The Fourth Department of Oncology, Affiliated Zhongshan Hospital of Dalian University, 6 Jiefang Street, Zhongshan District, Dalian, 116001, Liaoning, China.
Department of Pathology, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, Liaoning, China.
World J Surg Oncol. 2023 Mar 13;21(1):93. doi: 10.1186/s12957-023-02969-z.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Homeobox D9 (HOXD9), a member of the HOX family of transcription factors, plays a driver role in development of multiple cancers. Angiopoietin-2 (ANGPT2) is reportedly to facilitate angiogenesis, growth and metastasis in various cancers, including lung cancer. In addition, blocking ANGPT2 can effectively improve cancer immunotherapy via downregulation of Programmed death ligand-1 (PD-L1). The purpose of this study was to elucidate the role of HOXD9 in NSCLC and whether ANGPT2 is required for HOXD9-mediated malignant behaviors of NSCLC cells. By performing a series of in vitro functional experiments, we found that knockdown of HOXD9 induced proliferative inhibition, cell cycle G1 arrest, apoptosis, migratory suppression and invasive repression of NSCLC cells. Reduced PD-L1 expression in NSCLC cells was observed after HOXD9 silencing. Besides, HOXD9 deletion decreased the expression of ANGPT2 in NSCLC cells. In line with this, HOXD9 overexpression led to opposite alteration in NSCLC cells. Mechanistically, ANGPT2 was transcriptionally activated by HOXD9. Forced expression of ANGPT2 significantly regulated HOXD9-mediated malignant phenotypes, and enhanced PD-L1 expression of NSCLC cells. Our results expressing HOXD9 may function as an oncogene in NSCLC via trans-activation of ANGPT2.
非小细胞肺癌（NSCLC）是全球癌症相关死亡的主要原因。同源盒蛋白 D9（HOXD9）是转录因子 HOX 家族的成员，在多种癌症的发展中起驱动作用。血管生成素-2（ANGPT2）据报道可促进多种癌症（包括肺癌）的血管生成、生长和转移。此外，通过下调程序性死亡配体 1（PD-L1），阻断 ANGPT2 可有效改善癌症免疫治疗。本研究旨在阐明 HOXD9 在 NSCLC 中的作用，以及 ANGPT2 是否是 HOXD9 介导的 NSCLC 细胞恶性行为所必需的。通过一系列体外功能实验，我们发现敲低 HOXD9 可诱导 NSCLC 细胞增殖抑制、细胞周期 G1 期阻滞、凋亡、迁移抑制和侵袭抑制。HOXD9 沉默后观察到 NSCLC 细胞中 PD-L1 表达减少。此外，HOXD9 缺失可降低 NSCLC 细胞中 ANGPT2 的表达。与此一致，HOXD9 的过表达导致 NSCLC 细胞发生相反的变化。在机制上，HOXD9 可转录激活 ANGPT2。强制表达 ANGPT2 可显著调节 HOXD9 介导的恶性表型，并增强 NSCLC 细胞中 PD-L1 的表达。我们的研究结果表明，HOXD9 可能通过 ANGPT2 的反式激活在 NSCLC 中发挥癌基因作用。
