Objective:Previous studies have demonstrated that the metals cadmium and arsenic exhibit estrogen-like effects and may influence the occurrence and development of gynecological tumors.This study aims to explore the as...Objective:Previous studies have demonstrated that the metals cadmium and arsenic exhibit estrogen-like effects and may influence the occurrence and development of gynecological tumors.This study aims to explore the association between urinary cadmium and arsenic levels and the prevalence of gynecologic cancers using data from the National Health and Nutrition Examination Survey(NHANES).Methods:Data from female participants in NHANES 2003—2018 were analyzed.Using R software,datasets(DEMO,BMX,etc.)were merged,and complete cases were retained by intersecting row names,yielding a total of 2999 participants.After applying strict exclusion criteria,2802 participants were included:83 with gynecologic cancer(cancer group)and 2719 without(control group).Demographic,reproductive health,and urinary cadmium and arsenic data were collected.Binary Logistic regression models were employed to assess associations between urinary cadmium and arsenic levels and gynecologic cancer risk.Results:High urinary cadmium and arsenic levels were risk factors for gynecologic cancers,with odds ratios(ORs)of 1.623(95%CI 1.217 to 2.166)and 1.003(95%CI 1.001 to 1.005),respectively.After propensity score matching(PSM),the trend remained;cadmium was still a statistically significant risk factor with an OR of 2.182(95%CI 1.343 to 3.545),while arsenic’s association,though not statistically significant,still trended toward risk(OR=1.004,95%CI 0.999 to 1.009).Subgroup analyses showed that both cadmium and arsenic were risk factors for ovarian cancer(OR=1.745,95%CI 1.178 to 2.586 and OR=1.005,95%CI 1.002 to 1.008,respectively);these associations persisted after PSM.Additionally,cadmium increased the risk of endometrial cancer(OR=1.617,95%CI 1.109 to 2.356).Conclusion:Exposure to cadmium and arsenic is associated with an increased risk of ovarian and endometrial cancers.These findings suggest that reducing environmental exposure to heavy metals such as cadmium and arsenic may help prevent certain gynecologic cancers.展开更多
Objective:Ovarian cancer(OC)ranks among the leading causes of mortality among the female cancers worldwide.Numerous studies have explored the development and progression of OC at multiple genetic regulatory levels.How...Objective:Ovarian cancer(OC)ranks among the leading causes of mortality among the female cancers worldwide.Numerous studies have explored the development and progression of OC at multiple genetic regulatory levels.However,relatively few studies have explored the impact of post-translational modifications(PTM)on OC progression,which is essential for uncovering new therapeutic targets.This study aimed to systematically identify the key PTM types involved in OCprogression,and to explore and evaluate their translational potential as therapeutic targets.Methods:First,we utilized multiple general PTM antibodies to compare gross PTM levels between normal ovarian and OC tissues from clinical females.After identifying lactylation as the PTM with the most significant differences,we selected representative samples for label-free mass spectrometry to identify specific lactylation sites.Next,we transfected A2780(OC)cells with either wild-type(WT)or mutant(K192A[Q])poly(ADP-ribose)polymerase 1(PARP1)conjugated to enhanced green fluorescent protein(EGFP)with a StrepⅡpeptide tag and assessed various cellular indexes related to cell proliferation(clonogenicity assay),migration(scratch wound healing assay),and reactive oxygen species levels.Results:Pan-lactylation was significantly upregulated in clinical OC samples,with PARP1 lactylation at K192 being one of the most common modifications.The growth and migration of A2780 cells were markedly suppressed by overexpressing PARP1-WT but not mutant PARP1.Overexpressing PARP1 significantly downregulated the phosphorylation of extracellular signal-regulated kinases 1/2(ERK1/2).Conclusion:This study uncovered a novel PTM of PARP1 in OC,lactylation,and demonstrated that lactylation at K192 is crucial in regulating OC cell growth and migration via the ERK1/2 pathway.Further investigations are required to elucidate the broader functional implications of PARP1 lactylation and its therapeutic potential.展开更多
Cancer Biology&Medicine作为肿瘤领域学术交流的平台,向国际学术界展示中国肿瘤防治研究成果,向国内肿瘤学相关专业人员介绍全球肿瘤学前沿进展。以肿瘤临床医师、基础研究人员、相关交叉学科专业人员及医学生为读者对象。刊登稿...Cancer Biology&Medicine作为肿瘤领域学术交流的平台,向国际学术界展示中国肿瘤防治研究成果,向国内肿瘤学相关专业人员介绍全球肿瘤学前沿进展。以肿瘤临床医师、基础研究人员、相关交叉学科专业人员及医学生为读者对象。刊登稿件范畴:肿瘤表观遗传学、肿瘤干细胞生物学、分子与临床免疫学、肿瘤预防与流行病学、肿瘤标志物、肿瘤影像学、肿瘤临床试验、肿瘤靶向治疗、肿瘤生物治疗、肿瘤个体化医学与多学科综合治疗。展开更多
