H19促进肿瘤相关巨噬细胞的极化和可变剪接，从而促进胰腺癌进展。

H19 promotes polarization and alternative splicing in tumor-associated macrophages, facilitating pancreatic cancer progression.

作者信息

Liu Pengyi, Gao Xia, Yu Zhengwei, Liu Yang, Liu Yihao, Lin Jiayu, Cao Yizhi, Zhai Shuyu, Li Jingwei, Huang Yishu, Zou Siyi, Wen Chenlei, Fu Da, Lin Jiewei, Shen Baiyong

机构信息

Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.

Department of Pathology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

出版信息

Cancer Lett. 2024 Dec 7;611:217389. doi: 10.1016/j.canlet.2024.217389.

DOI:10.1016/j.canlet.2024.217389

PMID:39653238

Abstract

Tumor-associated macrophages (TAMs) play a crucial physiological role in the pancreatic tumor microenvironment. However, the role of long non-coding RNAs (lncRNAs) in TAMs within pancreatic tumors remains unclear. By lncRNA sequencing between TAMs and resident macrophages from normal tissues in pancreatic cancer, it is found that H19 is highly expressed in TAMs and is correlated with the prognosis and stages of pancreatic cancer. Constructing a co-culture model of THP-1 derived TAMs and pancreatic cancer cells, H19 promotes the polarization of TAMs towards the M2 phenotype and the secretion of IL-6, IL-10, and TGF-β, both in vivo and in vitro, indirectly enhancing pancreatic cancer proliferation and metastasis. Mechanistically, H19 competitively binds to the mRNA of YTHDC1 with MiR-107, and also interacts with the YTHDC1 protein, regulating the stability of SRSF1 and thereby affecting the alternative splicing of IL-6 and IL-10. Utilizing organoids and the patient-derived xenograft (PDX) model, it is found that ruxolitinib may represent a promising treatment option for PDAC patients with high H19 expression.

摘要

肿瘤相关巨噬细胞（TAM）在胰腺肿瘤微环境中发挥着关键的生理作用。然而，长链非编码RNA（lncRNA）在胰腺肿瘤中的TAM中的作用仍不清楚。通过对胰腺癌中TAM与正常组织中的驻留巨噬细胞进行lncRNA测序，发现H19在TAM中高表达，且与胰腺癌的预后和分期相关。构建THP-1来源的TAM与胰腺癌细胞的共培养模型，H19在体内和体外均促进TAM向M2表型极化以及IL-6、IL-10和TGF-β的分泌，间接增强胰腺癌的增殖和转移。机制上，H19与MiR-107竞争性结合YTHDC1的mRNA，还与YTHDC1蛋白相互作用，调节SRSF1的稳定性，从而影响IL-6和IL-10的可变剪接。利用类器官和患者来源的异种移植（PDX）模型，发现鲁索替尼可能是H19高表达的胰腺导管腺癌（PDAC）患者的一种有前景的治疗选择。