Choe Chungyoul, Kim Hyewon, Min Sol, Park Sangkyu, Seo Jeongmin, Roh Sangho
Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Republic of Korea,
Laboratory of Cellular Reprogramming and Embryo Biotechnology, School of Dentistry, Seoul National University, Seoul, Republic of Korea,
Onco Targets Ther. 2018 Sep 25;11:6197-6207. doi: 10.2147/OTT.S175810. eCollection 2018.
Non-small cell lung cancer (NSCLC) is difficult to treat successfully. This intractability is mainly due to the cancer progressing through invasion, metastasis, chemotherapeutic resistance and relapse. Stemness has been linked to the various steps of cancer progression in a variety of tumors, yet little is known regarding its role in NSCLC.
In this study, we sought to determine the role of SOX2, a master regulator of pluripotency, in the growth of extracellular matrix (ECM)-detached cells during cancer progression.
We established a three-dimensional (3D) Poly-2-hydroxyethyl methacrylate (poly-HEMA) culture of lung adenocarcinoma (LUAD) A549 cells as an ECM-detached cell growth model and examined the role of stemness genes using siRNA and small molecule inhibitor in comparison to standard two dimensional (2D) culture.
In poly-HEMA culture, A549 cells formed substratum-detached spheroids with characteristics of intermediate epithelial to mesenchymal transition (EMT) and exhibited greater expression of SOX2 than did control 2D cells. Knockdown of SOX2 markedly suppressed the growth of A549 cell aggregates in poly-HEMA culture conditions and furthermore increased their sensitivity to the anticancer drug vinblastine with concomitant downregulation of the activity of the anti-apoptotic AKT kinase. Interestingly, a small molecule, RepSox, which replaces SOX2, stimulated A549 cell growth in poly-HEMA 3D culture condition.
Our findings strongly indicate that SOX2 contributes to anchorage-independent growth and chemoresistance via its downstream signaling mediator AKT kinase during the disease progression of NSCLC. SOX2 may therefore be an invaluable therapeutic target of NSCLC.
非小细胞肺癌（NSCLC）难以成功治疗。这种难治性主要是由于癌症通过侵袭、转移、化疗耐药和复发而进展。干性已与多种肿瘤的癌症进展的各个步骤相关联，但关于其在NSCLC中的作用知之甚少。
在本研究中，我们试图确定多能性的主要调节因子SOX2在癌症进展过程中细胞外基质（ECM）分离细胞生长中的作用。
我们建立了肺腺癌（LUAD）A549细胞的三维（3D）聚甲基丙烯酸2-羟乙酯（聚-HEMA）培养作为ECM分离细胞生长模型，并与标准二维（2D）培养相比，使用siRNA和小分子抑制剂研究干性基因的作用。
在聚-HEMA培养中，A549细胞形成了与基质分离的球体，具有中间上皮-间充质转化（EMT）的特征，并且比对照2D细胞表现出更高的SOX2表达。敲低SOX2显著抑制了聚-HEMA培养条件下A549细胞聚集体的生长，并且进一步增加了它们对抗癌药物长春花碱的敏感性，同时下调了抗凋亡AKT激酶的活性。有趣的是，一种替代SOX2的小分子RepSox在聚-HEMA 3D培养条件下刺激了A549细胞的生长。
我们的研究结果强烈表明，在NSCLC疾病进展过程中，SOX2通过其下游信号介质AKT激酶促进非锚定依赖性生长和化疗耐药性。因此，SOX2可能是NSCLC的一个非常有价值的治疗靶点。
