目的探讨热休克蛋白90α(heat shock protein 90α,Hsp90α)在结肠癌中的表达及潜在的临床价值。方法采用生物信息学和免疫组化法分析结肠癌中Hsp90α的表达水平,及其与临床病理学特征、预后和免疫细胞浸润水平的关系;采用CCK-8细胞增...目的探讨热休克蛋白90α(heat shock protein 90α,Hsp90α)在结肠癌中的表达及潜在的临床价值。方法采用生物信息学和免疫组化法分析结肠癌中Hsp90α的表达水平,及其与临床病理学特征、预后和免疫细胞浸润水平的关系;采用CCK-8细胞增殖实验和平板克隆实验检测敲除Hsp90AA1前后结肠癌细胞的增殖能力。结果生物信息学分析结果显示,Hsp90AA1在结肠癌组织中异常高表达,其表达水平越高,患者预后越差;Hsp90AA1表达与CD4^(+)T细胞(Th2)、CD8^(+)T细胞、髓样抑制细胞、Tregs细胞、中性粒细胞、巨噬细胞、M1巨噬细胞、M2巨噬细胞的浸润水平呈正相关;免疫组化结果显示结肠癌组织中Hsp90α表达明显高于癌旁正常组织,Hsp90α表达与患者性别、肿瘤大小、位置、分化程度、TNM分期、淋巴结转移、脉管癌栓、神经侵犯、远处转移等无关(P>0.05),与结肠癌患者年龄具有相关性(P<0.05)。Hsp90α高表达是影响结肠癌患者预后的独立危险因素。细胞实验结果显示,敲除Hsp90AA1可抑制结肠癌细胞的生长及增殖能力。结论Hsp90α在结肠癌中高表达,可能是结肠癌预后不良的潜在分子学标志物。展开更多
Hsp90 (Heat Shock Protein 90)是一种在细胞应激条件下诱导表达的分子伴侣蛋白,在发现其可以作为癌症的诊断手段及治疗靶点后,其研究迎来了井喷式的发展。已有研究表明,Hsp90α不仅与肿瘤细胞的生存、增殖和迁移有关,还参与了肿瘤微环...Hsp90 (Heat Shock Protein 90)是一种在细胞应激条件下诱导表达的分子伴侣蛋白,在发现其可以作为癌症的诊断手段及治疗靶点后,其研究迎来了井喷式的发展。已有研究表明,Hsp90α不仅与肿瘤细胞的生存、增殖和迁移有关,还参与了肿瘤微环境的调控,其高表达与多种癌症类型的不良预后显著相关。近期的研究表明,p53也与Hsp90α拥有复杂而密切的联系,二者之间的交互作用对肿瘤的发生发展有十分重要的作用。在本综述中,我们将探讨Hsp90α在癌症发生和治疗中的作用,关注其与p53这一关键肿瘤抑制蛋白的相互作用。展开更多
BACKGROUND Pancreatic cancer(PC)is associated with some of the worst prognoses of all major cancers.Thymoquinone(TQ)has a long history in traditional medical practice and is known for its anti-cancer,anti-inflammatory...BACKGROUND Pancreatic cancer(PC)is associated with some of the worst prognoses of all major cancers.Thymoquinone(TQ)has a long history in traditional medical practice and is known for its anti-cancer,anti-inflammatory,anti-fibrosis and antioxidant pharmacological activities.Recent studies on hypoxia-inducible factor-1α(HIF-1α)and PC have shown that HIF-1αaffects the occurrence and development of PC in many aspects.In addition,TQ could inhibit the development of renal cancer by decreasing the expression of HIF-1α.Therefore,we speculate whether TQ affects HIF-1αexpression in PC cells and explore the mechanism.AIM To elucidate the effect of TQ in PC cells and the regulatory mechanism of HIF-1αexpression.METHODS Cell counting kit-8 assay,Transwell assay and flow cytometry were performed to detect the effects of TQ on the proliferative activity,migration and invasion ability and apoptosis of PANC-1 cells and normal pancreatic duct epithelial(hTERTHPNE)cells.Quantitative real-time polymerase chain reaction and western blot assay were performed to detect the expression of HIF-1αmRNA and protein in PC cells.The effects of TQ on the HIF-1αprotein initial expression pathway and ubiquitination degradation in PANC-1 cells were examined by western blot assay and co-immunoprecipitation.RESULTS TQ significantly inhibited proliferative activity,migration,and invasion ability and promoted apoptosis of PANC-1 cells;however,no significant effects on hTERT-HPNE cells were observed.TQ significantly reduced the mRNA and protein expression levels of HIF-1αin PANC-1,AsPC-1,and BxPC-3 cells.TQ significantly inhibited the expression of the HIF-1αinitial expression pathway(PI3K/AKT/mTOR)related proteins,and promoted the ubiquitination degradation of the HIF-1αprotein in PANC-1 cells.TQ had no effect on the hydroxylation