Objective:Oxaliplatin(OXA)and 5-fluorouracil(5-FU)are 2 commonly used chemotherapeutic agents for colorectal cancer(CRC).MicroRNAs(miRNAs,miRs)play crucial roles in the development of chemoresistance in various cancer...Objective:Oxaliplatin(OXA)and 5-fluorouracil(5-FU)are 2 commonly used chemotherapeutic agents for colorectal cancer(CRC).MicroRNAs(miRNAs,miRs)play crucial roles in the development of chemoresistance in various cancers.However,the role and mechanism of miR-224-5p in regulating CRC chemoresistance remain unclear.This study aims to investigate the function of miR-224-5p in chemoresistant CRC cells and the underlying mechanisms.Methods:CRC datasets GSE28702 and GSE69657 were downloaded from the Gene Expression Omnibus(GEO)database.Differentially expressed miRNAs between drug sensitive and resistant groups(OXA or 5-FU)were analyzed,and miR-224-5p was identified as the target miRNA.Chemoresistant cell lines HCT15-OXR,HCT15-5-FU,SW480-OXR,and SW480-5-FU were established.Transient transfections were performed using miR-224-5p mimics,inhibitors,and their respective negative controls(control mimic,control inhibitor)in these cell lines.Cells were treated with different concentrations of OXA or 5-FU post-transfection,and the half-maximal inhibitory concentration(IC_(50))was determined using the cell counting kit-8(CCK-8)assay.Cell proliferation was assessed by CCK-8 and colony formation assays.The expression levels of miR-224-5p,LC3,and P62 were measured by real-time polymerase chain reaction(real-time PCR)and/or Western blotting.Autophagic flux was assessed using a tandem fluorescent-tagged LC3 reporter assay.TargetScan 8.0,miRTarBase,miRPathDB,and HADb were used to predict B-cell lymphoma-2(Bcl-2)as a potential miR-244-5p target,which was further validated by dual luciferase reporter assays.Results:Chemoresistant CRC cells exhibited down-regulated miR-224-5p expression,whereas up-regulation of miR-224-5p enhanced chemotherapy sensitivity.Exposure to OXA or 5-FU significantly increased autophagic activity in chemoresistant CRC cells,which was reversed by miR-224-5p overexpression.Dual-luciferase assays verified Bcl-2 as a direct target of miR-224-5p.Conclusion:MiR-224-5p regulates chemoresistance in CRC by modulating autophagy through direct targeting of Bcl-2.展开更多
Objective:To investigate the biological functions and molecular regulatory mechanisms of kinesin family member 11(KIF11)in colorectal cancer(CRC).Methods:The expression of KIF11 in CRC was examined by qRT⁃PCR and publ...Objective:To investigate the biological functions and molecular regulatory mechanisms of kinesin family member 11(KIF11)in colorectal cancer(CRC).Methods:The expression of KIF11 in CRC was examined by qRT⁃PCR and public databases.Functional assays(CCK⁃8,colony formation,EdU,and Transwell)were employed to evaluate KIF11’s roles in CRC progression.Western blot,RIP⁃qPCR,MeRIP⁃qPCR,and RNA stability assays were performed to elucidate the molecular mechanism of N6⁃methyladenosine(m6A)modification for KIF11.RNA sequencing(RNA⁃seq)and correlation analysis were used to examine the downstream mechanism of KIF11 regulation.Results:KIF11 was highly expressed in CRC and promoted CRC proliferation and migration.Mechanistically,methyltransferase⁃like 3(METTL3)/insulin like growth factor 2 mRNA binding protein 2(IGF2BP2)enhanced KIF11 mRNA stability and expression in an m6A⁃dependent way.Furthermore,by means of the PROM1/PI3K/AKT pathway,KIF11 facilitated the progression of CRC.Conclusion:The m6A modification of KIF11 by METTL3/IGF2BP2 contributes to CRC progression via the PI3K/AKT signaling pathway,highlighting its potential as a prognostic biomarker and therapeutic target.展开更多
Drug resistance remains a major challenge in breast cancer chemotherapy,yet the metabolic alterations underlying this phenomenon are not fully understood.There is much evidence indicating the cellular heterogeneity am...Drug resistance remains a major challenge in breast cancer chemotherapy,yet the metabolic alterations underlying this phenomenon are not fully understood.There is much evidence indicating the cellular heterogeneity among cancer cells,which exhibit varying degrees of metabolic reprogramming and thus may result in differential contributions to drug resistance.A home-built single-cell quantitative mass spectrometry(MS)platform,which integrates micromanipulation and electro-osmotic sampling,was developed to quantitatively profile the tricarboxylic acid(TCA)cycle metabolites at the single-cell level.Using this platform,the metabolic profiles of drug-sensitive MCF-7 breast cancer cells and their drug-resistant derivative MCF-7/ADR cells were compared.This results revealed a selective upregulation of downstream TCA cycle metabolites includingα-ketoglutarate,succinate,fumarate,and malate in drug-resistant cancer cells,while early TCA metabolites remained largely unchanged.Furthermore,notable variations in the abundance of the metabolites were observed in individual cells.The comparative analysis also revealed that not all MCF-7/ADR cells exhibit the same degree of metabolic deviation from the parental line in the metabolites during resistance acquisition.The observed metabolic profiles indicate enhanced glutaminolysis,altered mitochondrial electron transport chain activity,and increased metabolic flexibility in drug-resistant cancer cells that support their survival under chemotherapeutic stress.The findings further suggest the potential for incorporating cellular metabolic heterogeneity into future drug resistance studies.展开更多
