Zhixin Huang, Ying Li, Yan Qian, Ertao Zhai, Zeyu Zhao, Tianhao Zhang, Yinan Liu, Linying Ye, Ran Wei, Risheng Zhao, Zikang Li, Zhi Liang, Shirong Cai, Jianhui Chen
{"title":"肿瘤分泌的LCN2通过自分泌抑制24p3R/JNK/c-Jun/SPARC轴阻碍胃癌进展","authors":"Zhixin Huang, Ying Li, Yan Qian, Ertao Zhai, Zeyu Zhao, Tianhao Zhang, Yinan Liu, Linying Ye, Ran Wei, Risheng Zhao, Zikang Li, Zhi Liang, Shirong Cai, Jianhui Chen","doi":"10.1038/s41419-024-07153-z","DOIUrl":null,"url":null,"abstract":"<p><p>Gastric cancer (GC) is one of the most lethal malignancies worldwide. Despite extensive efforts to develop novel therapeutic targets, effective drugs for GC remain limited. Recent studies have indicated that Lipocalin (LCN)2 abnormalities significantly impact GC progression; however, its regulatory network remains unclear. Our study investigates the functional role and regulatory mechanism of action of LCN2 in GC progression. We observed a positive correlation between LCN2 expression, lower GC grade, and better prognosis in patients with GC. LCN2 overexpression suppressed GC proliferation and metastasis both in vitro and in vivo. Transcriptome sequencing identified secreted protein acidic and rich in cysteine (SPARC) as a pivotal downstream target of LCN2. Mechanistically, c-Jun acted as a transcription factor inducing SPARC expression, and LCN2 downregulated SPARC by inhibiting the JNK/c-Jun pathway. Moreover, LCN2 bound to its receptor, 24p3R, via autocrine signaling, which directly inhibited JNK phosphorylation and then inhibited the JNK/c-Jun pathway. Finally, analysis of clinical data demonstrated that SPARC expression correlated negatively with lower GC grade and better prognosis, and that LCN2 expression correlated negatively with p-JNK, c-Jun, and SPARC expression in GC. These findings suggest that the LCN2/24p3R/JNK/c-Jun/SPARC axis is crucial in the malignant progression of GC, offering novel prognostic markers and therapeutic targets.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1000,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11489581/pdf/","citationCount":"0","resultStr":"{\"title\":\"Tumor-secreted LCN2 impairs gastric cancer progression via autocrine inhibition of the 24p3R/JNK/c-Jun/SPARC axis.\",\"authors\":\"Zhixin Huang, Ying Li, Yan Qian, Ertao Zhai, Zeyu Zhao, Tianhao Zhang, Yinan Liu, Linying Ye, Ran Wei, Risheng Zhao, Zikang Li, Zhi Liang, Shirong Cai, Jianhui Chen\",\"doi\":\"10.1038/s41419-024-07153-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Gastric cancer (GC) is one of the most lethal malignancies worldwide. Despite extensive efforts to develop novel therapeutic targets, effective drugs for GC remain limited. Recent studies have indicated that Lipocalin (LCN)2 abnormalities significantly impact GC progression; however, its regulatory network remains unclear. Our study investigates the functional role and regulatory mechanism of action of LCN2 in GC progression. We observed a positive correlation between LCN2 expression, lower GC grade, and better prognosis in patients with GC. LCN2 overexpression suppressed GC proliferation and metastasis both in vitro and in vivo. Transcriptome sequencing identified secreted protein acidic and rich in cysteine (SPARC) as a pivotal downstream target of LCN2. Mechanistically, c-Jun acted as a transcription factor inducing SPARC expression, and LCN2 downregulated SPARC by inhibiting the JNK/c-Jun pathway. Moreover, LCN2 bound to its receptor, 24p3R, via autocrine signaling, which directly inhibited JNK phosphorylation and then inhibited the JNK/c-Jun pathway. Finally, analysis of clinical data demonstrated that SPARC expression correlated negatively with lower GC grade and better prognosis, and that LCN2 expression correlated negatively with p-JNK, c-Jun, and SPARC expression in GC. These findings suggest that the LCN2/24p3R/JNK/c-Jun/SPARC axis is crucial in the malignant progression of GC, offering novel prognostic markers and therapeutic targets.</p>\",\"PeriodicalId\":9734,\"journal\":{\"name\":\"Cell Death & Disease\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":8.1000,\"publicationDate\":\"2024-10-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11489581/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Death & Disease\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1038/s41419-024-07153-z\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Death & Disease","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41419-024-07153-z","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Tumor-secreted LCN2 impairs gastric cancer progression via autocrine inhibition of the 24p3R/JNK/c-Jun/SPARC axis.
Gastric cancer (GC) is one of the most lethal malignancies worldwide. Despite extensive efforts to develop novel therapeutic targets, effective drugs for GC remain limited. Recent studies have indicated that Lipocalin (LCN)2 abnormalities significantly impact GC progression; however, its regulatory network remains unclear. Our study investigates the functional role and regulatory mechanism of action of LCN2 in GC progression. We observed a positive correlation between LCN2 expression, lower GC grade, and better prognosis in patients with GC. LCN2 overexpression suppressed GC proliferation and metastasis both in vitro and in vivo. Transcriptome sequencing identified secreted protein acidic and rich in cysteine (SPARC) as a pivotal downstream target of LCN2. Mechanistically, c-Jun acted as a transcription factor inducing SPARC expression, and LCN2 downregulated SPARC by inhibiting the JNK/c-Jun pathway. Moreover, LCN2 bound to its receptor, 24p3R, via autocrine signaling, which directly inhibited JNK phosphorylation and then inhibited the JNK/c-Jun pathway. Finally, analysis of clinical data demonstrated that SPARC expression correlated negatively with lower GC grade and better prognosis, and that LCN2 expression correlated negatively with p-JNK, c-Jun, and SPARC expression in GC. These findings suggest that the LCN2/24p3R/JNK/c-Jun/SPARC axis is crucial in the malignant progression of GC, offering novel prognostic markers and therapeutic targets.
期刊介绍:
Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism.
Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following:
Experimental medicine
Cancer
Immunity
Internal medicine
Neuroscience
Cancer metabolism