Department of Pulmonary Medicine, Zhongda Hospital, School of Medicine, South-east University, Ding jia qiao No. 87, Nanjing, Jiangsu, 210009, China; Medicine Department of Southeast University, Ding jia qiao No. 87, Nanjing, Jiangsu, 210009, China.
Department of Pulmonary Medicine, Zhongda Hospital, School of Medicine, South-east University, Ding jia qiao No. 87, Nanjing, Jiangsu, 210009, China.
Biochem Biophys Res Commun. 2019 Jun 30;514(3):853-860. doi: 10.1016/j.bbrc.2019.04.130. Epub 2019 May 9.
Delta-like protein 3 (DLL3) has been reported as a biomarker in various human tumors. However, the biological function and mechanism of it in advanced small cell lung cancer (SCLC) is rarely reported. This study was devised innovatively to explore the role of DLL3 in the progression of SCLC. Immunohistochemistry (IHC) analysis was used to examine DLL3 expression in paraffin-embedded SCLC tumor samples. Upregulation of DLL3 reduced chemotherapy sensitivity. Kaplan-Meier analysis was used to analyze the progression-free survival or overall survival of SCLC patients with high or low level of DLL3. The negative association between DLL3 expression and the PFS or OS rate of SCLC patients was identified. Relative high level of DLL3 was determined in SCLC cell lines by using qRT-PCR analysis. Loss-of function assays were performed to detect the biological functions of the silencing of DLL3 in SCLC. As a result, silencing of DLL3 led to the proliferative and migratory inhibition of SCLC cells and reversed EMT process. Mechanistically, DLL3 mRNA was stabilized by the RNA-binding protein lin-28 homolog B (LIN28B). Further mechanism investigation revealed that LIN28B and DLL3 are two downstream targets of miR-518d-5p. Finally, rescue assays demonstrated that LIN28B and miR-518d-5p could regulate DLL3-mediated cell proliferation and migration. Collectively, our present study revealed a novel molecular pathway in SCLC, which providing a new insight in exploring the therapeutic strategy for SCLC.
德尔塔样蛋白 3（DLL3）已被报道为多种人类肿瘤的生物标志物。然而，其在晚期小细胞肺癌（SCLC）中的生物学功能和机制很少有报道。本研究创新性地设计来探索 DLL3 在 SCLC 进展中的作用。免疫组织化学（IHC）分析用于检测石蜡包埋的 SCLC 肿瘤样本中 DLL3 的表达。DLL3 的上调降低了化疗敏感性。Kaplan-Meier 分析用于分析 DLL3 高表达或低表达的 SCLC 患者的无进展生存期或总生存期。确定了 DLL3 表达与 SCLC 患者 PFS 或 OS 率之间的负相关关系。通过 qRT-PCR 分析确定 SCLC 细胞系中 DLL3 的相对高表达。进行功能丧失测定以检测 DLL3 在 SCLC 中的沉默对其生物学功能的影响。结果表明，沉默 DLL3 导致 SCLC 细胞的增殖和迁移抑制，并逆转 EMT 过程。从机制上讲，DLL3 mRNA 由 RNA 结合蛋白 lin-28 同源物 B（LIN28B）稳定。进一步的机制研究表明，LIN28B 和 DLL3 是 miR-518d-5p 的两个下游靶标。最后，挽救实验表明，LIN28B 和 miR-518d-5p 可以调节 DLL3 介导的细胞增殖和迁移。总之，本研究揭示了 SCLC 中的一个新的分子途径，为探索 SCLC 的治疗策略提供了新的见解。
