Scholarship Council(grant no.202206240086)a regional innovation cooperation project of Sichuan Province(grant no.23QYCX0136)。
文摘The intricate relationship between cancer,circadian rhythms,and aging is increasingly recognized as a critical factor in understanding the mechanisms underlying tumorigenesis and cancer progression.Aging is a well-established primary risk factor for cancer,while disruptions in circadian rhythms are intricately associated with the tumorigenesis and progression of various tumors.Moreover,aging itself disrupts circadian rhythms,leading to physiological changes that may accelerate cancer development.Despite these connections,the specific interplay between these processes and their collective impact on cancer remains inadequately explored in the literature.In this review,we systematically explore the physiological mechanisms of circadian rhythms and their influence on cancer development.We discuss how core circadian genes impact tumor risk and prognosis,highlighting the shared hallmarks of cancer and aging such as genomic instability,cellular senescence,and chronic inflammation.Furthermore,we examine the interplay between circadian rhythms and aging,focusing on how this crosstalk contributes to tumorigenesis,tumor proliferation,and apoptosis,as well as the impact on cellular metabolism and genomic stability.By elucidating the common pathways linking aging,circadian rhythms,and cancer,this review provides new insights into the pathophysiology of cancer and identifies potential therapeutic strategies.We propose that targeting the circadian regulation of cancer hallmarks could pave the way for novel treatments,including chronotherapy and antiaging interventions,which may offer important benefits in the clinical management of cancer.
文摘Prostate cancer(PCa)is considered as an age-related disease and accounts for the most prevalence of urinary malignancies in men.1 We previously analyzed the cellular landscape of tumor microenvironment in PCa patients,where we found that cancer-related fibroblasts might play an important role in tumorigenesis and the development of PCa and tumor-associated macrophage(TAM)could function synergistically with them.2 Thus,we further integrated single-cell and bulk RNA sequencing with meta-analysis to specify the prognostic effect of TAM on PCa and construct molecular subgroups and predictive index to guide clinical practice.
