Targeting ITGB4/SOX2-driven cancer stem cells using proteasome inhibitors. Targeting ITGB4/SOX2-driven cancer stem cells using proteasome inhibitors

The transcription factor SOX2 required for pluripotency, is amplified in 40% of the lung squamous cell carcinoma (LUSC) cases. However, a long-term survival analysis using TCGA cohorts of LUSC patients revealed no significant differences between high versus low SOX2 expressing cases. The treatment options for irresectable LUSC are limited to chemotherapy where carboplatin or cisplatin is given in combination with gemcitabine. However, drug resistance remains a serious concern. We previously showed integrin β4 (ITGB4) and paxillin (PXN) play a critical role in platinum resistance in LUAD. Heterogenous NSCLC cells that up-regulate ITGB4 and PXN epigenetically, can switch phenotypes from cisplatin sensitive to tolerant. However, the significance of ITGB4 expression in SOX2 driven cancer stem cells (CSCs) in NSCLC remains unappreciated. In this study, we isolated CSCs from LUSC patients and characterized them. We elucidated the significance of ITGB4 and SOX2 expression in maintaining the stemness of CSCs and their response to cisplatin treatment. Finally, we showed that the proteasome inhibitor carfilzomib (CFZ) targets SOX2 dependent CSCs and this function of CFZ is independent of its proteasome inhibitory function. Overall design: Triplicates are provided for Control, Actinomycin D, and Carfilzomib (CFZ) in 3 Cell Lines (H520, SBC5, and COH2) >>>Raw data for human samples not available due to either unknown consent or lack of explicit consent<<<

作为维持细胞多能性所必需的转录因子SOX2，在40%的肺鳞状细胞癌（lung squamous cell carcinoma, LUSC）病例中发生扩增。然而，利用肺鳞状细胞癌患者的肿瘤基因组图谱（The Cancer Genome Atlas, TCGA）队列开展的长期生存分析显示，SOX2高表达与低表达病例之间无显著统计学差异。针对不可切除的肺鳞状细胞癌，现有治疗手段仅局限于化疗方案，即采用卡铂或顺铂联合吉西他滨，但耐药问题仍是亟待解决的重大临床难题。本团队此前已证实，整合素β4（integrin β4, ITGB4）与桩蛋白（paxillin, PXN）在肺腺癌（lung adenocarcinoma, LUAD）的铂类耐药过程中发挥关键调控作用。表观遗传上调整合素β4与桩蛋白表达的异质性非小细胞肺癌（non-small cell lung cancer, NSCLC）细胞，可将表型从顺铂敏感型转换为顺铂耐受型。然而，非小细胞肺癌中SOX2驱动的癌症干细胞（cancer stem cells, CSCs）内整合素β4表达的生物学意义仍未被充分阐明。本研究从肺鳞状细胞癌患者体内分离得到癌症干细胞并完成其表型鉴定，阐明了整合素β4与SOX2的表达在维持癌症干细胞干性以及其对顺铂治疗的响应中的核心作用。最后，本研究证实蛋白酶体抑制剂卡非佐米（carfilzomib, CFZ）可靶向SOX2依赖性癌症干细胞，且卡非佐米的这一功能与其本身的蛋白酶体抑制活性无关。实验整体设计：本研究在3株细胞系（H520、SBC5及COH2）中分别设置对照组、放线菌素D组与卡非佐米（carfilzomib, CFZ）组，每组均设置3次生物学重复。>>>由于人类样本的受试者知情同意情况未知或未获取明确知情同意，其原始数据暂未公开<<<