Ras/Raf/MEK/细胞外信号调节蛋白激酶（extracellular signal-regulated protein kinase,ERK）信号通路又称ERK通路,该通路主要由一个三级酶联功能单位构成,其通过＂瀑布式＂的级联反应,将细胞外刺激信号传至细胞内,引起一系列细胞反应...Ras/Raf/MEK/细胞外信号调节蛋白激酶（extracellular signal-regulated protein kinase,ERK）信号通路又称ERK通路,该通路主要由一个三级酶联功能单位构成,其通过＂瀑布式＂的级联反应,将细胞外刺激信号传至细胞内,引起一系列细胞反应,从而调控细胞增殖、分化、凋亡、转移等功能。展开更多
细胞在接受特定的细胞外信号刺激后会产生相应的特异性生理应答。Ras／Raf／MEK／ERK信号级联通路是一条可被广泛激活的有丝分裂原活化蛋白激酶（mitogen—activated protein kinase，MAPK）通路，它能将细胞外信号传递入细胞核内，引...细胞在接受特定的细胞外信号刺激后会产生相应的特异性生理应答。Ras／Raf／MEK／ERK信号级联通路是一条可被广泛激活的有丝分裂原活化蛋白激酶（mitogen—activated protein kinase，MAPK）通路，它能将细胞外信号传递入细胞核内，引起细胞内特异蛋白的表达谱变化，从而影响细胞命运。展开更多
Resistance to breast cancer(BCa) chemotherapy severely hampers the patient’s prognosis.MicroRNAs provide a potential therapeutic prospect for BCa.In this study,the reversal function of microRNA34 a(miR34 a) on doxoru...Resistance to breast cancer(BCa) chemotherapy severely hampers the patient’s prognosis.MicroRNAs provide a potential therapeutic prospect for BCa.In this study,the reversal function of microRNA34 a(miR34 a) on doxorubicin(Dox) resistance of BCa and the possible mechanism was investigated.We found that the relative level of miR34 a was significantly decreased in Dox-resistant breast cancer cell MCF-7(MCF-7/A) compared with Dox-sensitive MCF-7 cells.Transfection with miR34 a significantly suppressed the invasion,migration,adhesion of MCF-7/A cells without inhibiting their growth obviously.The combination of miR34 a and Dox could significantly inhibit the proliferation,migration,invasion and induce the apoptosis of MCF-7/A cells.The synergistic effect of this combination on resistant MCF-7/A cells has no obvious relation with the expressions of classical drug-resistant proteins P-GP,MRP and GST-π,while closely related with the down-regulation on TOP2 A and BCRP.Moreover,we found both protein and mRNA expression of Snail were significantly up-regulated in MCF-7/A cells in comparison with MCF-7 cells.Transfection with small interfering RNA(siRNA) of Snail could inhibit the invasion,migration and adhesion of drug-resistant MCF-7/A cells,while highexpression of Snail could remarkably promote the invasion,migration and adhesion of MCF-7 cells,which might be related with regulation of N-cadherin and E-cadherin.Transfection with miR34 a in MCF-7/A cells induced a decrease of Snail expression.The potential binding sites of miR34 a with 3’UTR of Snail were predicted by miRDB target prediction software,which was confirmed by luciferase reporter gene method.Results showed that the relative activity of luciferase was reduced in MCF-7/A cells after co-transfection of miR34 a and wild type(wt)-Snail,while did not change by co-transfection with miR34 a and 3’ UTR mutant type(mut) Snail.Combination of miR34 a and Dox induced a stronger decrease of Snail in MCF-7/A cells in comparison to miR34 a or Dox treatment alone.What’ more,for the first time,we also found miR34 a combined with Dox could obviously inhibit the expression of Snail through suppressing Notch/NF-κB and RAS/RAF/MEK/ERK pathway in MCF-7/A cells.In vivo study indicated that combination of miR34 a and Dox significantly slowed down tumor growth in MCF-7/A nude mouse xenograft model compared with Dox alone,which was manifested by the down-regulation of Snail and pro-apoptosis effect in tumor xenografts.These results together underline the relevance of miR34 a-driven regulation of Snail in drug resistance and co-administration of miR34 a and Dox may produce an effective therapy outcome in the future in clinic.展开更多
