三阴性乳腺癌(triple-negative breast cancer,TNBC)侵袭性强、复发率高且缺乏有效的治疗方法,是预后最差的乳腺癌亚型,因此寻找针对TNBC的有效靶向疗法成为当务之急.组织蛋白酶A(cathepsin A,CTSA)是一种酸性丝氨酸羧肽酶,在多种肿瘤组织中高表达,但是CTSA在TNBC中的作用及机制尚不明确.本研究发现CTSA在TNBC中表达上调,高表达的CTSA与TNBC患者不良预后呈现正相关.实验结果进一步显示,敲低CTSA抑制TNBC细胞的增殖、侵袭和克隆形成能力,提高其药物敏感性,抑制TNBC疾病进展.机制研究表明,CTSA通过阻碍早幼粒细胞白血病蛋白(promyelocytic leukemia protein,PML)与其E3泛素连接酶RNF4相互作用,抑制PML蛋白泛素化和降解,进而维持PML核小体(PML nuclear bodies,PML-NBs)结构稳定性.体外结果显示,CTSA抑制剂具有抑制TNBC干细胞性状的治疗效果.综上,本研究表明抑制CTSA促进PML的降解可能作为TNBC的潜在治疗策略.本实验所有动物实验获得中国医学科学院医药生物技术研究所伦理委员会批准(批准号:IMB-20240326D502).
Cathepsin A maintains the characteristics of tumor stem cells and promotes the occurrence and development of triple-negative breast cancer
Triple-negative breast cancer(TNBC)is a subtype of breast cancer known for the poor prognosis due to its strong invasiveness,high recurrence rate,and lack of effective treatment.Therefore,there is an urgent need to find targeted therapy for TNBC.Cathepsin A(CTSA)is an acidic serine carboxypeptidase that is highly expressed in various tumor tissues.However,the role and molecular mechanism of CTSA in TNBC are still unclear.This study found that the expression of CTSA was upregulated,and the high expression of CTSA was positively correlated with the poor prognosis of TNBC.The results further showed that knocking down CTSA inhibited the proliferation,invasion,and colony formation of TNBC cells,improved drug sensitivity of cells,and inhibited the progression of TNBC.Mechanistically,CTSA inhibited the ubiquitination and degradation of the promyelocytic leukemia protein(PML)protein by blocking the interaction between PML and its E3 ubiquitin ligase RNF4,thus maintaining the stability of PML nuclear bodies(PML-NBs).The inhibitor of CTSA had a positive therapeutic effect on inhibiting the characteristics of TNBC stem cells.In conclusion,this study demonstrates that inhibiting CTSA to decrease the stability of PML protein may be a promising therapeutic strategy for TNBC.All animal experiments in this experiment were approved by the Ethics Committee of Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical College(approval number:IMB-20240326D502).
triple-negative breast cancercathepsin APML-NBscancer stem cellubiquitination
NETL
NSTL
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