Secreted protease PRSS35 suppresses hepatocellular carcinoma by disabling CXCL2-mediated neutrophil extracellular traps

Ting Wang, Yingli Zhou, Zilong Zhou, Pinggen Zhang, Ronghui Yan, Linchong Sun, Wenhao Ma, Tong Zhang, Shengqi Shen, Haiying Liu, Hui Lu, Ling Ye, Junru Feng, Zhaolin Chen, Xiuying Zhong, Gao Wu, Yongping Cai, Weidong Jia, Ping Gao () and Huafeng Zhang ()
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Ting Wang: Division of Life Science and Medicine, University of Science and Technology of China
Yingli Zhou: Division of Life Science and Medicine, University of Science and Technology of China
Zilong Zhou: Division of Life Science and Medicine, University of Science and Technology of China
Pinggen Zhang: Division of Life Science and Medicine, University of Science and Technology of China
Ronghui Yan: Division of Life Science and Medicine, University of Science and Technology of China
Linchong Sun: Southern Medical University
Wenhao Ma: Division of Life Science and Medicine, University of Science and Technology of China
Tong Zhang: Southern Medical University
Shengqi Shen: Southern Medical University
Haiying Liu: Division of Life Science and Medicine, University of Science and Technology of China
Hui Lu: Division of Life Science and Medicine, University of Science and Technology of China
Ling Ye: Division of Life Science and Medicine, University of Science and Technology of China
Junru Feng: Division of Life Science and Medicine, University of Science and Technology of China
Zhaolin Chen: Division of Life Science and Medicine, University of Science and Technology of China
Xiuying Zhong: Southern Medical University
Gao Wu: University of Science and Technology of China
Yongping Cai: Anhui Medical University
Weidong Jia: Division of Life Science and Medicine, University of Science and Technology of China
Ping Gao: University of Science and Technology of China
Huafeng Zhang: Division of Life Science and Medicine, University of Science and Technology of China

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Hepatocytes function largely through the secretion of proteins that regulate cell proliferation, metabolism, and intercellular communications. During the progression of hepatocellular carcinoma (HCC), the hepatocyte secretome changes dynamically as both a consequence and a causative factor in tumorigenesis, although the full scope of secreted protein function in this process remains unclear. Here, we show that the secreted pseudo serine protease PRSS35 functions as a tumor suppressor in HCC. Mechanistically, we demonstrate that active PRSS35 is processed via cleavage by proprotein convertases. Active PRSS35 then suppresses protein levels of CXCL2 through targeted cleavage of tandem lysine (KK) recognition motif. Consequently, CXCL2 degradation attenuates neutrophil recruitment to tumors and formation of neutrophil extracellular traps, ultimately suppressing HCC progression. These findings expand our understanding of the hepatocyte secretome’s role in cancer development while providing a basis for the clinical translation of PRRS35 as a therapeutic target or diagnostic biomarker.

Date: 2023
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DOI: 10.1038/s41467-023-37227-z

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