and von Hippel Lindau protein mediated ubiquitination degradation of the HIF-1αprotein but affected the stability of the HIF-1αprotein by inhibiting the interaction between HIF-1αand HSP90,thus promoting its ubiquitination degradation.CONCLUSION The regulatory mechanism of TQ on HIF-1αprotein expression in PC cells was mainly to promote the ubiquitination degradation of the HIF-1αprotein by inhibiting the interaction between HIF-1αand HSP90;Secondly,TQ reduced the initial expression of HIF-1αprotein by inhibiting the PI3K/AKT/mTOR pathway.展开更多
Lymphatic metastasis(LM)emerges as an independent prognostic marker for hypopharyngeal squamous cell carcinoma(HSPSCC),chiefly contributing to treatment inefficacy.This study aimed to scrutinize the prognostic relevan...Lymphatic metastasis(LM)emerges as an independent prognostic marker for hypopharyngeal squamous cell carcinoma(HSPSCC),chiefly contributing to treatment inefficacy.This study aimed to scrutinize the prognostic relevance of HSP90AA1 and its potential regulatory mechanism of concerning LM in HPSCC.Methods:In a preceding investigation,HSP90AA1,a differential gene,was discovered through transcriptome sequencing of HPSCC tissues,considering both the presence and absence of LM.Validation of HSP90AA1 expression was accomplished via qRT-PCR,western-blotting(WB),and immunohistochemistry(IHC),while its prognostic significance was assessed employing Kaplan–Meier survival analysis(KMSA),log-rank test(LR),and Cox’s regression analysis(CRA).Bioinformatics techniques facilitated the prediction and analysis of its plausible mechanisms in LM,further substantiated by in vitro and in vivo experiments utilizing FaDu cell lines.Results:HSP90AA1 is substantially upregulated in HPSCC with LM and is identified as an independent prognostic risk determinant.The down-regulation of HSP90AA1 can achieve inhibition of tumor cell proliferation,migration and invasion.Both in vivo experiments and Bioinformatics exploration hint at promoting LM by Epithelial-mesenchymal transition(EMT),regulated by HSP90AA1.Conclusions:HSP90AA1,by controlling EMT,can foster LM in HPSCC.This finding sets the foundation for delving into new therapeutic targets for HPSCC.展开更多
Ginsenoside Rg5 is a rare ginsenoside showing promising tumor-suppressive effects.This study aimed to explore its radio-sensitizing effects and the underlying mechanisms.Human lung adenocarcinoma cell lines A549 and C...Ginsenoside Rg5 is a rare ginsenoside showing promising tumor-suppressive effects.This study aimed to explore its radio-sensitizing effects and the underlying mechanisms.Human lung adenocarcinoma cell lines A549 and Calu-3 were used for in vitro and in vivo analysis.Bioinformatic molecular docking prediction and following validation by surface plasmon resonance(SPR)technology,cellular thermal shift assay(CETSA),and isothermal titration calorimetry(ITC)were conducted to explore the binding between ginsenoside Rg5 and 90 kD heat shock protein alpha(HSP90a).The effects of ginsenoside Rg5 on HSP90-cell division cycle 37(CDC37)interaction,the client