Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan Key Laboratory of Organ Transplantation, Ministry of Education & NHC Key Laboratory of Organ Transplantation & Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, 430030, PR China; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China & Henan Key Laboratory of Digestive Organ Transplantation & Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities & ZhengZhou Key Laboratory of Hepatobiliary, Zhengzhou, 450052, PR China.
Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
Exp Cell Res. 2021 Aug 15;405(2):112655. doi: 10.1016/j.yexcr.2021.112655. Epub 2021 May 24.
Larynx carcinoma (LC) is the most prevalent head and neck cancer among adults. LC xenograft mouse model was generated to verify the effect of VEGF on macrophage polarization and tumor growth in vivo. EdU assay was performed to measure the cell proliferation. Transwell assay was applied to assess cell migration. The expression of YAP and STAT3 was also significantly increased in LC tumor tissues. Moreover, both YAP and STAT3 overexpression in LC cells promoted the proliferation, migration, as well as the secretion of PD-L1 in M2-like TAMs. Mechanistically, the interaction between YAP and STAT3 facilitated the transcription of VEGF. Moreover, with a co-culture system, VEGF secretion in LC cells enhanced PD-L1 expression in M2-like TAMs via activating VEGFR1-TGFβ signaling pathway. Furthermore, VEGF secreted from LC cells also promoted the tumor growth of LC in vivo. We revealed that dysregulated YAP/STAT3 activity in LC cells could enhance the secretion of VEGF, which then functioned on M2-like TAMs via activating VEGFR1-TGFββ pathway to promote the expression of PD-L1 and immunosuppressive function of M2-like TAMs. Therefore, VEGF and PD-L1 might have a pivotal crosstalk between M2-like TAMs and LC cells, which provided a novel therapeutic target in regulating the metastasis of LC in future.
喉癌（LC）是成年人中最常见的头颈部癌症。LC 异种移植小鼠模型的生成是为了验证 VEGF 对体内巨噬细胞极化和肿瘤生长的影响。EdU 检测用于测量细胞增殖。Transwell 检测用于评估细胞迁移。LC 肿瘤组织中 YAP 和 STAT3 的表达也明显增加。此外，LC 细胞中 YAP 和 STAT3 的过表达均促进了 M2 样 TAMs 的增殖、迁移和 PD-L1 的分泌。在机制上，YAP 和 STAT3 的相互作用促进了 VEGF 的转录。此外，在共培养系统中，LC 细胞中 VEGF 的分泌通过激活 VEGFR1-TGFβ 信号通路增强了 M2 样 TAMs 中的 PD-L1 表达。此外，LC 细胞分泌的 VEGF 还促进了 LC 在体内的肿瘤生长。我们揭示了 LC 细胞中失调的 YAP/STAT3 活性可增强 VEGF 的分泌，然后通过激活 VEGFR1-TGFββ 通路作用于 M2 样 TAMs，促进 PD-L1 的表达和 M2 样 TAMs 的免疫抑制功能。因此，VEGF 和 PD-L1 可能在 M2 样 TAMs 和 LC 细胞之间存在关键的串扰，这为未来调节 LC 转移提供了一个新的治疗靶点。
