首页|PSME2和STAT3双重抑制通过合成致死效应诱导食管鳞癌细胞死亡

PSME2和STAT3双重抑制通过合成致死效应诱导食管鳞癌细胞死亡

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蛋白酶体激活物复合物亚基2(proteasome activator complex subunit 2,PSME2)表达异常与多种肿瘤发生发展密切相关,但在食管鳞癌(esophageal squamous cell carcinoma,ESCC)中功能及临床意义尚不明确.本研究分析了TCGA-ESCC和GSE53625数据库中ESCC转录物组数据,发现PSME2高表达组ESCC患者预后不良,且ESCC组织中PSME2蛋白表达水平高于癌旁组织.沉默KYSE30细胞和NE6-T细胞中PSME2表达,ESCC细胞的增殖、侵袭、迁移和克隆能力均显著下降,同时伴随着LC3-Ⅱ/LC3-I蛋白表达明显升高、p62蛋白表达降低和自噬激活.GSEA富集分析表明,PSME2低表达组IL-6/STAT3信号通路激活,沉默KYSE30细胞和NE6-T细胞诱导了IL-6分泌和p-STAT3表达增加.上述PSME2沉默诱导的分子变化,能够被LMT28或WP1066逆转.PSME2沉默联合WP1066,使KYSE30与NE6-T细胞培养上清中LDH含量明显升高,Calcein/PI染色表明,死亡细胞率分别为36.69％和32.55％,显著高于PSME2沉默(6.78％和6.74％)或 WP1066单独处理组(18.34％和9.70％).本研究表明,PSME2促进ESCC恶性进展,PSME2沉默通过IL-6/STAT3信号通路代偿性激活ESCC自噬,联合PSME2沉默和STAT3抑制通过合成致死效应诱导食管鳞癌细胞死亡,表明PSME2是ESCC潜在分子治疗靶点,联合抑制PSME2和STAT3是ESCC治疗的新选择.
Dual Inhibition of PSME2 and STAT3 Induces Esophageal Squamous Cell Carcinoma Cell Death via Synthetic Lethal Effects
Abnormal expression of PSME2(proteasome activator complex subunit 2,PSME2)is closely correlated with the occurrence and development of various tumors,but its biological function and clinical significance in esophageal squamous cell carcinoma(ESCC)are still unclear.In this study,we analyzed the transcriptome data of ESCC from the TCGA-ESCC and GSE53625 databases and found that high expression of PSME2 in ESCC patients was associated with poor prognosis.Additionally,the protein expression level of PSME2 in ESCC tissues was higher than that in adjacent non-cancerous tissues.Silencing of PSME2 in KYSE30 cells and NE6-T cells resulted in significant decreases in proliferation,invasion,migration,and clonogenicity of ESCC cells.Moreover,this was accompanied by a significant increase in the expression of LC3-Ⅱ/LC3-I protein ratio and a decrease in p62 protein expression as well as activation of autophagy.GSEA enrichment analysis indicated that the IL-6/STAT3 signaling pathway was activated in the PSME2 low-expression group.Silencing of PSME2 in KYSE30 cells and NE6-T cells led to increased secretion of IL-6 and elevated p-STAT3 protein levels.The molecular changes induced by PSME2 silencing were abrogated by treatments with LMT28 or WP1066.The combination of PSME2 silencing and WP1066 treatment significantly increased the LDH content in the supernatant of KYSE30 and NE6-T cell cultures.Calcein/PI staining revealed a cell death rate of 36.69％and 32.55％,respectively,which was significantly higher than that of the PSME2 silencing group(6.78％and 6.74％)or the WP1066 treatment group alone(18.34％and 9.70％).This study demonstrates that PSME2 promotes the malignant progression of ESCC and that PSME2 silencing compensates for this by activating autophagy through the IL-6/STAT3 signaling pathway.Furthermore,the combined inhibition of PSME2 and STAT3 induces synthetic lethal effects and leads to cell death in esophageal squamous carcinoma cells,suggesting that PSME2 is a potential molecular therapeutic target and that the combined inhibition of PSME2 and STAT3 represents a new treatment option for ESCC.

proteasome activator complex subunit 2(PSME2)esophageal squamous cell carcinoma(ESCC)STAT3autophagysynthetic lethality

孙魁、陈攀、刘永萱、康永安、吴晓爽、程月月、程浩东、刘其伟、高社干、齐义军

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河南科技大学临床医学院,河南科技大学第一附属医院,肿瘤医院,省部共建食管癌防治国家重点实验室,河南省微生态与食管癌防治重点实验室,河南省肿瘤表观遗传重点实验室,河南,洛阳 471003

许昌学院医学院细胞行为学重点实验室,河南,许昌 461000

蛋白酶体激活物复合物亚基2 食管鳞癌 STAT3 自噬 合成致死

国家自然科学基金河南省科技攻关计划河南科技大学第一附属医院肿瘤学国家临床重点专科建设开放联合基金

81872037242102310220ZLKFJJ20230101

2024

10.13865/j.cnki.cjbmb.2024.02.1465

中国生物化学与分子生物学报
中国生物化学与分子生物学会 北京大学

中国生物化学与分子生物学报

CSTPCD北大核心
影响因子：0.617
ISSN：1007-7626
年,卷(期)：2024.40(4)
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