神经发育蛋白 POGZ 通过减弱 TGFβ 信号传导来抑制三阴性乳腺癌的转移。
The Neurodevelopmental Protein POGZ Suppresses Metastasis in Triple Negative Breast Cancer by Attenuating TGFβ Signaling.
发表日期：2024 Aug 13
作者：
John Heath, Caitlynn Mirabelli, Matthew G Annis, Valerie Sabourin, Steven Hébert, Steven Findlay, HaEun Kim, Michael Witcher, Claudia L Kleinman, Peter M Siegel, Alexandre Orthwein, Josie Ursini-Siegel
来源：
CANCER RESEARCH
摘要：
pogo 转座元件衍生的锌指蛋白 POGZ 通过其在基因转录中的作用与神经发育障碍密切相关。许多参与神经发育的蛋白质在癌症中常常失调，这表明 POGZ 在肿瘤生物学中具有潜在作用。在这里，我们提供了 POGZ 影响三阴性乳腺癌 (TNBC) 生长和转移扩散的实验证据。在充分表征的 TNBC 模型中，POGZ 发挥双重作用，既作为肿瘤促进者，又作为转移抑制者。从机制上讲，POGZ 的缺失增强了 TGFβ 通路的激活，以发挥细胞抑制作用，同时增加乳腺肿瘤的间充质和迁移特性。尽管 POGZ 水平在人类乳腺癌中升高，但最具侵袭性的 TNBC 肿瘤（包括那些具有增加的间质和转移特性的肿瘤）表现出 POGZ 水平下降，并且低 POGZ 表达与这些肿瘤类型的较差临床结果相关。总而言之，这些数据表明 POGZ 是转移级联早期阶段的关键抑制因子。
The pogo transposable element derived zinc finger protein, POGZ, is notably associated with neurodevelopmental disorders through its role in gene transcription. Many proteins involved in neurological development are often dysregulated in cancer, suggesting a potential role for POGZ in tumor biology. Here, we provided experimental evidence that POGZ influences the growth and metastatic spread of triple negative breast cancers (TNBC). In well-characterized models of TNBC, POGZ exerted a dual role, both as a tumor promoter and metastasis suppressor. Mechanistically, loss of POGZ potentiated TGFβ pathway activation to exert cytostatic effects while simultaneously increasing the mesenchymal and migratory properties of breast tumors. Whereas POGZ levels are elevated in human breast cancers, the most aggressive forms of TNBC tumors, including those with increased mesenchymal and metastatic properties, exhibit dampened POGZ levels, and low POGZ expression was associated with inferior clinical outcomes in these tumor types. Taken together, these data suggest that POGZ is a critical suppressor of the early stages of the metastatic cascade.