Oh Hyun-Ji, Min Ga-Hong, Kim Da-Eun, Shin Sol-Bi, Yim Hyungshin
Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do 15588, Republic of Korea.
Int J Biol Sci. 2025 Jul 24;21(11):4701-4718. doi: 10.7150/ijbs.115097. eCollection 2025.
TSG6 is highly expressed during PLK1-induced epithelial-mesenchymal transition (EMT). However, the role of TSG6 in the tumor microenvironment (TME) remains poorly understood. We investigate the function and regulatory mechanisms of TSG6 in immune plasticity within the TME of lung adenocarcinoma (LUAD). The simultaneous high expression of TSG6 and PLK1 in LUAD patients was associated with lower survival rates. TSG6 and CD44 were markedly upregulated during EMT driven by TGF-b or active PLK1 in A549 and HCC827 cells. TSG6 treatment enhanced EMT by increasing N-cadherin and phosphorylated Smad2 levels. TSG6 depletion blocked the effects, which was restored upon TSG6 retreatment. Additionally, TSG6 treatment induced polarization of THP-1 monocytes into M2d tumor-associated macrophages (TAMs). In cocultures of THP-1 monocytes with A549 cells expressing TSG6, M2d-inducing factors in A549 cells and M2d markers in THP-1 cells were upregulated. Immunoprecipitation showed that TSG6 binds CD44, enhancing CD44's interaction with TGFbR or EGFR. In TSG6-treated LUAD cells, both total CD44 and its cleaved intracellular domain increased by activating TGFβR1-Smad2/3 and MAPK-ERK1/2-AP-1 pathways. Thus, TSG6 promotes EMT and M2d-TAMs polarization by activating TGFβR1/Smad and MAPK/ERK pathway through direct interaction between CD44 and TGFβR1 or EGFR.
TSG6在PLK1诱导的上皮-间质转化（EMT）过程中高表达。然而，TSG6在肿瘤微环境（TME）中的作用仍知之甚少。我们研究了TSG6在肺腺癌（LUAD）TME中免疫可塑性方面的功能和调控机制。LUAD患者中TSG6和PLK1的同时高表达与较低的生存率相关。在A549和HCC827细胞中，由TGF-β或活性PLK1驱动的EMT过程中，TSG6和CD44显著上调。TSG6处理通过增加N-钙黏蛋白和磷酸化Smad2水平增强了EMT。TSG6缺失阻断了这些效应，重新给予TSG6处理后得以恢复。此外，TSG6处理诱导THP-1单核细胞极化为M2d肿瘤相关巨噬细胞（TAM）。在THP-1单核细胞与表达TSG6的A549细胞共培养时，A549细胞中的M2d诱导因子和THP-1细胞中的M2d标志物上调。免疫沉淀显示TSG6与CD-44结合，增强了CD-44与TGFβR或EGFR的相互作用。在TSG6处理的LUAD细胞中，总CD-44及其切割后的细胞内结构域均通过激活TGFβR1-Smad2/3和MAPK-ERK1/2-AP-1途径而增加。因此，TSG6通过CD-44与TGFβR1或EGFR之间的直接相互作用激活TGFβR1/Smad和MAPK/ERK途径，从而促进EMT和M2d-TAM极化。
