GABARAP suppresses EMT and breast cancer progression via the AKT/mTOR signaling pathway.
GABARAP suppresses EMT and breast cancer progression via the AKT/mTOR signaling pathway.
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DOI：
10.18632/aging.202510
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发表时间：
2021-02-11
期刊：
影响因子：
--
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Liu Y;Wang D;Lei M;Gao J;Cui Y;Jin X;Yu Q;Jiang Y;Guo Y;Liu Y;Cai L;Chen X
关于γ-氨基丁酸A型（GABAA）受体相关蛋白（GABARAP）在肿瘤进展中的作用研究较少。我们研究了GABARAP在乳腺癌中的表达和重要性。分析GABARAP的表达及其与临床病理特征和预后的关系。为了解释GABARAP在调节肿瘤发展中的作用和潜在机制，我们使用细胞系和小鼠异种移植模型进行了功能获得和丧失实验。我们发现，GABARAP抑制增殖，迁移和侵袭在体外和体内。值得注意的是，低水平的GABARAP诱导上皮-间充质转化（EMT）。低水平的GABARAP增加了p-AKT和p-mTOR水平，特异性AKT通路抑制剂逆转了GABARAP诱导的肿瘤进展的下调。GABARAP与肿瘤大小、TNM分期等临床病理特征呈负相关。值得注意的是，GABARAP水平低的患者预后不良。免疫组化（IHC）显示GABARAP表达与基质金属蛋白酶（MMP）2和MMP 14呈负相关。总之，这些数据表明GABARAP可能通过AKT/mTOR通路抑制乳腺癌的恶性行为。GABARAP的靶向作用可能会提高乳腺癌诊断和治疗策略的确定性。
Few studies have focused on γ-aminobutyric acid type A (GABAA) receptor-associated protein (GABARAP) in tumor progression. We investigated the expression and importance of GABARAP in breast cancer. We analyzed the expression of GABARAP and its relationship with clinicopathological features and prognosis (TCGA). To explain the role and potential mechanism of GABARAP in regulating tumor development, we performed acquisition and loss of function experiments using cell lines and models of mouse xenotransplantation. We found that GABARAP inhibited proliferation, migration and invasion in vitro and in vivo. Notably, low levels of GABARAP induced the epithelial-mesenchymal transition (EMT). Low levels of GABARAP increased p-AKT and p-mTOR levels, and a specific AKT pathway inhibitor reversed the downregulation of GABARAP-induced tumor progression. GABARAP negatively correlated with advanced clinicopathological features in clinical specimens, such as tumor size and TNM stage. Notably, patients with low GABARAP levels had a poor prognosis. Immunohistochemistry (IHC) revealed that GABARAP expression negatively correlated with matrix metalloproteinase (MMP) 2 and MMP14. Conclusively, these data indicate that GABARAP suppresses the malignant behaviors of breast cancer likely via the AKT/mTOR pathway. The targeting of GABARAP may improve the certainty of diagnosis and treatment strategies for breast cancer.
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