Cancer stem cells(CSCs)play an important role in metastasis development,tumor recurrence,and treatment resistance,and are essential for the eradication of cancer.Currently,therapies fail to eradicate CSCs due to their...Cancer stem cells(CSCs)play an important role in metastasis development,tumor recurrence,and treatment resistance,and are essential for the eradication of cancer.Currently,therapies fail to eradicate CSCs due to their therapeutic stress-induced cellular escape,which leads to enhanced aggressive behaviors compared with CSCs that have never been treated.However,the underlying mechanisms regulating the therapeutic escape remain unknown.To this end,we established a model to isolate the therapeutic escaped CSCs(TSCSCs)from breast CSCs and performed the transcription profile to reveal the mechanism.Mechanistically,we demonstrated that the behavior of therapeutic escape was regulated through the p38/MAPK signaling pathway,resulting in TSCSCs exhibiting enhanced motility and metastasis.Notably,blocking the p38/MAPK signaling pathway effectively reduced motility and metastasis ability both in vitro and in vivo,which were further supported by downregulated motility-related genes and epithelial-mesenchymal transition(EMT)-related proteins vimentin and N-cadherin.The obtained findings reveal the p38/MAPK pathway as a potential therapeutic target for TSCSCs and would provide profound implications for cancer therapy.展开更多
丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号通路是真核细胞功能高度保守的调节因子,在细胞受到外界刺激引起的炎症反应、应激反应等生理病理过程中起着重要调控作用。P38丝裂原活化蛋白激酶(p38 mitogen-activated...丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号通路是真核细胞功能高度保守的调节因子,在细胞受到外界刺激引起的炎症反应、应激反应等生理病理过程中起着重要调控作用。P38丝裂原活化蛋白激酶(p38 mitogen-activated protein kinase,p38-MAPK)信号通路是MAPK通路的亚族之一,在细胞炎症、组织再生、免疫反应中起着重要的作用。p38-MAPK信号通路的激活在染色质重塑和关键肌生成转录因子的激活中起着关键作用,而肌卫星细胞的激活又影响着骨骼肌的再生修复。本文对p38-MAPK信号通路的调控机制及其介导骨骼肌再生的研究进展进行了综述,以期为深入了解相关机制提供理论依据,并为进一步治疗骨骼肌损伤提供一定的临床参考。展开更多
Skeletal muscle differentiation is a highly coordinated process that involves many cellular signaling pathways and microRNAs(miRNAs).A group of muscle-specific miRNAs has been reported to promote myogenesis by suppres...Skeletal muscle differentiation is a highly coordinated process that involves many cellular signaling pathways and microRNAs(miRNAs).A group of muscle-specific miRNAs has been reported to promote myogenesis by suppressing key signaling pathways for cell growth.However,the functional role and regulatory mechanism of most non-muscle-specific miRNAs with stage-specific changes during differentiation are largely unclear.Here,we describe the functional characterization of miR-101a/b,a pair of non-muscle-specific miRNAs that show the largest change among a group of transiently upregulated miRNAs during myogenesis in C2C12 cells.The overexpression of miR-101a/b inhibits myoblast differentiation by suppressing the p38/MAPK,Interferon Gamma,and Wnt pathways and enhancing the C/EBP pathway.Mef2a,a key protein in the p38/MAPK pathway,was identified as a direct target of miR-101a/b.Interestingly,we found that the long non-coding RNA(lncRNA)Malat1,which promotes muscle differentiation,interacts with miR-101a/b,and this interaction competes with Mef2a mRNA to relieve the inhibition of the p38/MAPK pathway during myogenesis.These results uncovered a“braking”role in differentiation of transiently upregulated miRNAs and provided new insights into the competing endogenous RNA(ceRNA)regulatory mechanism in myoblast differentiation and myogenesis.展开更多
