Chemotherapy resistance plays a pivotal role in the prognosis and therapeutic failure of patients with colorectal cancer(CRC).Cisplatin(DDP)-resistant cells exhibit an inherent ability to evade the toxic chemotherapeu...Chemotherapy resistance plays a pivotal role in the prognosis and therapeutic failure of patients with colorectal cancer(CRC).Cisplatin(DDP)-resistant cells exhibit an inherent ability to evade the toxic chemotherapeutic drug effects which are characterized by the activation of slow-cycle programs and DNA repair.Among the elements that lead to DDP resistance,O^(6)-methylguanine(O^(6)-MG)-DNA-methyltransferase(MGMT),a DNA-repair enzyme,performs a quintessential role.In this study,we clarify the significant involvement of MGMT in conferring DDP resistance in CRC,elucidating the underlying mechanism of the regulatory actions of MGMT.A notable upregulation of MGMT in DDP-resistant cancer cells was found in our study,and MGMT repression amplifies the sensitivity of these cells to DDP treatment in vitro and in vivo.Conversely,in cancer cells,MGMT overexpression abolishes their sensitivity to DDP treatment.Mechanistically,the interaction between MGMT and cyclin dependent kinase 1(CDK1)inducing slow-cycling cells is attainted via the promotion of ubiquitination degradation of CDK1.Meanwhile,to achieve nonhomologous end joining,MGMT interacts with XRCC6 to resist chemotherapy drugs.Our transcriptome data from samples of 88 patients with CRC suggest that MGMT expression is co-related with the Wnt signaling pathway activation,and several Wnt inhibitors can repress drug-resistant cells.In summary,our results point out that MGMT is a potential therapeutic target and predictive marker of chemoresistance in CRC.展开更多
Sex control techniques are in great demand for aquaculture because of the huge benefits of mono-sex production.In a previous study on yellow catfish(Tachysurus fulvidraco),intersex individuals were produced by adminis...Sex control techniques are in great demand for aquaculture because of the huge benefits of mono-sex production.In a previous study on yellow catfish(Tachysurus fulvidraco),intersex individuals were produced by administrating 17α-methyltestosterone(MT)or aromatase inhibitor letrozole(LZ).The ovarian and testicular portions of intersexual gonads developed well and were completely separated,arousing our interest in producing self-fertilizable fish and clone-like fish populations.In this study,yellow catfish fry were treated with a combination of MT and LZ at a low dose(5 mg kg^(-1)MT,300 mg kg^(-1)LZ)at a low water temperature(27.0℃,mixed sex-producing temperature,LL group)and a high temperature(33.5◦C,male-producing temperature,HL group),and with a high dose(10 mg kg^(-1) MT,600 mg kg^(-1) LZ)at a low water temperature(LH group),during 12-65 days post-hatching,the critical period of sex differentiation.Both XX and XY intersex were produced with different percentages at the same time through co-treatment with MT and LZ,with or without the help of male-producing temperature.The highest percentage of XY intersex(53%in XY,36%in XX and XY)and XX intersex(47%in XX,25%in XX and XY)was produced in LH and HL groups,respectively.Results of gonadal morphology,histology,and sperm dynamic analysis indicate that some XX and XY intersex individuals were capable of self-fertilization through artificial insemination.The reproductive performance of these intersex individuals was then investigated by injecting spawning agents,dissecting gonads,and artificially fertilizing eggs with their own sperm.The XX,XY,and YY genotypic individuals were produced by the self-fertilization of XY intersex individuals.The present study successfully produced high percentages of XX and XY intersex and conducted self-fertilization by mating the eggs and sperm of a single intersex individual.Self-fertilization in fish will show great potential in aquaculture genetics and breeding,for example,generating highly homozygous(or"clonal")genetic material,producing mono-sex populations,and identifying unknown sex determination modes.In particular,the cloning method of producing genetic materials will be greatly beneficial for maintaining advantageous traits through self-fertilization generation after generation.展开更多
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.:82003807,82173394)the Shaanxi Province Science Foundation,China(Grant No.:2023-GHZD-19)+1 种基金the Medical Foundation-Clinical Integration Program of Xi'an Jiaotong University,China(Grant No.:YXJLRH2022043)the Xi'an Jiaotong University Free Exploration and Innovation-Teacher Project Foundation,China(Grant No.:xzy012023104).
