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
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
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: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:To explore the relationship between cancer awareness and the survival of the patients with non-small cell lung carcinoma(NSCLC).Methods:A total of 865 NSCLC patients were screened for the risk factors,includ...Objective:To explore the relationship between cancer awareness and the survival of the patients with non-small cell lung carcinoma(NSCLC).Methods:A total of 865 NSCLC patients were screened for the risk factors,including age,gender,address,tumor/lymph nodes/metastasis(TNM)stage,and cancer awareness.Survival of the patients was calculated by Kaplan-Meier method and Cox regression analysis.Results:After an average observation time of 304 d(ranging from 0 to 4718 d),62 of the 394 patients in the cancer awareness group survived,whereas 26 of the 471 patients in the cancer concealment group survived.Cancer-specific and all-cause survival was poorer in the cancer concealment group(P<0.001 for each,log-rank test).Cox multivariate regression analysis showed that cancer concealment displayed significantly lower cancer-specific survival[hazard ratio(HR)=1.534,95%con fi dence interval(CI)1.320 to 1.784,P<0.001]and all-cause survival(HR=1.558,95%CI 1.346 to 1.803,P<0.001).Conclusion:Cancer concealment is associated with a poor survival of NSCLC patients,which may prohibit the patients from obtaining the real“right to survival”.展开更多
目的:探讨蜘蛛香总黄酮对肝癌H22小鼠抗肿瘤作用及对pathways in cancer的影响。方法:建立H22肝癌皮下荷瘤模型,随机分为模型对照组、阳性对照组、蜘蛛香总黄酮高、低剂量组。给药10 d后,解剖称取瘤重,计算抑瘤率,并应用小鼠全基因组基...目的:探讨蜘蛛香总黄酮对肝癌H22小鼠抗肿瘤作用及对pathways in cancer的影响。方法:建立H22肝癌皮下荷瘤模型,随机分为模型对照组、阳性对照组、蜘蛛香总黄酮高、低剂量组。给药10 d后,解剖称取瘤重,计算抑瘤率,并应用小鼠全基因组基因芯片考察蜘蛛香总黄酮对瘤组织pathways in cancer的影响。结果:与模型对照组相比,阳性对照组、蜘蛛香总黄酮高、低剂量组的平均瘤重明显下降(P<0.01,P<0.05,P<0.05),各组抑瘤率分别为45.32%、30.06%、25.97%。给药组pathways in cancer中有17个基因表达同时发生了显著性变化,其中Ccne2、Cdkn2b、Ctbp2、Mmp1a、Myc和Vegfa的表达发生了上调,而Vegfc、Csf1r、Epas1、Figf、Fzd9、Igf1、Pdgfra、Pik3r1、Prkcb、Tcf7l1和Tcf7l2的表达发生了下调,主要从细胞周期调控、PI3K-AKT途径、Wnt途径抑制肿瘤增殖、迁移,促进其凋亡。结论:蜘蛛香总黄酮具有一定的抗肝癌活性,作用机理可能与调节pathways in cancer的信号转导相关。展开更多
OBJECTIVE To investigate the inhibitory effect of scutellarin on the self-renewal and differentiation of HT-29 cells-derived cancer stem-like cells(HT-29CSC)in vitro and in vivo,and to explore its mechanism.METHODS Th...OBJECTIVE To investigate the inhibitory effect of scutellarin on the self-renewal and differentiation of HT-29 cells-derived cancer stem-like cells(HT-29CSC)in vitro and in vivo,and to explore its mechanism.METHODS The effect of scutellarin on the growth of HT-29CSC was determined by 3D Culture assay.The effect of scutellarin on growth and transformation of HT-29CSC was probed by soft agar colony formation assay.The effect of scutellarin on the differentiation of HT-29CSC was determined by serum induction differentiation assay in vitro.The effects of scutellarin on the expressions of marker gene Lgr5,target gene c-Myc,proliferation gene CK20 and Nanog gene were measured by quantitative real-time RT-PCR.Investigate the effect of scutellarin on the expression of c-Myc,Gli1,and Lgr5 protein by Western blotting.A subcutaneous xenograft model of colon cancer in nude mice was established and administered by intraperitoneal injection.The change of body weight and tumor size of nude mice were observed every two days.Investi⁃gate the effects of scutellarin on the growth of