Guo Xiao-Fang, Wang Ling-Ling, Zheng Fei-Meng, Li He-Ping
Department of Medical Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Department of Breast Surgery, Heyuan Women and Children's Hospital and Health Institute, Heyuan, Guangdong, China.
Heliyon. 2025 Jan 10;11(2):e41795. doi: 10.1016/j.heliyon.2025.e41795. eCollection 2025 Jan 30.
Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer. The aberrant regulation of Paired box 6 (PAX6) expression has been proposed to play an important oncogenic role in several cancer types. Nevertheless, there is limited knowledge regarding its function in SCLC. Here, we find that PAX6 overexpression promotes SCLC cell proliferation and cell cycle progression, while downregulation of PAX6 expression suppresses SCLC cell proliferation and cell cycle progression. Moreover, PAX6 enhances the enrichment of the ALDEFLUOR+ and CD133+ population and promotes sphere formation in SCLC cells. Additionally, upregulation or downregulation of PAX6 expression does not induce apoptosis in SCLC cells. Upregulation of PAX6 expression alleviates cisplatin or etoposide-induced apoptosis in SCLC cells, while downregulation of PAX6 expression aggravates cisplatin or etoposide-induced apoptosis in SCLC cells. Furthermore, PAX6 promotes the expression of stem cell factor Nanog. Interestingly, the downregulation of Nanog expression abolishes PAX6 promoted cell proliferation and cell cycle progression. Moreover, the inhibition of Nanog expression results in the inability of PAX6 to promote the increase of the ALDEFLUOR+ population, as well as the inability to mitigate apoptosis produced by cisplatin or etoposide in SCLC cells. Mechanically, PAX6 suppresses the activation of the NOTCH pathway to enhance Nanog expression. NOTCH pathway activation abolishes PAX6 promoted cell proliferation, cell cycle progression, ALDEFLUOR+ population enrichment, and apoptosis protection effect in SCLC cells. Our data indicates that PAX6 could be a critical factor for controlling cell proliferation, cell cycle progression, cancer stem cell properties, and apoptosis in SCLC.
小细胞肺癌（SCLC）是一种侵袭性很强的肺癌。已有研究提出，配对盒6（PAX6）表达的异常调控在几种癌症类型中发挥重要的致癌作用。然而，关于其在SCLC中的功能，人们了解有限。在此，我们发现PAX6过表达促进SCLC细胞增殖和细胞周期进程，而PAX6表达下调则抑制SCLC细胞增殖和细胞周期进程。此外，PAX6增强了ALDEFLUOR+和CD133+细胞群体的富集，并促进SCLC细胞形成球状体。另外，PAX6表达上调或下调均不诱导SCLC细胞凋亡。PAX6表达上调减轻了顺铂或依托泊苷诱导的SCLC细胞凋亡，而PAX6表达下调则加重了顺铂或依托泊苷诱导的SCLC细胞凋亡。此外，PAX6促进干细胞因子Nanog 的表达。有趣的是，Nanog表达下调消除了PAX6促进的细胞增殖和细胞周期进程。此外，抑制Nanog表达导致PAX6无法促进ALDEFLUOR+细胞群体增加，也无法减轻顺铂或依托泊苷在SCLC细胞中产生的凋亡。从机制上讲，PAX6抑制NOTCH通路的激活以增强Nanog表达。NOTCH通路激活消除了PAX6促进的SCLC细胞增殖、细胞周期进程、ALDEFLUOR+细胞群体富集及凋亡保护作用。我们的数据表明，PAX6可能是控制SCLC细胞增殖、细胞周期进程、癌症干细胞特性及凋亡的关键因素。
