该文旨在探究胰腺癌中溶质载体家族38成员9(solute carrier family 38 member 9,SLC38A9)的表达水平及其对患者预后的影响。采用免疫组化方法分析胰腺癌临床样本组织芯片HPan Ade170Sur01中SLC38A9的表达,该芯片包含胰腺癌组织99例、癌...该文旨在探究胰腺癌中溶质载体家族38成员9(solute carrier family 38 member 9,SLC38A9)的表达水平及其对患者预后的影响。采用免疫组化方法分析胰腺癌临床样本组织芯片HPan Ade170Sur01中SLC38A9的表达,该芯片包含胰腺癌组织99例、癌旁组织71例,结合患者临床病理资料及生存数据进行Cox回归分析。通过CCK8实验分析敲低SLC38A9对胰腺癌细胞系增殖的影响,并利用Transwell小室实验分析敲低SLC38A9对胰腺癌细胞系迁移、侵袭的作用。此外,采用Western blot法检测敲低SLC38A9对细胞自噬相关蛋白表达的影响。免疫组化显示,胰腺癌组织中SLC38A9阳性表达率显著高于癌旁组织(38%vs 13%,P<0.001),且SLC38A9高表达患者中位总体生存期(OS)较对照组缩短25个月(10个月vs 35个月,P=0.0136)。Cox多因素分析证实,SLC38A9高表达是胰腺癌患者预后的独立危险因素(HR=2.237,95%CI:1.210~4.136,P=0.010)。CCK8实验结果表明,沉默SLC38A9可以显著抑制胰腺癌细胞增殖。Transwell小室实验结果显示,下调SLC38A9表达可以明显抑制胰腺癌细胞迁移和侵袭。机制研究发现,敲低SLC38A9导致自噬关键蛋白LC3-II及Beclin-1表达下调,p62累积(P<0.05),提示SLC38A9通过激活自噬促进肿瘤进展。SLC38A9在胰腺癌中异常高表达,是患者预后的独立不良预测因子。其可能通过激活细胞自噬通路,促进肿瘤细胞的恶性生物学行为,提示SLC38A9可作为胰腺癌靶向治疗和预后评估的潜在分子标志物。展开更多
Lysosomes represent a promising target for cancer therapy and reducing drug resistance.However,the short treatment time and low efficiency of lysosomal targeting have limited the application in lysosome-targeting anti...Lysosomes represent a promising target for cancer therapy and reducing drug resistance.However,the short treatment time and low efficiency of lysosomal targeting have limited the application in lysosome-targeting anticancer drugs.In this study,we proposed an adhesive-bandage approach and synthesized a new lysosomal targeting drug,namely long-term lysosome-targeting anticancer drug(LLAD).It contains a SLC38A9-targeting covalently bound moiety and an alkaline component both to prolong the inhibition of SLC38A9 in lysosomes and alkalinize lysosomes.Upon short term and low-dose treatment of HeLa cells,at passage 0,with LLAD,it rapidly alkalinized lysosomes and also can be detected in lysosomes even at passage 15.LLAD induced apoptosis in HeLa cells through long-term lysosomal damage,and showed better long-term anticancer effect than cisplatin in vivo.Overall,our study paves the way for developing long-term lysosomal targeting drugs to treat cancer and overcome the drug resistance of cancer cells,and also provides a candidate drug,LLAD,for treating cancer.展开更多
文摘该文旨在探究胰腺癌中溶质载体家族38成员9(solute carrier family 38 member 9,SLC38A9)的表达水平及其对患者预后的影响。采用免疫组化方法分析胰腺癌临床样本组织芯片HPan Ade170Sur01中SLC38A9的表达,该芯片包含胰腺癌组织99例、癌旁组织71例,结合患者临床病理资料及生存数据进行Cox回归分析。通过CCK8实验分析敲低SLC38A9对胰腺癌细胞系增殖的影响,并利用Transwell小室实验分析敲低SLC38A9对胰腺癌细胞系迁移、侵袭的作用。此外,采用Western blot法检测敲低SLC38A9对细胞自噬相关蛋白表达的影响。免疫组化显示,胰腺癌组织中SLC38A9阳性表达率显著高于癌旁组织(38%vs 13%,P<0.001),且SLC38A9高表达患者中位总体生存期(OS)较对照组缩短25个月(10个月vs 35个月,P=0.0136)。Cox多因素分析证实,SLC38A9高表达是胰腺癌患者预后的独立危险因素(HR=2.237,95%CI:1.210~4.136,P=0.010)。CCK8实验结果表明,沉默SLC38A9可以显著抑制胰腺癌细胞增殖。Transwell小室实验结果显示,下调SLC38A9表达可以明显抑制胰腺癌细胞迁移和侵袭。机制研究发现,敲低SLC38A9导致自噬关键蛋白LC3-II及Beclin-1表达下调,p62累积(P<0.05),提示SLC38A9通过激活自噬促进肿瘤进展。SLC38A9在胰腺癌中异常高表达,是患者预后的独立不良预测因子。其可能通过激活细胞自噬通路,促进肿瘤细胞的恶性生物学行为,提示SLC38A9可作为胰腺癌靶向治疗和预后评估的潜在分子标志物。
基金supported by the National Natural Science Foundation of China(No.82003566)Henan Excellent Youth Found(No.242300421091,China)Program for Inno-vative Research Team(in Science and Technology)in University of Henan Province(24IRTSTHN039,China).
文摘Lysosomes represent a promising target for cancer therapy and reducing drug resistance.However,the short treatment time and low efficiency of lysosomal targeting have limited the application in lysosome-targeting anticancer drugs.In this study,we proposed an adhesive-bandage approach and synthesized a new lysosomal targeting drug,namely long-term lysosome-targeting anticancer drug(LLAD).It contains a SLC38A9-targeting covalently bound moiety and an alkaline component both to prolong the inhibition of SLC38A9 in lysosomes and alkalinize lysosomes.Upon short term and low-dose treatment of HeLa cells,at passage 0,with LLAD,it rapidly alkalinized lysosomes and also can be detected in lysosomes even at passage 15.LLAD induced apoptosis in HeLa cells through long-term lysosomal damage,and showed better long-term anticancer effect than cisplatin in vivo.Overall,our study paves the way for developing long-term lysosomal targeting drugs to treat cancer and overcome the drug resistance of cancer cells,and also provides a candidate drug,LLAD,for treating cancer.