The incidence and mortality rate of lung cancer rank among the highest worldwide,severely endangering human health and life.Metformin,an anti-diabetes drug,has been shown to elicit anticancer activities in various tum...The incidence and mortality rate of lung cancer rank among the highest worldwide,severely endangering human health and life.Metformin,an anti-diabetes drug,has been shown to elicit anticancer activities in various tumors.However,its underlying mechanisms remain elusive.In this work,we explore the role of receptor-interacting protein 1(RIP1)which plays a crucial role in the process of cell death,in metformin-induced anticancer activities in lung cancer.Metformin inhibits lung cancer cell proliferation in a dose-dependent manner and promotes apoptotic cell death,as evidenced by metformin-induced PARP and caspase cleavage.Furthermore,the pan-caspase inhibitor z-VAD-fmk reverses metformin-induced cell death.Western blot and qPCR results suggest that metformin markedly downregulates RIP1 expression without affecting its mRNA and ubiquitination levels(0 vs 80 mmol/L,100%vs 20%,100%vs 15%).Additionally,co-immunoprecipitation and immunofluorescence results reveal that metformin may suppress RIP1 expression in an Hsp70-dependent manner,as metformin promotes Hsp70 degradation,and Hsp70 endogenously interacts with RIP1.Subsequent CCK-8,flow cytometry,and Western blot analyses suggest that metformin decreases Hsp70/RIP1 expression through AMPK/PKA/GSK-3βaxis.Consistently,results from a subcutaneous transplant tumor model indicate that metformin retards tumor growth without affecting mouse body weight.Collectively,these data highlight the part of RIP1 in metformin-induced anticancer activities in lung cancer in vitro and in vivo,providing novel strategy for lung cancer administration.展开更多
Objective:Albumin-globulin ratio(AGR),prognostic nutritional index(PNI),and platelet to-lymphocyte ratio(PLR)have been validated as prognostic factors for gastric cancer(GC).However,significant gender differences exis...Objective:Albumin-globulin ratio(AGR),prognostic nutritional index(PNI),and platelet to-lymphocyte ratio(PLR)have been validated as prognostic factors for gastric cancer(GC).However,significant gender differences exist in albumin levels and inflammatory cell counts,and further research is required to understand how these differences influence GC prognosis.This study aims to investigate the prognostic impact of nutritional and inflammatory indicators on GC patients undergoing radical surgery,as well as the influence of gender on these indicators’prognostic value.Methods:The study included 596 patients with advanced GC hospitalized in the Department of Gastrointestinal Surgery,General Surgery,Xiangya Hospital of Central South University from January 2012 to December 2016.Receiver operating characteristic(ROC)analysis was performed to determine cutoff values for nutritional and inflammatory factors.Univariate analysis was used to identify factors significantly affecting survival in GC patients,while multivariate and Kaplan-Meier analyses determined independent prognostic factors for GC.Results:Multivariate analysis revealed that postsurgical tumor node metastasis(pTNM)stage[stage II:hazard ratio(HR)=3.284,P=0.012;stage III:HR:8.062,P<0.001],low preoperative AGR(HR=1.499,P=0.012),and postoperative PNI(HR=1.503,P=0.008)were risk factors for overall survival in male patients after radical GC surgery.For female patients,pN2-3(HR=3.185,P<0.001),total gastrectomy(HR=2.286,P=0.004),low preoperative PLR(HR=1.702,P=0.027),and postoperative PNI(HR=1.943,P=0.011)were identified as risk factors for overall survival.Conclusion:Postoperative PNI is an independent risk factor for all advanced GC patients.Preoperative PLR is an independent prognostic factor only for female patients,while preoperative AGR is an independent prognostic factor only for male patients.Further research is warranted to investigate the gender-specific differences in GC prognosis.展开更多
Objective:The efficacy of monotherapy in alleviating psychological disorders like anxiety and depression among breast cancer patients is suboptimal,necessitating effective psychosocial interventions.Mindfulness-based ...Objective:The efficacy of monotherapy in alleviating psychological disorders like anxiety and depression among breast cancer patients is suboptimal,necessitating effective psychosocial interventions.Mindfulness-based interventions have been shown to mitigate anxiety-depression symptoms and encourage beneficial behaviors.The online mindfulness based cancer recovery(MBCR)offers flexibility and guides practice across various settings,facilitating full patient engagement.This study amis to analyze the impact of a 4-week internet-delivered mindfulness-based cancer recovery program on anxiety,depression,and mindfulness among Chinese