xenograft tumors in nude mice.The expression of CD133,Lgr5,Gli1,Ptch1,c-Myc,Ki67,CK20,Nanog gene in tumors were measured by quantitative real-time RT-PCR.The expression of c-Myc,Gli1,Lgr5,CD133,Ki67 protein were measured by Western blotting.RESULTS Scutellarin can inhibit the growth of HT-29CSC in 3D culture.Compared with the solvent control group,scutellarin can significantly inhibit the growth and transformation and differentiation of HT-29CSC in vitro(P<0.01).The expression levels of marker genes Lgr5,target gene c-Myc,proliferation gene CK20 and Nanog in HT-29CSC were down-regulated by scutellarin.Scutellarin can reduce the expression of c-Myc,Gli1,and Lgr5 protein in HT-29CSC.Scutellarin can inhibit the growth of colon cancer xenografts,lower CD133,Lgr5,Gli1,Ptch1,c-Myc,Ki67,CK20,and Nanog mRNA level of xenograft tumors,reduce the expression of c-Myc,Gli1,Lgr5,CD133,and Ki67 protein of xenograft tumors in nude mice.CONCLUSION Scutellarin,which is the main component of scutellaria barbata,can inhibit the differentiation of HT-29CSC and the mechanism is to inhibit the activity of Hedgehog signaling pathway.展开更多
Acknowledgements This work was supported by Educational Commission of Shanghai of China （2012JW19）; Key Research Innovation Project （13ZZ099）; Key Project from Department of Education of China （20123107130002）; ...Acknowledgements This work was supported by Educational Commission of Shanghai of China （2012JW19）; Key Research Innovation Project （13ZZ099）; Key Project from Department of Education of China （20123107130002）; Shanghai Eastern Scholar Program （2013-59） and Shanghai E-research Institute of Bioactive Constituent in TCM plan. Abstract： Aim This investigation was to identify whether Janus-activated kinase 2 （JAK2） and mitogen-activated protein kinase （MAPK） pathways were involved in the inhibitory effect of berberine hydrochloride （BER） on gastric cancer cell proliferation and IL-8 expression in vitro and in vivo. Methods CCK- 8 assay was used to assess the cell proliferation. IL-8 production was determined by ELISA and qPCR assay. Mo- lecular pathways involved were evaluated by ELISA and western-blotting methods. Results BER time- and dose- dependently inhibited the proliferation of MGC 803 and AGS cells. It also suppressed tumor growth in nude mice xenografted with MGC 803 cells. In addition, BER reduced interleukin-8 （IL-8） secretion of AGS cells as well as MGC 803 cells both in vitro and in vivo. Further study disclosed that inactivation of JAK2, p38 MAPK, ERK1/2 and JNK by BER contributed to the decreased proliferation and tumor growth as well as IL-8 expression in gastric cancer. Although there was no significantly synergistic inhibitory effect between BER and evodiamine on gastric cancer cell proliferation and tumor growth, BER could counteract the up-regulation of IL-8 induced by evodiamine in vitro and vivo. Conclusions Our results suggested that BER might be an efficient and safe drug candidate for treating gastric cancer through JAK2 and MAPK pathways.展开更多
