TFAP4/DLGAP5 promotes tumor progression and macrophage M2 polarization in prostate cancer by activating the JAK2/STAT3 signaling

IF 3.5 3区 生物学 Q3 CELL BIOLOGY
Sen Li, Qingchuan Dong, Wei Ren, Yi Sun, Zhigang Wang, Liang Pan
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引用次数: 0

Abstract

Background

M2-polarized macrophages exhibit pro-tumorigenic functions in multiple malignancies, including prostate cancer (PC). Discs large homolog-associated protein 5 (DLGAP5) acts as an oncogenic driver in PC. This study aims to delineate the precise role and mechanistic basis of DLGAP5 in regulating PC-associated macrophage polarization.

Methods

Bioinformatics analyses were used to observe the expression profiling and polarization association of DLGAP5 and its upstream transcription factors (TFs). Cell phenotypes were assessed by measuring cell invasion, migration, apoptosis, and proliferation. After co-culture with PC cells, M2 macrophage polarization was evaluated by measuring M2-associated markers through quantitative PCR, Western blot, and flow cytometry. Xenograft tumor models were employed to validate the oncogenic role of DLGAP5 in vivo. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were used to confirmed the functional interaction between transcription factor AP-4 (TFAP4) and the DLGAP5 promoter.

Results

DLGAP5 and TFAP4 were upregulated in PC tumors and cell lines. Elevated DLGAP5 expression was significantly associated with higher Gleason score, advanced clinical stage, and worse prognosis. Depletion of DLGAP5 suppressed cell growth, migration, and invasion capacities in vitro. Moreover, DLGAP5 depletion attenuated the M2 polarization of PC-associated macrophages. Also, knockdown of DLGAP5 decreased tumorigenicity and macrophage M2 polarization in vivo. Mechanistically, TFAP4 transcriptionally activated the DLGAP5 promoter to upregulate DLGAP5 expression. Loss of TFAP4 suppressed tumor cell growth, migratory capacity, and invasiveness, as well as macrophage M2 polarization, all of which could be rescued through DLGAP5 re-expression. Additionally, TFAP4 activated the JAK2/STAT3 signaling through DLGAP5 in PC cells. Inhibition of JAK2/STAT3 signaling reversed DLGAP5-mediated malignant phenotypes and macrophage M2 polarization.

Conclusion

Our findings demonstrate that TFAP4-transcriptionally activated DLGAP5 drives PC progression by promoting tumorigenic properties and macrophage M2 polarization, establishing the TFAP4/DLGAP5 axis as a potential therapeutic target for PC.
TFAP4/DLGAP5通过激活JAK2/STAT3信号通路促进前列腺癌的肿瘤进展和巨噬细胞M2极化。
背景:m2极化巨噬细胞在包括前列腺癌(PC)在内的多种恶性肿瘤中表现出促瘤功能。disc大同源相关蛋白5 (DLGAP5)在PC中起致癌驱动作用。本研究旨在阐明DLGAP5在调节pc相关巨噬细胞极化中的确切作用和机制基础。方法:采用生物信息学方法观察DLGAP5及其上游转录因子(TFs)的表达谱和极化关联。通过测量细胞侵袭、迁移、凋亡和增殖来评估细胞表型。与PC细胞共培养后,通过定量PCR、western blot和流式细胞术检测M2相关标志物,评估M2巨噬细胞极化情况。采用异种移植肿瘤模型验证DLGAP5在体内的致瘤作用。利用染色质免疫沉淀(ChIP)和荧光素酶报告基因检测证实转录因子AP-4 (TFAP4)和DLGAP5启动子之间的功能相互作用。结果:DLGAP5和TFAP4在PC肿瘤和细胞系中表达上调。DLGAP5表达升高与Gleason评分较高、临床分期较晚、预后较差相关。DLGAP5的缺失抑制了细胞的生长、迁移和体外侵袭能力。此外,DLGAP5缺失可减弱pc相关巨噬细胞的M2极化。此外,敲低DLGAP5可降低体内巨噬细胞的致瘤性和M2极化。机制上,TFAP4通过转录激活DLGAP5启动子上调DLGAP5的表达。TFAP4的缺失抑制了肿瘤细胞的生长、迁移能力、侵袭性以及巨噬细胞M2极化,这些都可以通过DLGAP5的重新表达来挽救。此外,在PC细胞中,TFAP4通过DLGAP5激活JAK2/STAT3信号。抑制JAK2/STAT3信号可逆转dlgap5介导的恶性表型和巨噬细胞M2极化。结论:我们的研究结果表明,TFAP4转录激活的DLGAP5通过促进肿瘤特性和巨噬细胞M2极化来驱动PC的进展,建立了TFAP4/DLGAP5轴作为PC的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Experimental cell research
Experimental cell research 医学-细胞生物学
CiteScore
7.20
自引率
0.00%
发文量
295
审稿时长
30 days
期刊介绍: Our scope includes but is not limited to areas such as: Chromosome biology; Chromatin and epigenetics; DNA repair; Gene regulation; Nuclear import-export; RNA processing; Non-coding RNAs; Organelle biology; The cytoskeleton; Intracellular trafficking; Cell-cell and cell-matrix interactions; Cell motility and migration; Cell proliferation; Cellular differentiation; Signal transduction; Programmed cell death.
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