patients with breast cancer,and to evaluate the degree of satisfaction breast cancer patients experienced after participating in this program.Methods:This study utilized a two-armed,parallel,randomized controlled trial design.A total of 103 patients with breast cancer from June 2020 to January 2021 in the ward of Breast and Thyroid Surgery of a tertiary hospital in Changsha,Hunan Province were selected and randomly assigned to an intervention group(n=51)and a control group(n=52).The intervention group participated in an internet-delivered mindfulness-based cancer recovery program,which was delivered once a week for 4 weeks.Meanwhile,the control group received weekly group health education for 4 weeks.The outcomes of hospital anxiety and depression scale and mindfulness Attention Awareness Scale were evaluated at 3 distinct time points:Baseline(T1),postintervention(T2),and 1-month follow-up(T3).The satisfaction questionnaire of 4-week mindful cancer rehabilitation training program was used at T2 to evaluate patients’satisfaction with the intervention program.Generalized estimation equations were used to assess differences in anxiety,depression and mindfulness levels between groups before and after the intervention.Results:There were no statistically significant differences in demographic data and outcome index scores between the 2 groups at T1(all P>0.05),indicating that the 2 groups were comparable.The generalized estimating equation analyses showed that the intervention group had significantly better improvement in outcomes compared to the control group,particularly for anxiety(T2β=−1.30,95%CI−1.87 to−0.72;T3β=−2.78,95%CI−3.51 to−2.05)and depression(T2β=−1.92,95%CI−2.78 to−1.06;T3β=−2.96,95%CI−4.05 to−1.87;all P<0.001).Moreover,the mindfulness score in the intervention group was significantly higher than that in the control group at T2(β=3.23,95%CI 0.73 to 5.72)and T3(β=8.06,95%CI 4.37 to 11.75;both P<0.05).In addition,patients in the intervention group were satisfied with the 4-week mindfulness-based cancer recovery intervention and teaching/learning activities used to implement the program.Conclusion:In patients with breast cancer,the 4-week internet-delivered mindfulness based cancer recovery program,as a low-threshold,short-term mental health intervention,has a positive effect on reducing anxiety and depression and improving mindfulness levels.This program holds great promise as a tool for clinical nursing practice,given the high satisfaction and applicability.展开更多
Objective Triple-negative breast cancer(TNBC)is the breast cancer subtype with the worst prognosis,and lacks effective therapeutic targets.Colony stimulating factors(CSFs)are cytokines that can regulate the production...Objective Triple-negative breast cancer(TNBC)is the breast cancer subtype with the worst prognosis,and lacks effective therapeutic targets.Colony stimulating factors(CSFs)are cytokines that can regulate the production of blood cells and stimulate the growth and development of immune cells,playing an important role in the malignant progression of TNBC.This article aims to construct a novel prognostic model based on the expression of colony stimulating factors-related genes(CRGs),and analyze the sensitivity of TNBC patients to immunotherapy and drug therapy.Methods We downloaded CRGs from public databases and screened for differentially expressed CRGs between normal and TNBC tissues in the TCGA-BRCA database.Through LASSO Cox regression analysis,we constructed a prognostic model and stratified TNBC patients into high-risk and low-risk groups based on the colony stimulating factors-related genes risk score(CRRS).We further analyzed the correlation between CRRS and patient prognosis,clinical features,tumor microenvironment(TME)in both high-risk and low-risk groups,and evaluated the relationship between CRRS and sensitivity to immunotherapy and drug therapy.Results We identified 842 differentially expressed CRGs in breast cancer tissues of TNBC patients and selected 13 CRGs for constructing the prognostic model.Kaplan-Meier survival curves,time-dependent receiver operating characteristic curves,and other analyses confirmed that TNBC patients with high CRRS had shorter overall survival,and the predictive ability of CRRS prognostic model was further validated using the GEO dataset.Nomogram combining clinical features confirmed that CRRS was an independent factor for the prognosis of TNBC patients.Moreover,patients in the high-risk group had lower levels of immune infiltration in the TME and were sensitive to chemotherapeutic drugs such as 5-fluorouracil,ipatasertib,and paclitaxel.Conclusion We have developed a CRRS-based prognostic model composed of 13 differentially expressed CRGs,which may serve as a useful tool for predicting the prognosis of TNBC patients and guiding clinical treatment.Moreover,the key genes within this model may represent potential molecular targets for future therapies of TNBC.展开更多
基金supported by the Science and Technology Innovation Program of Hunan Province,China(2020SK2073).
