Par6 Enhances Glioma Invasion by Activating MEK/ERK Pathway Through a LIN28/let-7d Positive Feedback Loop
Par6 Enhances Glioma Invasion by Activating MEK/ERK Pathway Through a LIN28/let-7d Positive Feedback Loop
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Par6 通过 LIN28/let-7d 正反馈环路激活 MEK/ERK 通路增强胶质瘤侵袭
DOI：
10.1007/s12035-022-03171-0
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发表时间：
2022-12-21
影响因子：
5.1
通讯作者：
Yang，Xiaojun
中科院分区：
文献类型：
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作者：
Huang，Yishan;Liu，Pei;Yang，Xiaojun
胶质母细胞瘤的侵袭性常导致胶质瘤患者的复发和预后不良。然而，胶质瘤侵袭的潜在机制仍不明确。在本研究中，胶质瘤标本的免疫组化分析表明，Par 6的高表达与胶质瘤患者的恶性程度和预后不良呈正相关。Par 6过表达的胶质瘤细胞表现出更多的成纤维细胞样形态，表明Par 6表达的调节可能与胶质瘤细胞的肿瘤侵袭有关。进一步的研究表明，Par 6过表达随后通过激活MEK/ERK/STAT 3通路，在体内和体外增加CD 44和N-cadherin的表达，从而增强胶质瘤的侵袭。此外，我们发现LIN 28/let-7 d轴通过正反馈环参与了这一过程，这表明MEK/ERK/LIN 28/let-7 d/STAT 3级联可能是Par 6介导的胶质瘤侵袭所必需的。因此，这些数据突出了Par 6在胶质瘤侵袭中的作用，Par 6可能作为胶质瘤患者的潜在治疗靶点。
The invasion of glioblastoma usually results in the recurrence and poor prognosis in patients with glioma. However, the underlying mechanisms involved in glioma invasion remains undefined. In this study, immunohistochemistry analyses of glioma specimens demonstrated that high expression of Par6 was positively correlated with malignancy and poor prognosis of patients with glioma. Par6-overexpressing glioma cells showed much more fibroblast-like morphology, suggesting that regulation of Par6 expression might be associated with tumor invasion in glioma cells. Further study indicated that Par6 overexpression subsequently increased CD44 and N-cadherin expression to enhance glioma invasion through activating MEK/ERK/STAT3 pathway, in vivo and in vitro. Moreover, we found that LIN28/let-7d axis was involved in this process via a positive feedback loop, suggesting that MEK/ERK/LIN28/let-7d/STAT3 cascade might be essential for Par6-mediated glioma invasion. Therefore, these data highlight the roles of Par6 in glioma invasion, and Par6 may serve as a potential therapeutic target for patients with glioma.