Department of Pathology and Experimental Medicine, Graduate School of Medical Science, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto, 860-8556, Japan.
Department of Respiratory Medicine, Graduate School of Medical Science, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto, 860-8556, Japan.
Lab Invest. 2020 Dec;100(12):1575-1588. doi: 10.1038/s41374-020-00479-0. Epub 2020 Aug 14.
SOX2 is recognized as an oncogene in human small cell lung cancer (SCLC), which is an aggressive neuroendocrine (NE) tumor. However, the role of SOX2 in SCLC is not completely understood, and strategies to selectively target SOX2 in SCLC cells remain elusive. Here, we show, using next-generation sequencing, that SOX2 expressed in the ASCL1-high SCLC (SCLC-A) subtype cell line is dependent on ASCL1, which is a lineage-specific transcriptional factor, and is involved in NE differentiation and tumorigenesis. ASCL1 recruits SOX2, which promotes INSM1 and WNT11 expression. Immunohistochemical studies revealed that SCLC tissue samples expressed SOX2, ASCL1, and INSM1 in 18 out of the 30 cases (60%). Contrary to the ASCL1-SOX2 signaling axis controlling SCLC biology in the SCLC-A subtype, SOX2 targets distinct genes such as those related to the Hippo pathway in the ASCL1-negative, YAP1-high SCLC (SCLC-Y) subtype. Although SOX2 knockdown experiments suppressed NE differentiation and cell proliferation in the SCLC-A subtype, they did not sufficiently impair the growth of the SCLC-Y subtype cell lines in vitro and ex vivo. The present results support the importance of the ASCL1-SOX2 axis as a main subtype of SCLC, and suggest the therapeutic potential of targeting the ASCL1-SOX2 axis.
SOX2 被认为是人类小细胞肺癌（SCLC）中的致癌基因，SCLC 是一种侵袭性神经内分泌（NE）肿瘤。然而，SOX2 在 SCLC 中的作用尚不完全清楚，并且针对 SCLC 细胞中 SOX2 的选择性靶向策略仍然难以捉摸。在这里，我们使用下一代测序技术表明，在 ASCL1 高表达的 SCLC（SCLC-A）亚型细胞系中表达的 SOX2 依赖于 ASCL1，ASCL1 是一种谱系特异性转录因子，参与 NE 分化和肿瘤发生。ASCL1 招募 SOX2，促进 INSM1 和 WNT11 的表达。免疫组织化学研究表明，在 30 例 SCLC 组织样本中的 18 例（60%）中表达 SOX2、ASCL1 和 INSM1。与 ASCL1-SOX2 信号轴在 SCLC-A 亚型中控制 SCLC 生物学的情况相反，SOX2 在 ASCL1 阴性、YAP1 高表达的 SCLC（SCLC-Y）亚型中靶向不同的基因，如与 Hippo 通路相关的基因。尽管 SOX2 敲低实验抑制了 SCLC-A 亚型中的 NE 分化和细胞增殖，但它们并没有充分削弱体外和体外 SCLC-Y 亚型细胞系的生长。本研究结果支持 ASCL1-SOX2 轴作为 SCLC 的主要亚型的重要性，并表明靶向 ASCL1-SOX2 轴的治疗潜力。