文摘Objective:Previous studies have demonstrated that the metals cadmium and arsenic exhibit estrogen-like effects and may influence the occurrence and development of gynecological tumors.This study aims to explore the association between urinary cadmium and arsenic levels and the prevalence of gynecologic cancers using data from the National Health and Nutrition Examination Survey(NHANES).Methods:Data from female participants in NHANES 2003—2018 were analyzed.Using R software,datasets(DEMO,BMX,etc.)were merged,and complete cases were retained by intersecting row names,yielding a total of 2999 participants.After applying strict exclusion criteria,2802 participants were included:83 with gynecologic cancer(cancer group)and 2719 without(control group).Demographic,reproductive health,and urinary cadmium and arsenic data were collected.Binary Logistic regression models were employed to assess associations between urinary cadmium and arsenic levels and gynecologic cancer risk.Results:High urinary cadmium and arsenic levels were risk factors for gynecologic cancers,with odds ratios(ORs)of 1.623(95%CI 1.217 to 2.166)and 1.003(95%CI 1.001 to 1.005),respectively.After propensity score matching(PSM),the trend remained;cadmium was still a statistically significant risk factor with an OR of 2.182(95%CI 1.343 to 3.545),while arsenic’s association,though not statistically significant,still trended toward risk(OR=1.004,95%CI 0.999 to 1.009).Subgroup analyses showed that both cadmium and arsenic were risk factors for ovarian cancer(OR=1.745,95%CI 1.178 to 2.586 and OR=1.005,95%CI 1.002 to 1.008,respectively);these associations persisted after PSM.Additionally,cadmium increased the risk of endometrial cancer(OR=1.617,95%CI 1.109 to 2.356).Conclusion:Exposure to cadmium and arsenic is associated with an increased risk of ovarian and endometrial cancers.These findings suggest that reducing environmental exposure to heavy metals such as cadmium and arsenic may help prevent certain gynecologic cancers.
文摘Objective:Ovarian cancer(OC)ranks among the leading causes of mortality among the female cancers worldwide.Numerous studies have explored the development and progression of OC at multiple genetic regulatory levels.However,relatively few studies have explored the impact of post-translational modifications(PTM)on OC progression,which is essential for uncovering new therapeutic targets.This study aimed to systematically identify the key PTM types involved in OCprogression,and to explore and evaluate their translational potential as therapeutic targets.Methods:First,we utilized multiple general PTM antibodies to compare gross PTM levels between normal ovarian and OC tissues from clinical females.After identifying lactylation as the PTM with the most significant differences,we selected representative samples for label-free mass spectrometry to identify specific lactylation sites.Next,we transfected A2780(OC)cells with either wild-type(WT)or mutant(K192A[Q])poly(ADP-ribose)polymerase 1(PARP1)conjugated to enhanced green fluorescent protein(EGFP)with a StrepⅡpeptide tag and assessed various cellular indexes related to cell proliferation(clonogenicity assay),migration(scratch wound healing assay),and reactive oxygen species levels.Results:Pan-lactylation was significantly upregulated in clinical OC samples,with PARP1 lactylation at K192 being one of the most common modifications.The growth and migration of A2780 cells were markedly suppressed by overexpressing PARP1-WT but not mutant PARP1.Overexpressing PARP1 significantly downregulated the phosphorylation of extracellular signal-regulated kinases 1/2(ERK1/2).Conclusion:This study uncovered a novel PTM of PARP1 in OC,lactylation,and demonstrated that lactylation at K192 is crucial in regulating OC cell growth and migration via the ERK1/2 pathway.Further investigations are required to elucidate the broader functional implications of PARP1 lactylation and its therapeutic potential.