文摘Ras/Raf/MEK/细胞外信号调节蛋白激酶（extracellular signal-regulated protein kinase,ERK）信号通路又称ERK通路,该通路主要由一个三级酶联功能单位构成,其通过＂瀑布式＂的级联反应,将细胞外刺激信号传至细胞内,引起一系列细胞反应,从而调控细胞增殖、分化、凋亡、转移等功能。
文摘细胞在接受特定的细胞外信号刺激后会产生相应的特异性生理应答。Ras／Raf／MEK／ERK信号级联通路是一条可被广泛激活的有丝分裂原活化蛋白激酶（mitogen—activated protein kinase，MAPK）通路，它能将细胞外信号传递入细胞核内，引起细胞内特异蛋白的表达谱变化，从而影响细胞命运。
基金supported by Natural Science Foundation of Shandong Province(ZR2020MH419,China)Key Research and Development Program of Shandong Province(2017CXGC1401,China)+1 种基金Chinae Australia Centre for Health Sciences Research(CACHSR No.2019GJ01)Major Basic Research Projects of Shandong Province(ZR2018ZC0233,China)
文摘Resistance to breast cancer(BCa) chemotherapy severely hampers the patient’s prognosis.MicroRNAs provide a potential therapeutic prospect for BCa.In this study,the reversal function of microRNA34 a(miR34 a) on doxorubicin(Dox) resistance of BCa and the possible mechanism was investigated.We found that the relative level of miR34 a was significantly decreased in Dox-resistant breast cancer cell MCF-7(MCF-7/A) compared with Dox-sensitive MCF-7 cells.Transfection with miR34 a significantly suppressed the invasion,migration,adhesion of MCF-7/A cells without inhibiting their growth obviously.The combination of miR34 a and Dox could significantly inhibit the proliferation,migration,invasion and induce the apoptosis of MCF-7/A cells.The synergistic effect of this combination on resistant MCF-7/A cells has no obvious relation with the expressions of classical drug-resistant proteins P-GP,MRP and GST-π,while closely related with the down-regulation on TOP2 A and BCRP.Moreover,we found both protein and mRNA expression of Snail were significantly up-regulated in MCF-7/A cells in comparison with MCF-7 cells.Transfection with small interfering RNA(siRNA) of Snail could inhibit the invasion,migration and adhesion of drug-resistant MCF-7/A cells,while highexpression of Snail could remarkably promote the invasion,migration and adhesion of MCF-7 cells,which might be related with regulation of N-cadherin and E-cadherin.Transfection with miR34 a in MCF-7/A cells induced a decrease of Snail expression.The potential binding sites of miR34 a with 3’UTR of Snail were predicted by miRDB target prediction software,which was confirmed by luciferase reporter gene method.Results showed that the relative activity of luciferase was reduced in MCF-7/A cells after co-transfection of miR34 a and wild type(wt)-Snail,while did not change by co-transfection with miR34 a and 3’ UTR mutant type(mut) Snail.Combination of miR34 a and Dox induced a stronger decrease of Snail in MCF-7/A cells in comparison to miR34 a or Dox treatment alone.What’ more,for the first time,we also found miR34 a combined with Dox could obviously inhibit the expression of Snail through suppressing Notch/NF-κB and RAS/RAF/MEK/ERK pathway in MCF-7/A cells.In vivo study indicated that combination of miR34 a and Dox significantly slowed down tumor growth in MCF-7/A nude mouse xenograft model compared with Dox alone,which was manifested by the down-regulation of Snail and pro-apoptosis effect in tumor xenografts.These results together underline the relevance of miR34 a-driven regulation of Snail in drug resistance and co-administration of miR34 a and Dox may produce an effective therapy outcome in the future in clinic.
