Jin Fang, Miao Yajing, Xu Pengyu, Qiu Xiaofei
Department of Pathology, Tianjin Medical University, Tianjin, China,
Respiratory Department, Tianjin Medical University General Hospital, Tianjin, China.
Onco Targets Ther. 2018 Sep 11;11:5723-5731. doi: 10.2147/OTT.S161760. eCollection 2018.
Cancer stem cells (CSCs) are a small population of cancer cells located within a tumor that are highly tumorigenic, capable of tumor initiation, and resistant to cancer therapies. We identified the potential genes involved in regulating stemness properties and investigated the mechanisms in small-cell lung cancer (SCLC).
Whole transcriptome sequencing technology was used to screen the potential genes involved in regulating stemness properties from SCLC-SCs (uPAR) and differentiated cells (uPAR) in the H446 cell line. The selected genes were validated by quantitative reverse transcription PCR and ELISAs. The effect of IL-8 on stemness of sphere-forming cells was determined through tumor sphere formation, wound healing migration, and in vivo tumorigenesis assays.
In our study, uPAR and uPAR cells showed different gene expression profiles. IL-8 was upregulated in SCLC sphere-forming cells. Blocking IL-8 expression with siRNA led to loss of stemness, including the self-renewal capability, migration, expression of stemness-related genes, and in vivo tumorigenicity, in sphere-forming cells. Consistently, exogenously added IL-8 enhanced stemness properties in parental cells.
IL-8 was upregulated in SCLC sphere-forming cells, and critical for the acquisition and/or maintenance of the stemness features in the SCLC cell line H446. Our results suggest that blocking IL-8 signaling may provide a novel therapeutic approach for targeting SCLC-SCs and improve treatment and outcomes in SCLC.
癌症干细胞（CSCs）是肿瘤内一小群具有高度致瘤性、能够引发肿瘤且对癌症治疗具有抗性的癌细胞。我们鉴定了参与调控干性特性的潜在基因，并研究了小细胞肺癌（SCLC）中的相关机制。
利用全转录组测序技术，从H446细胞系中的SCLC-SCs（uPAR）和分化细胞（uPAR）中筛选参与调控干性特性的潜在基因。通过定量逆转录PCR和酶联免疫吸附测定法对所选基因进行验证。通过肿瘤球形成、伤口愈合迁移和体内肿瘤发生试验，确定白细胞介素-8（IL-8）对成球细胞干性的影响。
在我们的研究中，uPAR和uPAR细胞表现出不同的基因表达谱。IL-8在SCLC成球细胞中上调。用小干扰RNA（siRNA）阻断IL-8表达会导致成球细胞丧失干性，包括自我更新能力、迁移能力、干性相关基因的表达以及体内致瘤性。同样，外源性添加IL-8可增强亲本细胞的干性特性。
IL-8在SCLC成球细胞中上调，对SCLC细胞系H446干性特征的获得和/或维持至关重要。我们的结果表明，阻断IL-8信号通路可能为靶向SCLC-SCs提供一种新的治疗方法，并改善SCLC的治疗效果和预后。
