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

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

doi:10.1016/j.canlet.2024.217389

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

Cancer Lett. 2024 Dec 7:611:217389. doi: 10.1016/j.canlet.2024.217389. Online ahead of print.

Authors

Pengyi Liu¹, Xia Gao², Zhengwei Yu³, Yang Liu⁴, Yihao Liu⁴, Jiayu Lin⁴, Yizhi Cao⁴, Shuyu Zhai⁴, Jingwei Li⁴, Yishu Huang⁴, Siyi Zou⁴, Chenlei Wen⁴, Da Fu⁵, Jiewei Lin⁶, Baiyong Shen⁷

Affiliations

¹ 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. Electronic address: [email protected].
² Department of Pathology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Cardiothoracic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
⁴ 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.
⁵ 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. Electronic address: [email protected].
⁶ Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: [email protected].
⁷ 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. Electronic address: [email protected].

PMID: 39653238
DOI: 10.1016/j.canlet.2024.217389

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.

Keywords: Alternative splicing; H19; Pancreatic cancer; Ruxolitinib; Tumor-associated macrophages.