Secreted protease PRSS35 suppresses hepatocellular carcinoma by disabling CXCL2-mediated neutrophil extracellular traps.
Secreted protease PRSS35 suppresses hepatocellular carcinoma by disabling CXCL2-mediated neutrophil extracellular traps.
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DOI：
10.1038/s41467-023-37227-z
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发表时间：
2023-03-18
影响因子：
16.6
通讯作者：
Zhang, Huafeng
中科院分区：
文献类型：
--
作者：
Wang, Ting;Zhou, Yingli;Zhou, Zilong;Zhang, Pinggen;Yan, Ronghui;Sun, Linchong;Ma, Wenhao;Zhang, Tong;Shen, Shengqi;Liu, Haiying;Lu, Hui;Ye, Ling;Feng, Junru;Chen, Zhaolin;Zhong, Xiuying;Wu, Gao;Cai, Yongping;Jia, Weidong;Gao, Ping;Zhang, Huafeng
肝细胞主要通过分泌调节细胞增殖、代谢和细胞间通讯的蛋白质来发挥功能。在肝细胞癌（HCC）的进展过程中，肝细胞分泌组动态地变化，作为肿瘤发生的结果和致病因素，尽管在此过程中分泌蛋白功能的全部范围仍不清楚。在这里，我们表明，分泌的伪丝氨酸蛋白酶PRSS 35的功能作为一种肿瘤抑制剂在肝癌。从机制上讲，我们证明了活性PRSS35是通过前蛋白转化酶切割加工的。然后，活性PRSS 35通过靶向切割串联赖氨酸（KK）识别基序来抑制CXCL 2的蛋白水平。因此，CXCL2降解减弱了中性粒细胞向肿瘤的募集和中性粒细胞胞外陷阱的形成，最终抑制HCC进展。这些发现扩展了我们对肝细胞分泌组在癌症发展中的作用的理解，同时为PRRS 35作为治疗靶点或诊断生物标志物的临床翻译提供了基础。肝细胞和肝细胞癌（HCC）细胞的分泌物组可促进癌症进展。在这里，作者表明PRSS 35通过CXCL 2的蛋白水解消耗和随后减少中性粒细胞向肿瘤的募集来抑制HCC进展。
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. The secretome of hepatocytes and hepatocellular carcinoma (HCC) cells can contribute to cancer progression. Here the authors show that PRSS35 inhibits HCC progression through proteolytic depletion of CXCL2 and subsequently decreased neutrophil recruitment to tumours.
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影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
64.8
作者：
Finisguerra V;Di Conza G;Di Matteo M;Serneels J;Costa S;Thompson AA;Wauters E;Walmsley S;Prenen H;Granot Z;Casazza A;Mazzone M
通讯作者：
Mazzone M
影响因子：
29
作者：
Deshmukh, Atul S.;Peijs, Lone;Scheele, Camilla
通讯作者：
Scheele, Camilla
影响因子：
5.8
作者：
Gershkovitz, Maya;Fainsod-Levi, Tanya;Granot, Zvi
通讯作者：
Granot, Zvi
影响因子：
2.7
作者：
Gungor, Nejla;Knaapen, Ad M.;van Schooten, Frederik J.
通讯作者：
van Schooten, Frederik J.