Hypoxia,as an important hallmark of the tumor microenvironment,is a major cause of oxidative stress and plays a central role in various malignant tumors,including glioblastoma.Elevated reactive oxygen species(ROS)in a...Hypoxia,as an important hallmark of the tumor microenvironment,is a major cause of oxidative stress and plays a central role in various malignant tumors,including glioblastoma.Elevated reactive oxygen species(ROS)in a hypoxic microenvironment promote glioblastoma progression;however,the underlying mechanism has not been clarified.Herein,we found that hypoxia promoted ROS production,and the proliferation,migration,and invasion of glioblastoma cells,while this promotion was restrained by ROS scavengers N-acetyl-L-cysteine(NAC)and diphenyleneiodonium chloride(DPI).Hypoxia-induced ROS activated hypoxia-inducible factor-1α(HIF-1α)signaling,which enhanced cell migration and invasion by epithelial-mesenchymal transition(EMT).Furthermore,the induction of serine protease inhibitor family E member 1(SERPINE1)was ROS-dependent under hypoxia,and HIF-1αmediated SERPINE1 increase induced by ROS via binding to the SERPINE1 promoter region,thereby facilitating glioblastoma migration and invasion.Taken together,our data revealed that hypoxia-induced ROS reinforce the hypoxic adaptation of glioblastoma by driving the HIF-1α-SERPINE1 signaling pathway,and that targeting ROS may be a promising therapeutic strategy for glioblastoma.展开更多
Accumulating evidence has confirmed the links between transfer RNA(tRNA)modifications and tumor progression.The present study is the first to explore the role of tRNA methyltransferase 5(TRMT5),which catalyzes the m1G...Accumulating evidence has confirmed the links between transfer RNA(tRNA)modifications and tumor progression.The present study is the first to explore the role of tRNA methyltransferase 5(TRMT5),which catalyzes the m1G37 modification of mitochondrial tRNAs in hepatocellular carcinoma(HCC)progression.Here,based on bioinformatics and clinical analyses,we identified that TRMT5 expression was upregulated in HCC,which correlated with poor prognosis.Silencing TRMT5 attenuated HCC proliferation and metastasis both in vivo and in vitro,which may be partially explained by declined extracellular acidification rate(ECAR)and oxygen consumption rate(OCR).Mechanistically,we discovered that knockdown of TRMT5 inactivated the hypoxia-inducible factor-1(HIF-1)signaling pathway by preventing HIF-1αstability through the enhancement of cellular oxygen content.Moreover,our data indicated that inhibition of TRMT5 sensitized HCC to doxorubicin by adjusting HIF-1α.In conclusion,our study revealed that targeting TRMT5 could inhibit HCC progression and increase the susceptibility of tumor cells to chemotherapy drugs.Thus,TRMT5 might be a carcinogenesis candidate gene that could serve as a potential target for HCC therapy.展开更多
It has been revealed that hypoxia is dynamic in hypertrophic scars;therefore,we considered that it may have different effects on hypoxia-inducible factor-1α(HIF-1α)and p53 expression.Herein,we aimed to confirm the p...It has been revealed that hypoxia is dynamic in hypertrophic scars;therefore,we considered that it may have different effects on hypoxia-inducible factor-1α(HIF-1α)and p53 expression.Herein,we aimed to confirm the presence of a teeterboard-like conversion between HIF-1αand p53,which is correlated with scar formation and regression.Thus,we obtained samples of normal skin and hypertrophic scars to identify the differences in HIF-1αand autophagy using immunohistochemistry and transmission electron microscopy.In addition,we used moderate hypoxia in vitro to simulate the proliferative scar,and silenced HIF-1αor p53 gene expression or triggered overexpression to investigate the changes of HIF-1αand p53 expression,autophagy,apoptosis,and cell proliferation under this condition.HIF-1α,p53,and autophagy-related proteins were assayed using western blotting and immunofluorescence,whereas apoptosis was detected using flow cytometry analysis,and cell proliferation was detected using cell counting kit-8(CCK-8)and 