基金supported by the National Natural Science Foundation(82072729)Wuhan Municipal Health Commission Medical Research Project(WX19Q30),China。
文摘Objective:Oxaliplatin(OXA)and 5-fluorouracil(5-FU)are 2 commonly used chemotherapeutic agents for colorectal cancer(CRC).MicroRNAs(miRNAs,miRs)play crucial roles in the development of chemoresistance in various cancers.However,the role and mechanism of miR-224-5p in regulating CRC chemoresistance remain unclear.This study aims to investigate the function of miR-224-5p in chemoresistant CRC cells and the underlying mechanisms.Methods:CRC datasets GSE28702 and GSE69657 were downloaded from the Gene Expression Omnibus(GEO)database.Differentially expressed miRNAs between drug sensitive and resistant groups(OXA or 5-FU)were analyzed,and miR-224-5p was identified as the target miRNA.Chemoresistant cell lines HCT15-OXR,HCT15-5-FU,SW480-OXR,and SW480-5-FU were established.Transient transfections were performed using miR-224-5p mimics,inhibitors,and their respective negative controls(control mimic,control inhibitor)in these cell lines.Cells were treated with different concentrations of OXA or 5-FU post-transfection,and the half-maximal inhibitory concentration(IC_(50))was determined using the cell counting kit-8(CCK-8)assay.Cell proliferation was assessed by CCK-8 and colony formation assays.The expression levels of miR-224-5p,LC3,and P62 were measured by real-time polymerase chain reaction(real-time PCR)and/or Western blotting.Autophagic flux was assessed using a tandem fluorescent-tagged LC3 reporter assay.TargetScan 8.0,miRTarBase,miRPathDB,and HADb were used to predict B-cell lymphoma-2(Bcl-2)as a potential miR-244-5p target,which was further validated by dual luciferase reporter assays.Results:Chemoresistant CRC cells exhibited down-regulated miR-224-5p expression,whereas up-regulation of miR-224-5p enhanced chemotherapy sensitivity.Exposure to OXA or 5-FU significantly increased autophagic activity in chemoresistant CRC cells,which was reversed by miR-224-5p overexpression.Dual-luciferase assays verified Bcl-2 as a direct target of miR-224-5p.Conclusion:MiR-224-5p regulates chemoresistance in CRC by modulating autophagy through direct targeting of Bcl-2.
基金江苏省卫生健康委员会医学科研重点项目(K2023024)789 Outstanding Talent Program of SAHNMU(789ZYRC202090147)。
文摘Objective:To investigate the biological functions and molecular regulatory mechanisms of kinesin family member 11(KIF11)in colorectal cancer(CRC).Methods:The expression of KIF11 in CRC was examined by qRT⁃PCR and public databases.Functional assays(CCK⁃8,colony formation,EdU,and Transwell)were employed to evaluate KIF11’s roles in CRC progression.Western blot,RIP⁃qPCR,MeRIP⁃qPCR,and RNA stability assays were performed to elucidate the molecular mechanism of N6⁃methyladenosine(m6A)modification for KIF11.RNA sequencing(RNA⁃seq)and correlation analysis were used to examine the downstream mechanism of KIF11 regulation.Results:KIF11 was highly expressed in CRC and promoted CRC proliferation and migration.Mechanistically,methyltransferase⁃like 3(METTL3)/insulin like growth factor 2 mRNA binding protein 2(IGF2BP2)enhanced KIF11 mRNA stability and expression in an m6A⁃dependent way.Furthermore,by means of the PROM1/PI3K/AKT pathway,KIF11 facilitated the progression of CRC.Conclusion:The m6A modification of KIF11 by METTL3/IGF2BP2 contributes to CRC progression via the PI3K/AKT signaling pathway,highlighting its potential as a prognostic biomarker and therapeutic target.