Aim Breast cancer is one of the lethal gynecological malignancy in the world. Tamoxifen （TAM） and fulvestrant （FUL） are the major drugs for patients with estrogen receptor-positive （ER ＋ ） breast cancers. Howev...Aim Breast cancer is one of the lethal gynecological malignancy in the world. Tamoxifen （TAM） and fulvestrant （FUL） are the major drugs for patients with estrogen receptor-positive （ER ＋ ） breast cancers. Howev- er, the development of endocrine resistance is the impediment for successful treatment. In this study, we explored the mechanisms of endocrine resistance and therapeutic strategy for overcoming resistance against TAM and FUL. Methods The experiments were performed in Ell ＋ and estrogen/TAM-sensitive MCF7 cells and antiestrogen-re- sistant MCF7/LCC9 cells. Western blot and confocal microscopy were used to determine cell autophagy. Cell trans- fection and luciferase activity assay were performed to identify the target gene of miR-214. Results It showed that 4-OHT/FUL treatment induced apoptosis as well as autophagy in breast cancer cells. The increase of autophagy might be the major cause of endocrine resistance to 4-OHT or FUL. Mill-214 increased the sensitivity of breast cancer cells to the 4-OHT/FUL-induced apoptosis through inhibition of autophagy. Importantly, a negative correla- tion was established between miR-214 and UCP2 in human breast cancer tissue specimens by RT-qPCR assay. UCP2 was identified to be a direct target of mill-214. Further study in MCF7/LCC9 cells indicated that endocrine resistance might arise from activation of the PI3 K-Akt-mTOll pathway, thereby inducing autophagy by overexpres- sion of UCP2. Conclusions MiR-214 increased the sensitivity of breast cancer cells to TAM and FUL through in- hibition of autophagy by targeting UCP2. Mill-214 shows potential as a novel therapeutic strategy for overcoming endocrine resistance in ER ＋ breast cancers.展开更多
OBJECTIVE To discover a small molecule targeting ULK1-modulated cell death of triple negative breast cancer and exploreits potential mechanisms.METHODS ULK1 expression was analyzed by The Cancer Genome Atlas(TCGA)anal...OBJECTIVE To discover a small molecule targeting ULK1-modulated cell death of triple negative breast cancer and exploreits potential mechanisms.METHODS ULK1 expression was analyzed by The Cancer Genome Atlas(TCGA)analysis and tissue microarray(TMA)analysis.ULK1agonist was designed by using in silico screening,as well as modified by chemical synthesis and screened by kinase and anti-proliferative activities.The amino acid residues that key to the activation site of LYN-1604 were determined by site-directed mutagenesis,as well as in vitro kinase assay and ADP-Glo kinase assay.The mechanisms of LYN-1604 induced cell death were investigated by fluorescence microscope,western blotting,flow cytometry analysis,immunocytochemistry,as well as si RNA and GFP-m RFP-LC3 plasmid transfections.Potential ULK1 interactors were discovered by performing comparative microarray analysis and the therapeutic effect of LYN-1604 was assessed by xenograft breast cancer mouse model.RESULTS We found that ULK1 was remarkably downregulated in breast cancer tissue samples,especial y in triple negative breast cancer(TNBC).32 candidate smal molecules were synthesized,and we discovered a small molecule named LYN-1604 as the best candidate ULK1agonist.Additionally,we identified that three amino acid residues(LYS50,LEU53 and TYR89)were key to the activation site of LYN-1604 and ULK1.Subsequently,we demonstrated that LYN-1604 could induce autophagy-associated cell death via ULK complex(ULK1-m ATG13-FIP200-ATG101)in MDA-MB-231 cells.We also found that LYN-1604 induced cell death involved in ATF3,RAD21 and caspase 3,accompanied with autophagy and apoptosis.Moreover,we demonstrated that LYN-1604 had a good therapeutic potential on TNBC by targeting ULK1-modulated cell death in vivo.CONCLUSION We discovered a small molecule(LYN-1604)has therapeutic potential by targeting ULK1-modulated cell death associated with autophagy and apoptosis of TNBC in vitro and in vivo,which could be utilized as a new anti-TNBC drug candidate.展开更多
