MAPK4 silencing in gastric cancer drives liver metastasis by positive feedback between cancer cells and macrophages

Shuang Li; Dongyang Guo; Qiang Sun; Lu Zhang; Yun Cui; Min Liu; Xixi Ma; Yiman Liu; Wenyu Cui; Leimin Sun; Lisong Teng; Liangjing Wang; Aifu Lin; Wei Liu; Wei Zhuo; Tianhua Zhou

doi:10.1038/s12276-023-00946-w

MAPK4 silencing in gastric cancer drives liver metastasis by positive feedback between cancer cells and macrophages

Exp Mol Med. 2023 Feb;55(2):457-469. doi: 10.1038/s12276-023-00946-w. Epub 2023 Feb 17.

Authors

Shuang Li^#^{1

2

3}, Dongyang Guo^#^{1

2

3}, Qiang Sun^#^{1

2}, Lu Zhang^#^{1

2}, Yun Cui^{1

2}, Min Liu^{1

2}, Xixi Ma^{1

2}, Yiman Liu^{1

2}, Wenyu Cui^{1

2}, Leimin Sun^{2

3}, Lisong Teng^{2

4}, Liangjing Wang^{2

3

5}, Aifu Lin^{2

6}, Wei Liu⁷, Wei Zhuo^{8

9

10}, Tianhua Zhou^{11

12

13

14}

Affiliations

¹ Department of Cell Biology and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² Cancer Center, Zhejiang University, Hangzhou, China.
³ Institute of Gastroenterology, Zhejiang University School of Medicine, Hangzhou, China.
⁴ Department of Oncology, First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
⁵ Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
⁶ College of Life Sciences, Zhejiang University, Hangzhou, China.
⁷ Department of Biochemistry, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁸ Department of Cell Biology and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. wzhuo@zju.edu.cn.
⁹ Cancer Center, Zhejiang University, Hangzhou, China. wzhuo@zju.edu.cn.
¹⁰ Institute of Gastroenterology, Zhejiang University School of Medicine, Hangzhou, China. wzhuo@zju.edu.cn.
¹¹ Department of Cell Biology and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. tzhou@zju.edu.cn.
¹² Cancer Center, Zhejiang University, Hangzhou, China. tzhou@zju.edu.cn.
¹³ Institute of Gastroenterology, Zhejiang University School of Medicine, Hangzhou, China. tzhou@zju.edu.cn.
¹⁴ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. tzhou@zju.edu.cn.

^# Contributed equally.

Abstract

Liver metastasis is a major cause of death in gastric cancer patients, but the underlying mechanisms are poorly understood. Through a combination of in vivo screening and transcriptome profiling followed by quantitative RT-PCR and tissue array analyses, we found that mitogen-activated protein kinase 4 (MAPK4) downregulation in gastric cancer tissues from patients is significantly associated with liver metastasis and poor prognosis. The knockdown of MAPK4 in gastric cancer cells promotes liver metastasis in orthotopic mouse models. MAPK4 depletion in gastric cancer cells induces the secretion of macrophage migration inhibitory factor (MIF) to polarize tumor-associated macrophages (TAMs) in orthotopic xenograft tumors. Moreover, TAMs activate epithelial-mesenchymal transition of gastric cancer cells to suppress MAPK4 expression, which further increases MIF secretion to polarize TAMs. Taken together, our results suggest a previously undescribed positive feedback loop between cancer cells and macrophages mediated by MAPK4 silencing that facilitates gastric cancer liver metastasis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Cell Movement
Epithelial-Mesenchymal Transition / genetics
Feedback
Gene Expression Regulation, Neoplastic
Humans
Liver Neoplasms* / pathology
Macrophages / metabolism
Mice
Mitogen-Activated Protein Kinases / metabolism
Neoplasm Metastasis / pathology
Stomach Neoplasms* / pathology

Substances

Mitogen-Activated Protein Kinases