基金supported by National Natural Science Foundation of China(22374080,22174068,21722504)Primary Research&Development Plan of Jiangsu Province(BK20221303,BE2022796)+1 种基金Open Foundation of State Key Laboratory of Reproductive Medicine(SKLRM-2022BP1,JX116GSP20240507)Science and Technology Development Fund of NJMU(NJMUQY2022003)。
文摘Drug resistance remains a major challenge in breast cancer chemotherapy,yet the metabolic alterations underlying this phenomenon are not fully understood.There is much evidence indicating the cellular heterogeneity among cancer cells,which exhibit varying degrees of metabolic reprogramming and thus may result in differential contributions to drug resistance.A home-built single-cell quantitative mass spectrometry(MS)platform,which integrates micromanipulation and electro-osmotic sampling,was developed to quantitatively profile the tricarboxylic acid(TCA)cycle metabolites at the single-cell level.Using this platform,the metabolic profiles of drug-sensitive MCF-7 breast cancer cells and their drug-resistant derivative MCF-7/ADR cells were compared.This results revealed a selective upregulation of downstream TCA cycle metabolites includingα-ketoglutarate,succinate,fumarate,and malate in drug-resistant cancer cells,while early TCA metabolites remained largely unchanged.Furthermore,notable variations in the abundance of the metabolites were observed in individual cells.The comparative analysis also revealed that not all MCF-7/ADR cells exhibit the same degree of metabolic deviation from the parental line in the metabolites during resistance acquisition.The observed metabolic profiles indicate enhanced glutaminolysis,altered mitochondrial electron transport chain activity,and increased metabolic flexibility in drug-resistant cancer cells that support their survival under chemotherapeutic stress.The findings further suggest the potential for incorporating cellular metabolic heterogeneity into future drug resistance studies.
文摘The incidence and mortality rate of lung cancer rank among the highest worldwide,severely endangering human health and life.Metformin,an anti-diabetes drug,has been shown to elicit anticancer activities in various tumors.However,its underlying mechanisms remain elusive.In this work,we explore the role of receptor-interacting protein 1(RIP1)which plays a crucial role in the process of cell death,in metformin-induced anticancer activities in lung cancer.Metformin inhibits lung cancer cell proliferation in a dose-dependent manner and promotes apoptotic cell death,as evidenced by metformin-induced PARP and caspase cleavage.Furthermore,the pan-caspase inhibitor z-VAD-fmk reverses metformin-induced cell death.Western blot and qPCR results suggest that metformin markedly downregulates RIP1 expression without affecting its mRNA and ubiquitination levels(0 vs 80 mmol/L,100%vs 20%,100%vs 15%).Additionally,co-immunoprecipitation and immunofluorescence results reveal that metformin may suppress RIP1 expression in an Hsp70-dependent manner,as metformin promotes Hsp70 degradation,and Hsp70 endogenously interacts with RIP1.Subsequent CCK-8,flow cytometry,and Western blot analyses suggest that metformin decreases Hsp70/RIP1 expression through AMPK/PKA/GSK-3βaxis.Consistently,results from a subcutaneous transplant tumor model indicate that metformin retards tumor growth without affecting mouse body weight.Collectively,these data highlight the part of RIP1 in metformin-induced anticancer activities in lung cancer in vitro and in vivo,providing novel strategy for lung cancer administration.
基金supported by the National Natural Science Foundation of China(8197103463).
文摘Objective:Albumin-globulin ratio(AGR),prognostic nutritional index(PNI),and platelet to-lymphocyte ratio(PLR)have been validated as prognostic factors for gastric cancer(GC).However,significant gender differences exist in albumin levels and inflammatory cell counts,and further research is required to understand how these differences influence GC prognosis.This study aims to investigate the prognostic impact of nutritional and inflammatory indicators on GC patients undergoing radical surgery,as well as the influence of gender on these indicators’prognostic value.Methods:The study included 596 patients with advanced GC hospitalized in the Department of Gastrointestinal Surgery,General Surgery,Xiangya Hospital of Central South University from January 2012 to December 2016.Receiver operating characteristic(ROC)analysis was performed to determine cutoff values for nutritional and inflammatory factors.Univariate analysis was used to identify factors significantly affecting survival in GC patients,while multivariate and Kaplan-Meier analyses determined independent prognostic factors for GC.Results:Multivariate analysis revealed that postsurgical tumor node metastasis(pTNM)stage[stage II:hazard ratio(HR)=3.284,P=0.012;stage III:HR:8.062,P<0.001],low preoperative AGR(HR=1.499,P=0.012),and postoperative PNI(HR=1.503,P=0.008)were risk factors for overall survival in male patients after radical GC surgery.For female patients,pN2-3(HR=3.185,P<0.001),total gastrectomy(HR=2.286,P=0.004),low preoperative PLR(HR=1.702,P=0.027),and postoperative PNI(HR=1.943,P=0.011)were identified as risk factors for overall survival.Conclusion:Postoperative PNI is an independent risk factor for all advanced GC patients.Preoperative PLR is an independent prognostic factor only for female patients,while preoperative AGR is an independent prognostic factor only for male patients.Further research is warranted to investigate the gender-specific differences in GC prognosis.
基金supported by the National Science Fund for Distinguished Young Scholars(81703084)the National Natural Science Foundation of General Program(82272924),and the Hunan Women’s Federation(19WTB03),China.