Resistance to cancer therapy continues to be a major limitation for the successful treatment of cancer. There are many published studies on therapy resistance in breast and prostate cancers; however, there are current...Resistance to cancer therapy continues to be a major limitation for the successful treatment of cancer. There are many published studies on therapy resistance in breast and prostate cancers; however, there are currently no data on molecular markers associated with resistance. The conflicting data were reported regarding the AKT/m-TOR signaling pathway components as markers predicting resistance. The AKT/m-TOR signaling pathway is involved in the development of many human cancers; its activation is related to cell proliferation, angiogenesis, apoptosis, as well as to therapy resistance. Molecular alterations in the AKT/m-TOR signaling pathway provide a platform to identify universal markers associated with the development of resistance to cancer therapy.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(81572870)
文摘Objective:To explore the relationship between cancer awareness and the survival of the patients with non-small cell lung carcinoma(NSCLC).Methods:A total of 865 NSCLC patients were screened for the risk factors,including age,gender,address,tumor/lymph nodes/metastasis(TNM)stage,and cancer awareness.Survival of the patients was calculated by Kaplan-Meier method and Cox regression analysis.Results:After an average observation time of 304 d(ranging from 0 to 4718 d),62 of the 394 patients in the cancer awareness group survived,whereas 26 of the 471 patients in the cancer concealment group survived.Cancer-specific and all-cause survival was poorer in the cancer concealment group(P<0.001 for each,log-rank test).Cox multivariate regression analysis showed that cancer concealment displayed significantly lower cancer-specific survival[hazard ratio(HR)=1.534,95%con fi dence interval(CI)1.320 to 1.784,P<0.001]and all-cause survival(HR=1.558,95%CI 1.346 to 1.803,P<0.001).Conclusion:Cancer concealment is associated with a poor survival of NSCLC patients,which may prohibit the patients from obtaining the real“right to survival”.
文摘目的:探讨蜘蛛香总黄酮对肝癌H22小鼠抗肿瘤作用及对pathways in cancer的影响。方法:建立H22肝癌皮下荷瘤模型,随机分为模型对照组、阳性对照组、蜘蛛香总黄酮高、低剂量组。给药10 d后,解剖称取瘤重,计算抑瘤率,并应用小鼠全基因组基因芯片考察蜘蛛香总黄酮对瘤组织pathways in cancer的影响。结果:与模型对照组相比,阳性对照组、蜘蛛香总黄酮高、低剂量组的平均瘤重明显下降(P<0.01,P<0.05,P<0.05),各组抑瘤率分别为45.32%、30.06%、25.97%。给药组pathways in cancer中有17个基因表达同时发生了显著性变化,其中Ccne2、Cdkn2b、Ctbp2、Mmp1a、Myc和Vegfa的表达发生了上调,而Vegfc、Csf1r、Epas1、Figf、Fzd9、Igf1、Pdgfra、Pik3r1、Prkcb、Tcf7l1和Tcf7l2的表达发生了下调,主要从细胞周期调控、PI3K-AKT途径、Wnt途径抑制肿瘤增殖、迁移,促进其凋亡。结论:蜘蛛香总黄酮具有一定的抗肝癌活性,作用机理可能与调节pathways in cancer的信号转导相关。
基金National Natural Science Foundation of China(8157381381173598)+1 种基金Excellent Talent Program of Chengdu University of Traditional Chinese Medicine(YXRC2019002)Fund of Scientific Research Innovation Team Construction in Sichuan Provincial University(18TD0017)