protein stability,and the downstream regulations were further explored.Results showed that ginsenoside Rg5 could induce cell-cycle arrest at the G1 phase and enhance irradiationinduced cell apoptosis.It could bind to HSP90a with a high affinity,but the affinity was drastically decreased by HSP90a Y61A mutation.Co-immunoprecipitation(Co-IP)and ITC assays confirmed that ginsenoside Rg5 disrupts the HSP90-CDC37 interaction in a dose-dependent manner.It reduced irradiation-induced upregulation of the HSP90-CDC37 client proteins,including SRC,CDK4,RAF1,and ULK1 in A549 cell-derived xenograft(CDX)tumors.Ginsenoside Rg5 or MRT67307(an IKKε/TBK1 inhibitor)pretreatment suppressed irradiation-induced elevation of the LC3-II/b ratio and restored irradiation-induced downregulation of p62 expression.In A549 CDX tumors,ginsenoside Rg5 treatment suppressed LC3 expression and enhanced irradiation-induced DNA damage.In conclusion,ginsenoside Rg5 may be a potential radiosensitizer for lung adenocarcinoma.It interacts with HSP90a and reduces the binding between HSP90 and CDC37,thereby increasing the ubiquitin-mediated proteasomal degradation of the HSP90-CDC37 client proteins.展开更多
Ionizing radiation is a popular and effective treatment option for glioblastoma(GBM).However,resistance to radiation therapy inevitably occurs during treatment.It is urgent to investigate the mechanisms of radioresist...Ionizing radiation is a popular and effective treatment option for glioblastoma(GBM).However,resistance to radiation therapy inevitably occurs during treatment.It is urgent to investigate the mechanisms of radioresistance in GBM and to find ways to improve radiosensitivity.Here,we found that heat shock protein 90 beta family member 1(HSP90B1)was significantly upregulated in radioresistant GBM cell lines.More importantly,HSP90B1 promoted the localization of glucose transporter type 1,a key rate-limiting factor of glycolysis,on the plasma membrane,which in turn enhanced glycolytic activity and subsequently tumor growth and radioresistance of GBM cells.These findings imply that targeting HSP90B1 may effectively improve the efficacy of radiotherapy for GBM patients,a potential new approach to the treatment of glioblastoma.展开更多
文摘目的探讨热休克蛋白90α(heat shock protein 90α,Hsp90α)在结肠癌中的表达及潜在的临床价值。方法采用生物信息学和免疫组化法分析结肠癌中Hsp90α的表达水平,及其与临床病理学特征、预后和免疫细胞浸润水平的关系;采用CCK-8细胞增殖实验和平板克隆实验检测敲除Hsp90AA1前后结肠癌细胞的增殖能力。结果生物信息学分析结果显示,Hsp90AA1在结肠癌组织中异常高表达,其表达水平越高,患者预后越差;Hsp90AA1表达与CD4^(+)T细胞(Th2)、CD8^(+)T细胞、髓样抑制细胞、Tregs细胞、中性粒细胞、巨噬细胞、M1巨噬细胞、M2巨噬细胞的浸润水平呈正相关;免疫组化结果显示结肠癌组织中Hsp90α表达明显高于癌旁正常组织,Hsp90α表达与患者性别、肿瘤大小、位置、分化程度、TNM分期、淋巴结转移、脉管癌栓、神经侵犯、远处转移等无关(P>0.05),与结肠癌患者年龄具有相关性(P<0.05)。Hsp90α高表达是影响结肠癌患者预后的独立危险因素。细胞实验结果显示,敲除Hsp90AA1可抑制结肠癌细胞的生长及增殖能力。结论Hsp90α在结肠癌中高表达,可能是结肠癌预后不良的潜在分子学标志物。
文摘Hsp90 (Heat Shock Protein 90)是一种在细胞应激条件下诱导表达的分子伴侣蛋白,在发现其可以作为癌症的诊断手段及治疗靶点后,其研究迎来了井喷式的发展。已有研究表明,Hsp90α不仅与肿瘤细胞的生存、增殖和迁移有关,还参与了肿瘤微环境的调控,其高表达与多种癌症类型的不良预后显著相关。近期的研究表明,p53也与Hsp90α拥有复杂而密切的联系,二者之间的交互作用对肿瘤的发生发展有十分重要的作用。在本综述中,我们将探讨Hsp90α在癌症发生和治疗中的作用,关注其与p53这一关键肿瘤抑制蛋白的相互作用。
基金Supported by Health Commission of Qinghai Province,No.2021-wjzdx-18.
