School of Medicine, Anhui University of Science and Technology, Huainan, Anhui, China; Anhui Occupational Health and Safety Engineering Laboratory, Huainan, Anhui, China.
School of Medicine, Anhui University of Science and Technology, Huainan, Anhui, China; Anhui Occupational Health and Safety Engineering Laboratory, Huainan, Anhui, China.
Cell Signal. 2024 Aug;120:111179. doi: 10.1016/j.cellsig.2024.111179. Epub 2024 Apr 18.
S100P, a member of the S100 calcium-binding protein family, is closely associated with abnormal proliferation, invasion, and metastasis of various cancers. However, its role in the lung adenocarcinoma (LUAD) tumor microenvironment (TME) remains unclear. In this study, we observed specific expression of S100P on tumor cells in LUAD patients through tissue immunofluorescence analysis. Furthermore, this expression was strongly correlated with the recruitment and polarization of tumor-associated macrophages (TAMs). Bioinformatics analysis revealed that high S100P expression is associated with poorer overall survival in LUAD patients. Subsequently, a subcutaneous mouse model demonstrated that S100P promotes recruitment and polarization of TAMs towards the M2 type. Finally, in vitro studies on LUAD cells revealed that S100P enhances the secretion of chemokines and polarizing factors by activating the PKA/c-Jun pathway, which is implicated in TAM recruitment and polarization towards the M2 phenotype. Moreover, inhibition of c-Jun expression impedes the ability of TAMs to infiltrate and polarize towards the M2 phenotype. In conclusion, our study demonstrates that S100P facilitates LUAD cells growth by recruiting M2 TAMs through PKA/c-Jun signaling, resulting in the production of various cytokines. Considering these findings, S100P holds promise as an important diagnostic marker and potential therapeutic target for LUAD.
S100P 是 S100 钙结合蛋白家族的一员，与各种癌症的异常增殖、侵袭和转移密切相关。然而，其在肺腺癌（LUAD）肿瘤微环境（TME）中的作用尚不清楚。在本研究中，我们通过组织免疫荧光分析观察到 LUAD 患者肿瘤细胞中 S100P 的特异性表达。此外，这种表达与肿瘤相关巨噬细胞（TAMs）的募集和极化强烈相关。生物信息学分析显示，S100P 高表达与 LUAD 患者总体生存率降低相关。随后，皮下小鼠模型表明 S100P 通过激活 PKA/c-Jun 通路促进 TAMs 向 M2 型募集和极化。最后，对 LUAD 细胞的体外研究表明，S100P 通过激活 PKA/c-Jun 通路增强趋化因子和极化因子的分泌，从而招募和极化 TAMs 向 M2 表型。此外，抑制 c-Jun 的表达会阻碍 TAMs 浸润和向 M2 表型极化的能力。总之，本研究表明，S100P 通过 PKA/c-Jun 信号通路招募 M2 TAMs 促进 LUAD 细胞生长，从而产生各种细胞因子。鉴于这些发现，S100P 有望成为 LUAD 的重要诊断标志物和潜在治疗靶点。
