Brain Metastases Are Regulated by Immuno-inflammatory Signaling Pathways Governed by STAT3, MAPK and Tumor Suppressor p53 Status: Possible Therapeutic Targets

被引:2
|
作者
Zeller, Sabrina L. [1 ]
Spirollari, Eris [1 ]
Dicpinigaitis, Alis J. [1 ]
Wainwright, John, V
Hanft, Simon J. [1 ]
Gandhi, Chirag D. [1 ]
Jhanwar-Uniyal, Meena [1 ,2 ]
机构
[1] New York Med Coll, Westchester Med Ctr, Dept Neurosurg, Valhalla, NY USA
[2] New York Med Coll, Dept Neurosurg, Valhalla, NY 10595 USA
关键词
Metastatic brain tumors; p53; STAT3; MAPK; PD-L1; immunotherapeutic targets; CANCER METASTASIS; MUTANT P53; EXPRESSION; ACTIVATION; GROWTH; TRANSCRIPTION-3; TRANSDUCER; MUTATIONS; MELANOMA; SURVIVAL;
D O I
10.21873/anticanres.16783
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background/Aim: Brain metastasis (BM) is a complex multi-step process involving various immune checkpoint proteins. Mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases 1/2 (ERK1/2), and signal transducer and activator of transcription 3 (STAT3) are implicated in tumorigenesis and are critical upstream regulators of Programmed Death Ligand 1 (PD-L1), an immunotherapy target. Tumor suppressor p53, dysregulated in cancers, regulates STAT3 and ERK1/2 signaling. This study examined the roles of STAT3, MAPK and p53 status in BM initiation and maintenance. Materials and Methods: Twentysix BM, with various primary malignancies, were used (IRBapproved) to determine mutant p53 (p53mt), pSTAT3Tyr705, pERK1/2Thr202/Tyr204, and PD-L1 expression using immunohistochemistry. cDNA microarray was used for gene expression analysis. Brain-metastatic breast cancer cells (MDA-MB-231) were treated with STAT3 (NSC74859) or MAPK/ERK1/2 (U0126) inhibitors in regular or astrocytic media. ERK1/2 pathway was assessed using western blotting, and cell proliferation and migration were determined using MTT and scratch-wound assays, respectively. Results: pSTAT3Tyr705 and pERK1/2Thr202/Tyr204 were expressed at tumor margins, whereas p53mt and PD-L1 were uniformly expressed, with significant overlap between expression of these proteins. Gene expression analysis identified alterations in 18 p53- and 32 STAT3- or MAPK-associated genes contributing to dysregulated immune responses and cell cycle regulation. U0126 and NSC74859 reduced pERK1/2Thr202/Tyr204 expression. Cell proliferation decreased following each treatment (p <= 0.01). Migration stagnated following U0126 treatment in astrocytic media (p <= 0.01). Conclusion: Activation of STAT3 and ERK1/2 promotes BM and provides compelling evidence for use of STAT3, ERK1/2 and p53 status as potential immunotherapeutic targets in BM.
引用
收藏
页码:13 / 22
页数:10
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