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
肿瘤细胞因癌基因突变、缺氧及营养受限而高度依赖未折叠蛋白反应(unfolded protein response,UPR)。细胞通过内质网(endoplasmic reticulum,ER)膜上3个跨膜蛋白感知未折叠蛋白信号,引起未折叠蛋白反应,动态调控内质网折叠能力,一方面...肿瘤细胞因癌基因突变、缺氧及营养受限而高度依赖未折叠蛋白反应(unfolded protein response,UPR)。细胞通过内质网(endoplasmic reticulum,ER)膜上3个跨膜蛋白感知未折叠蛋白信号,引起未折叠蛋白反应,动态调控内质网折叠能力,一方面通过暂时减缓翻译和加快蛋白质流出减少ER蛋白质折叠负担,另一方面通过转录因子提高伴侣分子合成,增加ER折叠能力。未折叠的蛋白质长时间积聚在ER会对细胞产生毒性,引起不能缓解的ER应激状态,启动细胞凋亡程序。热休克蛋白90(heat shock protein 90,Hsp90)是一种进化保守的伴侣分子,参与了300多种新生蛋白质的折叠与成熟,其中包括UPR重要信号IRE1α(inositol-requiring enzyme 1α)。Hsp90抑制剂导致细胞产生大量未折叠蛋白质,同时直接诱导IRE1α的降解,从而破坏UPR恢复蛋白质平衡的能力,诱导UPR相关凋亡。目前,Hsp90抑制剂可有效诱导分泌型肿瘤细胞如骨髓瘤以及RAS突变肿瘤UPR途径的凋亡。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.
文摘肿瘤细胞因癌基因突变、缺氧及营养受限而高度依赖未折叠蛋白反应(unfolded protein response,UPR)。细胞通过内质网(endoplasmic reticulum,ER)膜上3个跨膜蛋白感知未折叠蛋白信号,引起未折叠蛋白反应,动态调控内质网折叠能力,一方面通过暂时减缓翻译和加快蛋白质流出减少ER蛋白质折叠负担,另一方面通过转录因子提高伴侣分子合成,增加ER折叠能力。未折叠的蛋白质长时间积聚在ER会对细胞产生毒性,引起不能缓解的ER应激状态,启动细胞凋亡程序。热休克蛋白90(heat shock protein 90,Hsp90)是一种进化保守的伴侣分子,参与了300多种新生蛋白质的折叠与成熟,其中包括UPR重要信号IRE1α(inositol-requiring enzyme 1α)。Hsp90抑制剂导致细胞产生大量未折叠蛋白质,同时直接诱导IRE1α的降解,从而破坏UPR恢复蛋白质平衡的能力,诱导UPR相关凋亡。目前,Hsp90抑制剂可有效诱导分泌型肿瘤细胞如骨髓瘤以及RAS突变肿瘤UPR途径的凋亡。