文摘Objective:The efficacy of monotherapy in alleviating psychological disorders like anxiety and depression among breast cancer patients is suboptimal,necessitating effective psychosocial interventions.Mindfulness-based interventions have been shown to mitigate anxiety-depression symptoms and encourage beneficial behaviors.The online mindfulness based cancer recovery(MBCR)offers flexibility and guides practice across various settings,facilitating full patient engagement.This study amis to analyze the impact of a 4-week internet-delivered mindfulness-based cancer recovery program on anxiety,depression,and mindfulness among Chinese patients with breast cancer,and to evaluate the degree of satisfaction breast cancer patients experienced after participating in this program.Methods:This study utilized a two-armed,parallel,randomized controlled trial design.A total of 103 patients with breast cancer from June 2020 to January 2021 in the ward of Breast and Thyroid Surgery of a tertiary hospital in Changsha,Hunan Province were selected and randomly assigned to an intervention group(n=51)and a control group(n=52).The intervention group participated in an internet-delivered mindfulness-based cancer recovery program,which was delivered once a week for 4 weeks.Meanwhile,the control group received weekly group health education for 4 weeks.The outcomes of hospital anxiety and depression scale and mindfulness Attention Awareness Scale were evaluated at 3 distinct time points:Baseline(T1),postintervention(T2),and 1-month follow-up(T3).The satisfaction questionnaire of 4-week mindful cancer rehabilitation training program was used at T2 to evaluate patients’satisfaction with the intervention program.Generalized estimation equations were used to assess differences in anxiety,depression and mindfulness levels between groups before and after the intervention.Results:There were no statistically significant differences in demographic data and outcome index scores between the 2 groups at T1(all P>0.05),indicating that the 2 groups were comparable.The generalized estimating equation analyses showed that the intervention group had significantly better improvement in outcomes compared to the control group,particularly for anxiety(T2β=−1.30,95%CI−1.87 to−0.72;T3β=−2.78,95%CI−3.51 to−2.05)and depression(T2β=−1.92,95%CI−2.78 to−1.06;T3β=−2.96,95%CI−4.05 to−1.87;all P<0.001).Moreover,the mindfulness score in the intervention group was significantly higher than that in the control group at T2(β=3.23,95%CI 0.73 to 5.72)and T3(β=8.06,95%CI 4.37 to 11.75;both P<0.05).In addition,patients in the intervention group were satisfied with the 4-week mindfulness-based cancer recovery intervention and teaching/learning activities used to implement the program.Conclusion:In patients with breast cancer,the 4-week internet-delivered mindfulness based cancer recovery program,as a low-threshold,short-term mental health intervention,has a positive effect on reducing anxiety and depression and improving mindfulness levels.This program holds great promise as a tool for clinical nursing practice,given the high satisfaction and applicability.
文摘Objective Triple-negative breast cancer(TNBC)is the breast cancer subtype with the worst prognosis,and lacks effective therapeutic targets.Colony stimulating factors(CSFs)are cytokines that can regulate the production of blood cells and stimulate the growth and development of immune cells,playing an important role in the malignant progression of TNBC.This article aims to construct a novel prognostic model based on the expression of colony stimulating factors-related genes(CRGs),and analyze the sensitivity of TNBC patients to immunotherapy and drug therapy.Methods We downloaded CRGs from public databases and screened for differentially expressed CRGs between normal and TNBC tissues in the TCGA-BRCA database.Through LASSO Cox regression analysis,we constructed a prognostic model and stratified TNBC patients into high-risk and low-risk groups based on the colony stimulating factors-related genes risk score(CRRS).We further analyzed the correlation between CRRS and patient prognosis,clinical features,tumor microenvironment(TME)in both high-risk and low-risk groups,and evaluated the relationship between CRRS and sensitivity to immunotherapy and drug therapy.Results We identified 842 differentially expressed CRGs in breast cancer tissues of TNBC patients and selected 13 CRGs for constructing the prognostic model.Kaplan-Meier survival curves,time-dependent receiver operating characteristic curves,and other analyses confirmed that TNBC patients with high CRRS had shorter overall survival,and the predictive ability of CRRS prognostic model was further validated using the GEO dataset.Nomogram combining clinical features confirmed that CRRS was an independent factor for the prognosis of TNBC patients.Moreover,patients in the high-risk group had lower levels of immune infiltration in the TME and were sensitive to chemotherapeutic drugs such as 5-fluorouracil,ipatasertib,and paclitaxel.Conclusion We have developed a CRRS-based prognostic model composed of 13 differentially expressed CRGs,which may serve as a useful tool for predicting the prognosis of TNBC patients and guiding clinical treatment.Moreover,the key genes within this model may represent potential molecular targets for future therapies of TNBC.
