Guo Yinghao, Miao Shuangda, Jin Yun, Li Qi, Wang Yihang, Zhang Xiaoxiao, Li Jiangtao
Department of Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China.
Department of Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China.
Ann Hepatol. 2025 Jan-Jun;30(1):101773. doi: 10.1016/j.aohep.2024.101773. Epub 2024 Dec 12.
Tumor-associated macrophages (TAM) can influence both cancer growth and chemoresistance, but the specific mechanisms involved in these processes in cholangiocarcinoma (CCA) are unclear.
We explored the distribution of TAM in CCA samples by multiplex immunofluorescence staining and tested the effects of TAM on CCA in vitro and in vivo. We then investigated the mechanisms underlying these effects using the Luminex assay, RNA sequencing, western blotting, flow cytometry, and co-immunoprecipitation.
The infiltration of TAM was strongly increased in the cholangiocarcinoma tumor microenvironment. Oncostain M (OSM) secreted by TAM increased the proliferation and chemotherapeutic resistance of CCA cells both in vitro and in vivo. The results of transcriptome sequencing analysis, Western blot analysis, and immunofluorescence staining confirmed that OSM can promote Yap nuclear translocation and its subsequent formation of complexes with SMADs to upregulate the expression of inhibitor of DNA binding 1 (ID1).
TAM promotes CCA progression and chemoresistance through activating OSM-Yap-ID1.
肿瘤相关巨噬细胞（TAM）可影响癌症生长和化疗耐药性，但这些过程在胆管癌（CCA）中所涉及的具体机制尚不清楚。
我们通过多重免疫荧光染色探究了TAM在CCA样本中的分布，并在体外和体内测试了TAM对CCA的影响。然后，我们使用Luminex检测、RNA测序、蛋白质免疫印迹、流式细胞术和免疫共沉淀研究了这些影响的潜在机制。
在胆管癌肿瘤微环境中，TAM的浸润显著增加。TAM分泌的抑瘤素M（OSM）在体外和体内均增加了CCA细胞的增殖和化疗耐药性。转录组测序分析、蛋白质免疫印迹分析和免疫荧光染色结果证实，OSM可促进Yes相关蛋白（Yap）核转位及其随后与SMAD蛋白形成复合物以上调DNA结合抑制因子1（ID1）的表达。
TAM通过激活OSM-Yap-ID1促进CCA进展和化疗耐药。
