PTPN20 promotes metastasis through activating NF-κB signaling in triple-negative breast cancer.

IF 7.4 1区 医学 Q1 Medicine
Xiaoxiao Zuo, Xiaohan Zhao, Xiaofei Zhang, Qingyuan Li, Xingyu Jiang, Shumei Huang, Xuwei Chen, Xiangfu Chen, Weihua Jia, Hequn Zou, Dongni Shi, Xueke Qian
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引用次数: 0

Abstract

Background: Cancer metastasis remains a major challenge in the clinical management of triple-negative breast cancer (TNBC). The NF-κB signaling pathway has been implicated as a crucial factor in the development of metastases, but the underlying molecular mechanisms remain largely unclear.

Methods: PTPN20 expression was evaluated using data from the Sweden Cancerome Analysis Network-Breast and The Cancer Genome Atlas database, as well as by western blotting and immunohistochemistry in 88 TNBC patients. The ability of PTPN20 to activate NF-κB was assessed by luciferase reporter assays. The effects of PTPN20 overexpression and knockdown via short hairpin RNA were examined in TNBC cell lines by wound healing and transwell matrix penetration assays. Additionally, we analyzed the growth and metastasis abilitiy of 4T1 xenograft tumors in nude mice.

Results: PTPN20 levels were elevated in TNBC cell lines and patient samples compared to controls, and higher protein levels correlated with metastasis-free survival. Overexpression of PTPN20 enhanced migration and invasion in vitro, and promoted lung metastasis in vivo. Our finding revealed that PTPN20 activates NF-κB signaling by dephosphorylating p65 at Ser468, preventing its binding to COMMD1, thereby protecting p65 from degradation. Downregulation of PTPN20 effectively inhibit, while p65 S468A mutant restored the migratory and invasive abilities of TNBC cells.

Conclusions: Collectively, our results demonstrate that PTPN20 plays a critical role in TNBC metastasis through the activation of NF-κB signaling. We propose that PTPN20 may serve as a novel prognostic marker and potential therapeutic target for the treatment of TNBC.

PTPN20 通过激活三阴性乳腺癌中的 NF-κB 信号促进转移。
背景:癌症转移仍然是三阴性乳腺癌(TNBC)临床治疗的一大挑战。NF-κB信号通路被认为是导致转移的关键因素,但其潜在的分子机制在很大程度上仍不清楚:方法:利用瑞典乳腺癌组分析网络(Sweden Cancerome Analysis Network-Breast)和癌症基因组图谱(The Cancer Genome Atlas)数据库的数据,以及88例TNBC患者的免疫印迹和免疫组化方法,对PTPN20的表达进行了评估。荧光素酶报告实验评估了PTPN20激活NF-κB的能力。通过伤口愈合和透孔基质穿透实验检测了PTPN20过表达和通过短发夹RNA敲除对TNBC细胞系的影响。此外,我们还分析了裸鼠 4T1 异种移植肿瘤的生长和转移能力:结果:与对照组相比,PTPN20水平在TNBC细胞系和患者样本中升高,较高的蛋白水平与无转移生存率相关。过表达 PTPN20 可增强体外迁移和侵袭,促进体内肺转移。我们的研究发现,PTPN20通过使p65在Ser468处去磷酸化来激活NF-κB信号,阻止其与COMMD1结合,从而保护p65不被降解。下调PTPN20可有效抑制TNBC细胞的迁移和侵袭能力,而p65 S468A突变体则可恢复其迁移和侵袭能力:总之,我们的研究结果表明,PTPN20通过激活NF-κB信号在TNBC转移中起着关键作用。我们认为,PTPN20可作为治疗TNBC的新型预后标志物和潜在治疗靶点。
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来源期刊
CiteScore
12.00
自引率
0.00%
发文量
76
审稿时长
12 weeks
期刊介绍: Breast Cancer Research, an international, peer-reviewed online journal, publishes original research, reviews, editorials, and reports. It features open-access research articles of exceptional interest across all areas of biology and medicine relevant to breast cancer. This includes normal mammary gland biology, with a special emphasis on the genetic, biochemical, and cellular basis of breast cancer. In addition to basic research, the journal covers preclinical, translational, and clinical studies with a biological basis, including Phase I and Phase II trials.
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