5-bromo-2′-deoxyuridine(BrdU)staining.Furthermore,immunoprecipitation was performed to verify the binding of HIF-1αand p53 to transcription cofactor p300.Our results demonstrated that,in scar tissue,HIF-1αexpression increased in parallel with autophagosome formation.Under hypoxia,HIF-1αexpression and autophagy were upregulated,whereas p53 expression and apoptosis were downregulated in vitro.HIF-1αknockdown downregulated autophagy,proliferation,and p300-bound HIF-1α,and upregulated p53 expression,apoptosis,and p300-bound p53.Meanwhile,p53 knockdown induced the opposite effects and enhanced HIF-1α,whereas p53 overexpression resulted in the same effects and reduced HIF-1α.Our results suggest a teeterboard-like conversion between HIF-1αand p53,which is linked with scar hyperplasia and regression.展开更多
The blocking of the immune checkpoint pathway with antibodies,especially targeting to programmed death-1/programmed death ligand-1(PD-1/PD-L1)pathway,was currently a widely used treatment strategy in clinical practice...The blocking of the immune checkpoint pathway with antibodies,especially targeting to programmed death-1/programmed death ligand-1(PD-1/PD-L1)pathway,was currently a widely used treatment strategy in clinical practice.However,the shortcomings of PD-L1 antibodies were constantly exposed with the deepening of its research and their therapeutic effect was limited by the translocation and redistribution of intracellular PD-L1.Herein,we proposed to improve immune checkpoint blockade therapy by using liposomes-coated CaO_(2)(CaO_(2)@Lipo)nanoparticles to inhibit the de novo biosynthesis of PD-L1.CaO_(2)@Lipo would produce oxygen and reduce hypoxia-inducible factor-1α(HIF-1α)level,which then downregulated the expression of PD-L1.Our in vitro and in vivo results have confirmed CaO_(2)@Lipo promoted the degradation of HIF-1αand then downregulated the expression of PD-L1 in cancer cells for avoiding immune escape.Furthermore,to mimicking the clinical protocol of anti-PD-L1 antibodies+chemo-drugs,CaO_(2)@Lipo was combined with doxorubicin(DOX)to investigate the tumor inhibition efficiency.We found CaO_(2)@Lipo enhanced DOX-induced immunogenic cell death(ICD)effect,which then promoted the infiltration of T cells,strengthened the blocking effect,thus provided an effective means to overcome the traditional immune checkpoint blockade treatment.展开更多
基金This work was supported by the National Natural Science Foundation of China(Nos.81772688 and 81372698)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)+1 种基金the Research Foundation for Talented Scholars of Xuzhou Medical University(No.RC20552223)the Postgraduate Research&Practice Innovation Program of Jiangsu Province(No.KYCX20_2463),China。
文摘Hypoxia,as an important hallmark of the tumor microenvironment,is a major cause of oxidative stress and plays a central role in various malignant tumors,including glioblastoma.Elevated reactive oxygen species(ROS)in a hypoxic microenvironment promote glioblastoma progression;however,the underlying mechanism has not been clarified.Herein,we found that hypoxia promoted ROS production,and the proliferation,migration,and invasion of glioblastoma cells,while this promotion was restrained by ROS scavengers N-acetyl-L-cysteine(NAC)and diphenyleneiodonium chloride(DPI).Hypoxia-induced ROS activated hypoxia-inducible factor-1α(HIF-1α)signaling,which enhanced cell migration and invasion by epithelial-mesenchymal transition(EMT).Furthermore,the induction of serine protease inhibitor family E member 1(SERPINE1)was ROS-dependent under hypoxia,and HIF-1αmediated SERPINE1 increase induced by ROS via binding to the SERPINE1 promoter region,thereby facilitating glioblastoma migration and invasion.Taken together,our data revealed that hypoxia-induced ROS reinforce the hypoxic adaptation of glioblastoma by driving the HIF-1α-SERPINE1 signaling pathway,and that targeting ROS may be a promising therapeutic strategy for glioblastoma.
基金This work was supported by the National Key Research and Development Program of China(Nos.2020YFA0113003 and 2018YFC1004803)the Fundamental Research Funds for the Central Universities.