文摘BACKGROUND Pancreatic cancer(PC)is associated with some of the worst prognoses of all major cancers.Thymoquinone(TQ)has a long history in traditional medical practice and is known for its anti-cancer,anti-inflammatory,anti-fibrosis and antioxidant pharmacological activities.Recent studies on hypoxia-inducible factor-1α(HIF-1α)and PC have shown that HIF-1αaffects the occurrence and development of PC in many aspects.In addition,TQ could inhibit the development of renal cancer by decreasing the expression of HIF-1α.Therefore,we speculate whether TQ affects HIF-1αexpression in PC cells and explore the mechanism.AIM To elucidate the effect of TQ in PC cells and the regulatory mechanism of HIF-1αexpression.METHODS Cell counting kit-8 assay,Transwell assay and flow cytometry were performed to detect the effects of TQ on the proliferative activity,migration and invasion ability and apoptosis of PANC-1 cells and normal pancreatic duct epithelial(hTERTHPNE)cells.Quantitative real-time polymerase chain reaction and western blot assay were performed to detect the expression of HIF-1αmRNA and protein in PC cells.The effects of TQ on the HIF-1αprotein initial expression pathway and ubiquitination degradation in PANC-1 cells were examined by western blot assay and co-immunoprecipitation.RESULTS TQ significantly inhibited proliferative activity,migration,and invasion ability and promoted apoptosis of PANC-1 cells;however,no significant effects on hTERT-HPNE cells were observed.TQ significantly reduced the mRNA and protein expression levels of HIF-1αin PANC-1,AsPC-1,and BxPC-3 cells.TQ significantly inhibited the expression of the HIF-1αinitial expression pathway(PI3K/AKT/mTOR)related proteins,and promoted the ubiquitination degradation of the HIF-1αprotein in PANC-1 cells.TQ had no effect on the hydroxylation and von Hippel Lindau protein mediated ubiquitination degradation of the HIF-1αprotein but affected the stability of the HIF-1αprotein by inhibiting the interaction between HIF-1αand HSP90,thus promoting its ubiquitination degradation.CONCLUSION The regulatory mechanism of TQ on HIF-1αprotein expression in PC cells was mainly to promote the ubiquitination degradation of the HIF-1αprotein by inhibiting the interaction between HIF-1αand HSP90;Secondly,TQ reduced the initial expression of HIF-1αprotein by inhibiting the PI3K/AKT/mTOR pathway.
基金supported by the National Natural Science Foundation of China(Grant No.82173303)Natural Science Foundation of Chongqing,China(Grant No.cstc2021ycjh-bgzxm0149).