基金supported by National Natural Science Foundation of China(31971304,21807021)Science Fund for Creative Research Groups of Nature Science Foundation of Hebei Province(B2021201038)+5 种基金The central government-guided special funds for local scientific and technological development(226Z2603G)Science and Technology Research Project of Higher Education Institutions in Hebei Province(JZX2023001,ZD2022075)Hebei Youth Top Talent Project.National High-End Foreign Expert Recruitment Plan(G2022003007L)The Research and Innovation Team of Hebei University(IT2023C06,IT2023A01)Natural Science Foundation of Hebei province(B2020201055)Hebei Province Innovation Capability Enhancement Plan Project(22567632H)。
文摘Cancer stem cells(CSCs)play an important role in metastasis development,tumor recurrence,and treatment resistance,and are essential for the eradication of cancer.Currently,therapies fail to eradicate CSCs due to their therapeutic stress-induced cellular escape,which leads to enhanced aggressive behaviors compared with CSCs that have never been treated.However,the underlying mechanisms regulating the therapeutic escape remain unknown.To this end,we established a model to isolate the therapeutic escaped CSCs(TSCSCs)from breast CSCs and performed the transcription profile to reveal the mechanism.Mechanistically,we demonstrated that the behavior of therapeutic escape was regulated through the p38/MAPK signaling pathway,resulting in TSCSCs exhibiting enhanced motility and metastasis.Notably,blocking the p38/MAPK signaling pathway effectively reduced motility and metastasis ability both in vitro and in vivo,which were further supported by downregulated motility-related genes and epithelial-mesenchymal transition(EMT)-related proteins vimentin and N-cadherin.The obtained findings reveal the p38/MAPK pathway as a potential therapeutic target for TSCSCs and would provide profound implications for cancer therapy.
文摘丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号通路是真核细胞功能高度保守的调节因子,在细胞受到外界刺激引起的炎症反应、应激反应等生理病理过程中起着重要调控作用。P38丝裂原活化蛋白激酶(p38 mitogen-activated protein kinase,p38-MAPK)信号通路是MAPK通路的亚族之一,在细胞炎症、组织再生、免疫反应中起着重要的作用。p38-MAPK信号通路的激活在染色质重塑和关键肌生成转录因子的激活中起着关键作用,而肌卫星细胞的激活又影响着骨骼肌的再生修复。本文对p38-MAPK信号通路的调控机制及其介导骨骼肌再生的研究进展进行了综述,以期为深入了解相关机制提供理论依据,并为进一步治疗骨骼肌损伤提供一定的临床参考。
基金supported by the National Natural Science Foundation of China(31970604,31701116,31770879,31771459,31900903,81870449,81974436)the Major Research Plan of the National Natural Science Foundation of China(91940000)+1 种基金the Fundamental Research Funds for the Central Universities(20lgpy112)Science and Technology New Star in ZhuJiang Guangzhou City(201806010151).
文摘Skeletal muscle differentiation is a highly coordinated process that involves many cellular signaling pathways and microRNAs(miRNAs).A group of muscle-specific miRNAs has been reported to promote myogenesis by suppressing key signaling pathways for cell growth.However,the functional role and regulatory mechanism of most non-muscle-specific miRNAs with stage-specific changes during differentiation are largely unclear.Here,we describe the functional characterization of miR-101a/b,a pair of non-muscle-specific miRNAs that show the largest change among a group of transiently upregulated miRNAs during myogenesis in C2C12 cells.The overexpression of miR-101a/b inhibits myoblast differentiation by suppressing the p38/MAPK,Interferon Gamma,and Wnt pathways and enhancing the C/EBP pathway.Mef2a,a key protein in the p38/MAPK pathway,was identified as a direct target of miR-101a/b.Interestingly,we found that the long non-coding RNA(lncRNA)Malat1,which promotes muscle differentiation,interacts with miR-101a/b,and this interaction competes with Mef2a mRNA to relieve the inhibition of the p38/MAPK pathway during myogenesis.These results uncovered a“braking”role in differentiation of transiently upregulated miRNAs and provided new insights into the competing endogenous RNA(ceRNA)regulatory mechanism in myoblast differentiation and myogenesis.
