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

IF 8.1 1区 生物学 Q1 CELL BIOLOGY Cell Death & Disease Pub Date : 2024-10-18 DOI:10.1038/s41419-024-07153-z
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
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引用次数: 0

摘要

胃癌(GC)是全球致死率最高的恶性肿瘤之一。尽管人们一直在努力开发新的治疗靶点,但治疗胃癌的有效药物仍然有限。最近的研究表明,脂联素(LCN)2 异常会显著影响 GC 的进展;然而,其调控网络仍不清楚。我们的研究探讨了 LCN2 在 GC 进展中的功能作用和调控机制。我们观察到 LCN2 表达、较低的 GC 分级和较好的 GC 患者预后之间存在正相关。LCN2 的过表达抑制了 GC 在体外和体内的增殖和转移。转录组测序发现,富含半胱氨酸的酸性分泌蛋白(SPARC)是LCN2的关键下游靶标。从机制上讲,c-Jun是诱导SPARC表达的转录因子,而LCN2通过抑制JNK/c-Jun通路来下调SPARC。此外,LCN2通过自分泌信号与其受体24p3R结合,直接抑制JNK磷酸化,进而抑制JNK/c-Jun通路。最后,对临床数据的分析表明,SPARC的表达与较低的GC分级和较好的预后呈负相关,LCN2的表达与GC中p-JNK、c-Jun和SPARC的表达呈负相关。这些研究结果表明,LCN2/24p3R/JNK/c-Jun/SPARC 轴在 GC 的恶性进展中至关重要,它提供了新的预后标记和治疗靶点。
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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.

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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
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
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