文摘Lymphatic metastasis(LM)emerges as an independent prognostic marker for hypopharyngeal squamous cell carcinoma(HSPSCC),chiefly contributing to treatment inefficacy.This study aimed to scrutinize the prognostic relevance of HSP90AA1 and its potential regulatory mechanism of concerning LM in HPSCC.Methods:In a preceding investigation,HSP90AA1,a differential gene,was discovered through transcriptome sequencing of HPSCC tissues,considering both the presence and absence of LM.Validation of HSP90AA1 expression was accomplished via qRT-PCR,western-blotting(WB),and immunohistochemistry(IHC),while its prognostic significance was assessed employing Kaplan–Meier survival analysis(KMSA),log-rank test(LR),and Cox’s regression analysis(CRA).Bioinformatics techniques facilitated the prediction and analysis of its plausible mechanisms in LM,further substantiated by in vitro and in vivo experiments utilizing FaDu cell lines.Results:HSP90AA1 is substantially upregulated in HPSCC with LM and is identified as an independent prognostic risk determinant.The down-regulation of HSP90AA1 can achieve inhibition of tumor cell proliferation,migration and invasion.Both in vivo experiments and Bioinformatics exploration hint at promoting LM by Epithelial-mesenchymal transition(EMT),regulated by HSP90AA1.Conclusions:HSP90AA1,by controlling EMT,can foster LM in HPSCC.This finding sets the foundation for delving into new therapeutic targets for HPSCC.
基金supported by grants from the Project of Sichuan Science and Technology Department,China(Grant No.:2021YJ0010).
文摘Ginsenoside Rg5 is a rare ginsenoside showing promising tumor-suppressive effects.This study aimed to explore its radio-sensitizing effects and the underlying mechanisms.Human lung adenocarcinoma cell lines A549 and Calu-3 were used for in vitro and in vivo analysis.Bioinformatic molecular docking prediction and following validation by surface plasmon resonance(SPR)technology,cellular thermal shift assay(CETSA),and isothermal titration calorimetry(ITC)were conducted to explore the binding between ginsenoside Rg5 and 90 kD heat shock protein alpha(HSP90a).The effects of ginsenoside Rg5 on HSP90-cell division cycle 37(CDC37)interaction,the client protein stability,and the downstream regulations were further explored.Results showed that ginsenoside Rg5 could induce cell-cycle arrest at the G1 phase and enhance irradiationinduced cell apoptosis.It could bind to HSP90a with a high affinity,but the affinity was drastically decreased by HSP90a Y61A mutation.Co-immunoprecipitation(Co-IP)and ITC assays confirmed that ginsenoside Rg5 disrupts the HSP90-CDC37 interaction in a dose-dependent manner.It reduced irradiation-induced upregulation of the HSP90-CDC37 client proteins,including SRC,CDK4,RAF1,and ULK1 in A549 cell-derived xenograft(CDX)tumors.Ginsenoside Rg5 or MRT67307(an IKKε/TBK1 inhibitor)pretreatment suppressed irradiation-induced elevation of the LC3-II/b ratio and restored irradiation-induced downregulation of p62 expression.In A549 CDX tumors,ginsenoside Rg5 treatment suppressed LC3 expression and enhanced irradiation-induced DNA damage.In conclusion,ginsenoside Rg5 may be a potential radiosensitizer for lung adenocarcinoma.It interacts with HSP90a and reduces the binding between HSP90 and CDC37,thereby increasing the ubiquitin-mediated proteasomal degradation of the HSP90-CDC37 client proteins.
基金supported by the National Natural Science Foundation of China(Grant Nos.82072765 to X.Q.and 82172667 to X.W.).
文摘Ionizing radiation is a popular and effective treatment option for glioblastoma(GBM).However,resistance to radiation therapy inevitably occurs during treatment.It is urgent to investigate the mechanisms of radioresistance in GBM and to find ways to improve radiosensitivity.Here,we found that heat shock protein 90 beta family member 1(HSP90B1)was significantly upregulated in radioresistant GBM cell lines.More importantly,HSP90B1 promoted the localization of glucose transporter type 1,a key rate-limiting factor of glycolysis,on the plasma membrane,which in turn enhanced glycolytic activity and subsequently tumor growth and radioresistance of GBM cells.These findings imply that targeting HSP90B1 may effectively improve the efficacy of radiotherapy for GBM patients,a potential new approach to the treatment of glioblastoma.