文摘OBJECTIVE To investigate the inhibitory effect of scutellarin on the self-renewal and differentiation of HT-29 cells-derived cancer stem-like cells(HT-29CSC)in vitro and in vivo,and to explore its mechanism.METHODS The effect of scutellarin on the growth of HT-29CSC was determined by 3D Culture assay.The effect of scutellarin on growth and transformation of HT-29CSC was probed by soft agar colony formation assay.The effect of scutellarin on the differentiation of HT-29CSC was determined by serum induction differentiation assay in vitro.The effects of scutellarin on the expressions of marker gene Lgr5,target gene c-Myc,proliferation gene CK20 and Nanog gene were measured by quantitative real-time RT-PCR.Investigate the effect of scutellarin on the expression of c-Myc,Gli1,and Lgr5 protein by Western blotting.A subcutaneous xenograft model of colon cancer in nude mice was established and administered by intraperitoneal injection.The change of body weight and tumor size of nude mice were observed every two days.Investi⁃gate the effects of scutellarin on the growth of xenograft tumors in nude mice.The expression of CD133,Lgr5,Gli1,Ptch1,c-Myc,Ki67,CK20,Nanog gene in tumors were measured by quantitative real-time RT-PCR.The expression of c-Myc,Gli1,Lgr5,CD133,Ki67 protein were measured by Western blotting.RESULTS Scutellarin can inhibit the growth of HT-29CSC in 3D culture.Compared with the solvent control group,scutellarin can significantly inhibit the growth and transformation and differentiation of HT-29CSC in vitro(P<0.01).The expression levels of marker genes Lgr5,target gene c-Myc,proliferation gene CK20 and Nanog in HT-29CSC were down-regulated by scutellarin.Scutellarin can reduce the expression of c-Myc,Gli1,and Lgr5 protein in HT-29CSC.Scutellarin can inhibit the growth of colon cancer xenografts,lower CD133,Lgr5,Gli1,Ptch1,c-Myc,Ki67,CK20,and Nanog mRNA level of xenograft tumors,reduce the expression of c-Myc,Gli1,Lgr5,CD133,and Ki67 protein of xenograft tumors in nude mice.CONCLUSION Scutellarin,which is the main component of scutellaria barbata,can inhibit the differentiation of HT-29CSC and the mechanism is to inhibit the activity of Hedgehog signaling pathway.
文摘Acknowledgements This work was supported by Educational Commission of Shanghai of China （2012JW19）; Key Research Innovation Project （13ZZ099）; Key Project from Department of Education of China （20123107130002）; Shanghai Eastern Scholar Program （2013-59） and Shanghai E-research Institute of Bioactive Constituent in TCM plan. Abstract： Aim This investigation was to identify whether Janus-activated kinase 2 （JAK2） and mitogen-activated protein kinase （MAPK） pathways were involved in the inhibitory effect of berberine hydrochloride （BER） on gastric cancer cell proliferation and IL-8 expression in vitro and in vivo. Methods CCK- 8 assay was used to assess the cell proliferation. IL-8 production was determined by ELISA and qPCR assay. Mo- lecular pathways involved were evaluated by ELISA and western-blotting methods. Results BER time- and dose- dependently inhibited the proliferation of MGC 803 and AGS cells. It also suppressed tumor growth in nude mice xenografted with MGC 803 cells. In addition, BER reduced interleukin-8 （IL-8） secretion of AGS cells as well as MGC 803 cells both in vitro and in vivo. Further study disclosed that inactivation of JAK2, p38 MAPK, ERK1/2 and JNK by BER contributed to the decreased proliferation and tumor growth as well as IL-8 expression in gastric cancer. Although there was no significantly synergistic inhibitory effect between BER and evodiamine on gastric cancer cell proliferation and tumor growth, BER could counteract the up-regulation of IL-8 induced by evodiamine in vitro and vivo. Conclusions Our results suggested that BER might be an efficient and safe drug candidate for treating gastric cancer through JAK2 and MAPK pathways.
