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TGFβ 调控 NDRG1 在三阴性乳腺癌进展中的多效活性。

TGFβ Governs the Pleiotropic Activity of NDRG1 in Triple-Negative Breast Cancer Progression.

机构信息

Department of Biochemistry and Molecular Biology 2, School of Pharmacy, University of Granada, 18011 Granada, Spain.

GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, Spain.

出版信息

Int J Biol Sci. 2023 Jan 1;19(1):204-224. doi: 10.7150/ijbs.78738. eCollection 2023.

DOI:10.7150/ijbs.78738
PMID:36594086
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9760438/
Abstract

In triple-negative breast cancer (TNBC), the pleiotropic NDRG1 (N-Myc downstream regulated gene 1) promotes progression and worse survival, yet contradictory results were documented, and the mechanisms remain unknown. Phosphorylation and localization could drive NDRG1 pleiotropy, nonetheless, their role in TNBC progression and clinical outcome was not investigated. We found enhanced p-NDRG1 (Thr346) by TGFβ1 and explored whether it drives NDRG1 pleiotropy and TNBC progression. In tissue microarrays of 81 TNBC patients, we identified that staining and localization of NDRG1 and p-NDRG1 (Thr346) are biomarkers and risk factors associated with shorter overall survival. We found that TGFβ1 leads NDRG1, downstream of GSK3β, and upstream of NF-κB, to differentially regulate migration, invasion, epithelial-mesenchymal transition, tumor initiation, and maintenance of different populations of cancer stem cells (CSCs), depending on the progression stage of tumor cells, and the combination of TGFβ and GSK3β inhibitors impaired CSCs. The present study revealed the striking importance to assess both total NDRG1 and p-NDRG1 (Thr346) positiveness and subcellular localization to evaluate patient prognosis and their stratification. NDRG1 pleiotropy is driven by TGFβ to differentially promote metastasis and/or maintenance of CSCs at different stages of tumor progression, which could be abrogated by the inhibition of TGFβ and GSK3β.

摘要

在三阴性乳腺癌（TNBC）中，多效性 NDRG1（N-Myc 下游调节基因 1）促进肿瘤进展和生存预后更差，但已有研究结果相互矛盾，其作用机制仍不清楚。磷酸化和定位可能驱动 NDRG1 的多效性，但它们在 TNBC 进展和临床结局中的作用尚未被研究。我们发现 TGFβ1 可增强 NDRG1 的磷酸化（Thr346），并探索其是否驱动 NDRG1 的多效性和 TNBC 的进展。在 81 例 TNBC 患者的组织微阵列中，我们确定了 NDRG1 和 p-NDRG1（Thr346）的染色和定位是与总生存期更短相关的生物标志物和风险因素。我们发现，TGFβ1 导致 NDRG1 在 GSK3β 下游和 NF-κB 上游的不同调节迁移、侵袭、上皮间质转化、肿瘤起始和维持不同肿瘤干细胞（CSC）亚群，这取决于肿瘤细胞的进展阶段，以及 TGFβ 和 GSK3β 抑制剂的联合应用可削弱 CSCs。本研究揭示了评估总 NDRG1 和 p-NDRG1（Thr346）阳性和亚细胞定位的重要性，以评估患者的预后及其分层。TGFβ 驱动 NDRG1 的多效性，以不同的方式促进转移和/或在肿瘤进展的不同阶段维持 CSCs，这可以通过抑制 TGFβ 和 GSK3β 来阻断。

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