文摘Accumulating evidence has confirmed the links between transfer RNA(tRNA)modifications and tumor progression.The present study is the first to explore the role of tRNA methyltransferase 5(TRMT5),which catalyzes the m1G37 modification of mitochondrial tRNAs in hepatocellular carcinoma(HCC)progression.Here,based on bioinformatics and clinical analyses,we identified that TRMT5 expression was upregulated in HCC,which correlated with poor prognosis.Silencing TRMT5 attenuated HCC proliferation and metastasis both in vivo and in vitro,which may be partially explained by declined extracellular acidification rate(ECAR)and oxygen consumption rate(OCR).Mechanistically,we discovered that knockdown of TRMT5 inactivated the hypoxia-inducible factor-1(HIF-1)signaling pathway by preventing HIF-1αstability through the enhancement of cellular oxygen content.Moreover,our data indicated that inhibition of TRMT5 sensitized HCC to doxorubicin by adjusting HIF-1α.In conclusion,our study revealed that targeting TRMT5 could inhibit HCC progression and increase the susceptibility of tumor cells to chemotherapy drugs.Thus,TRMT5 might be a carcinogenesis candidate gene that could serve as a potential target for HCC therapy.
基金This work was supported by the National Natural Science Foundation of China(No.81671914).
文摘It has been revealed that hypoxia is dynamic in hypertrophic scars;therefore,we considered that it may have different effects on hypoxia-inducible factor-1α(HIF-1α)and p53 expression.Herein,we aimed to confirm the presence of a teeterboard-like conversion between HIF-1αand p53,which is correlated with scar formation and regression.Thus,we obtained samples of normal skin and hypertrophic scars to identify the differences in HIF-1αand autophagy using immunohistochemistry and transmission electron microscopy.In addition,we used moderate hypoxia in vitro to simulate the proliferative scar,and silenced HIF-1αor p53 gene expression or triggered overexpression to investigate the changes of HIF-1αand p53 expression,autophagy,apoptosis,and cell proliferation under this condition.HIF-1α,p53,and autophagy-related proteins were assayed using western blotting and immunofluorescence,whereas apoptosis was detected using flow cytometry analysis,and cell proliferation was detected using cell counting kit-8(CCK-8)and 5-bromo-2′-deoxyuridine(BrdU)staining.Furthermore,immunoprecipitation was performed to verify the binding of HIF-1αand p53 to transcription cofactor p300.Our results demonstrated that,in scar tissue,HIF-1αexpression increased in parallel with autophagosome formation.Under hypoxia,HIF-1αexpression and autophagy were upregulated,whereas p53 expression and apoptosis were downregulated in vitro.HIF-1αknockdown downregulated autophagy,proliferation,and p300-bound HIF-1α,and upregulated p53 expression,apoptosis,and p300-bound p53.Meanwhile,p53 knockdown induced the opposite effects and enhanced HIF-1α,whereas p53 overexpression resulted in the same effects and reduced HIF-1α.Our results suggest a teeterboard-like conversion between HIF-1αand p53,which is linked with scar hyperplasia and regression.
基金the National Natural Science Foundation of China(Nos.31971304,32271420,and 21977024)the Beijing-Tianjin-Hebei Basic Research Cooperation Project(No.19JCZDJC64100)+3 种基金Cross-disciplinary Project of Hebei University(No.DXK201916)One Hundred Talent Project of Hebei Province(No.E2018100002)Science Fund for Creative Research Groups of Nature Science Foundation of Hebei Province(No.B2021201038)Guangdong Basic and Applied Basic Research Foundation(No.2021B1515120065).
文摘The blocking of the immune checkpoint pathway with antibodies,especially targeting to programmed death-1/programmed death ligand-1(PD-1/PD-L1)pathway,was currently a widely used treatment strategy in clinical practice.However,the shortcomings of PD-L1 antibodies were constantly exposed with the deepening of its research and their therapeutic effect was limited by the translocation and redistribution of intracellular PD-L1.Herein,we proposed to improve immune checkpoint blockade therapy by using liposomes-coated CaO_(2)(CaO_(2)@Lipo)nanoparticles to inhibit the de novo biosynthesis of PD-L1.CaO_(2)@Lipo would produce oxygen and reduce hypoxia-inducible factor-1α(HIF-1α)level,which then downregulated the expression of PD-L1.Our in vitro and in vivo results have confirmed CaO_(2)@Lipo promoted the degradation of HIF-1αand then downregulated the expression of PD-L1 in cancer cells for avoiding immune escape.Furthermore,to mimicking the clinical protocol of anti-PD-L1 antibodies+chemo-drugs,CaO_(2)@Lipo was combined with doxorubicin(DOX)to investigate the tumor inhibition efficiency.We found CaO_(2)@Lipo enhanced DOX-induced immunogenic cell death(ICD)effect,which then promoted the infiltration of T cells,strengthened the blocking effect,thus provided an effective means to overcome the traditional immune checkpoint blockade treatment.