文摘Aim Breast cancer is one of the lethal gynecological malignancy in the world. Tamoxifen （TAM） and fulvestrant （FUL） are the major drugs for patients with estrogen receptor-positive （ER ＋ ） breast cancers. Howev- er, the development of endocrine resistance is the impediment for successful treatment. In this study, we explored the mechanisms of endocrine resistance and therapeutic strategy for overcoming resistance against TAM and FUL. Methods The experiments were performed in Ell ＋ and estrogen/TAM-sensitive MCF7 cells and antiestrogen-re- sistant MCF7/LCC9 cells. Western blot and confocal microscopy were used to determine cell autophagy. Cell trans- fection and luciferase activity assay were performed to identify the target gene of miR-214. Results It showed that 4-OHT/FUL treatment induced apoptosis as well as autophagy in breast cancer cells. The increase of autophagy might be the major cause of endocrine resistance to 4-OHT or FUL. Mill-214 increased the sensitivity of breast cancer cells to the 4-OHT/FUL-induced apoptosis through inhibition of autophagy. Importantly, a negative correla- tion was established between miR-214 and UCP2 in human breast cancer tissue specimens by RT-qPCR assay. UCP2 was identified to be a direct target of mill-214. Further study in MCF7/LCC9 cells indicated that endocrine resistance might arise from activation of the PI3 K-Akt-mTOll pathway, thereby inducing autophagy by overexpres- sion of UCP2. Conclusions MiR-214 increased the sensitivity of breast cancer cells to TAM and FUL through in- hibition of autophagy by targeting UCP2. Mill-214 shows potential as a novel therapeutic strategy for overcoming endocrine resistance in ER ＋ breast cancers.
基金supported by National Natural Science Foundation of China(81402496,81673455and 81602627)China Postdoctoral Special Science Foundation(2017T100704)China Postdoctoral Science Foundation(2015M580794)
文摘OBJECTIVE To discover a small molecule targeting ULK1-modulated cell death of triple negative breast cancer and exploreits potential mechanisms.METHODS ULK1 expression was analyzed by The Cancer Genome Atlas(TCGA)analysis and tissue microarray(TMA)analysis.ULK1agonist was designed by using in silico screening,as well as modified by chemical synthesis and screened by kinase and anti-proliferative activities.The amino acid residues that key to the activation site of LYN-1604 were determined by site-directed mutagenesis,as well as in vitro kinase assay and ADP-Glo kinase assay.The mechanisms of LYN-1604 induced cell death were investigated by fluorescence microscope,western blotting,flow cytometry analysis,immunocytochemistry,as well as si RNA and GFP-m RFP-LC3 plasmid transfections.Potential ULK1 interactors were discovered by performing comparative microarray analysis and the therapeutic effect of LYN-1604 was assessed by xenograft breast cancer mouse model.RESULTS We found that ULK1 was remarkably downregulated in breast cancer tissue samples,especial y in triple negative breast cancer(TNBC).32 candidate smal molecules were synthesized,and we discovered a small molecule named LYN-1604 as the best candidate ULK1agonist.Additionally,we identified that three amino acid residues(LYS50,LEU53 and TYR89)were key to the activation site of LYN-1604 and ULK1.Subsequently,we demonstrated that LYN-1604 could induce autophagy-associated cell death via ULK complex(ULK1-m ATG13-FIP200-ATG101)in MDA-MB-231 cells.We also found that LYN-1604 induced cell death involved in ATF3,RAD21 and caspase 3,accompanied with autophagy and apoptosis.Moreover,we demonstrated that LYN-1604 had a good therapeutic potential on TNBC by targeting ULK1-modulated cell death in vivo.CONCLUSION We discovered a small molecule(LYN-1604)has therapeutic potential by targeting ULK1-modulated cell death associated with autophagy and apoptosis of TNBC in vitro and in vivo,which could be utilized as a new anti-TNBC drug candidate.
文摘Resistance to cancer therapy continues to be a major limitation for the successful treatment of cancer. There are many published studies on therapy resistance in breast and prostate cancers; however, there are currently no data on molecular markers associated with resistance. The conflicting data were reported regarding the AKT/m-TOR signaling pathway components as markers predicting resistance. The AKT/m-TOR signaling pathway is involved in the development of many human cancers; its activation is related to cell proliferation, angiogenesis, apoptosis, as well as to therapy resistance. Molecular alterations in the AKT/m-TOR signaling pathway provide a platform to identify universal markers associated with the development of resistance to cancer therapy.
