期刊
ONCOTARGETS AND THERAPY
卷 11, 期 -, 页码 6197-6207出版社
DOVE MEDICAL PRESS LTD
DOI: 10.2147/OTT.S175810
关键词
SOX2; lung cancer; NSCLC; EMT; stemness; vinblastine
资金
- National Research Foundation of Korea (NRF) - Ministry of Science, ICT & Future Planning, Republic of Korea [2013R1A1A2062457, 2016R1A6A3A11932167, 2016R1D1A1B03931864]
Background: 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. Sternness has been linked to the various steps of cancer progression in a variety of tumors, yet little is known regarding its role in NSCLC. Purpose: 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. Methods: 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 sternness genes using siRNA and small molecule inhibitor in comparison to standard two dimensional (2D) culture. Results: 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. Conclusion: 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.
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