文摘Chemotherapy resistance plays a pivotal role in the prognosis and therapeutic failure of patients with colorectal cancer(CRC).Cisplatin(DDP)-resistant cells exhibit an inherent ability to evade the toxic chemotherapeutic drug effects which are characterized by the activation of slow-cycle programs and DNA repair.Among the elements that lead to DDP resistance,O^(6)-methylguanine(O^(6)-MG)-DNA-methyltransferase(MGMT),a DNA-repair enzyme,performs a quintessential role.In this study,we clarify the significant involvement of MGMT in conferring DDP resistance in CRC,elucidating the underlying mechanism of the regulatory actions of MGMT.A notable upregulation of MGMT in DDP-resistant cancer cells was found in our study,and MGMT repression amplifies the sensitivity of these cells to DDP treatment in vitro and in vivo.Conversely,in cancer cells,MGMT overexpression abolishes their sensitivity to DDP treatment.Mechanistically,the interaction between MGMT and cyclin dependent kinase 1(CDK1)inducing slow-cycling cells is attainted via the promotion of ubiquitination degradation of CDK1.Meanwhile,to achieve nonhomologous end joining,MGMT interacts with XRCC6 to resist chemotherapy drugs.Our transcriptome data from samples of 88 patients with CRC suggest that MGMT expression is co-related with the Wnt signaling pathway activation,and several Wnt inhibitors can repress drug-resistant cells.In summary,our results point out that MGMT is a potential therapeutic target and predictive marker of chemoresistance in CRC.
基金supported by the National Natural Science Foundation of China(32273122)Major Science and Technology project of Hubei Province(2023BBA001)+1 种基金Fundamental Research Funds for the Central Universities(2662021SCPY001)the Natural Science Foundation of Hubei Province(2018CFB215).
文摘Sex control techniques are in great demand for aquaculture because of the huge benefits of mono-sex production.In a previous study on yellow catfish(Tachysurus fulvidraco),intersex individuals were produced by administrating 17α-methyltestosterone(MT)or aromatase inhibitor letrozole(LZ).The ovarian and testicular portions of intersexual gonads developed well and were completely separated,arousing our interest in producing self-fertilizable fish and clone-like fish populations.In this study,yellow catfish fry were treated with a combination of MT and LZ at a low dose(5 mg kg^(-1)MT,300 mg kg^(-1)LZ)at a low water temperature(27.0℃,mixed sex-producing temperature,LL group)and a high temperature(33.5◦C,male-producing temperature,HL group),and with a high dose(10 mg kg^(-1) MT,600 mg kg^(-1) LZ)at a low water temperature(LH group),during 12-65 days post-hatching,the critical period of sex differentiation.Both XX and XY intersex were produced with different percentages at the same time through co-treatment with MT and LZ,with or without the help of male-producing temperature.The highest percentage of XY intersex(53%in XY,36%in XX and XY)and XX intersex(47%in XX,25%in XX and XY)was produced in LH and HL groups,respectively.Results of gonadal morphology,histology,and sperm dynamic analysis indicate that some XX and XY intersex individuals were capable of self-fertilization through artificial insemination.The reproductive performance of these intersex individuals was then investigated by injecting spawning agents,dissecting gonads,and artificially fertilizing eggs with their own sperm.The XX,XY,and YY genotypic individuals were produced by the self-fertilization of XY intersex individuals.The present study successfully produced high percentages of XX and XY intersex and conducted self-fertilization by mating the eggs and sperm of a single intersex individual.Self-fertilization in fish will show great potential in aquaculture genetics and breeding,for example,generating highly homozygous(or"clonal")genetic material,producing mono-sex populations,and identifying unknown sex determination modes.In particular,the cloning method of producing genetic materials will be greatly beneficial for maintaining advantageous traits through self-fertilization generation after generation.