Targeted intervention of eIF4A1 inhibits EMT and metastasis of pancreatic cancer cells via c-MYC/miR-9 signaling.
Targeted intervention of eIF4A1 inhibits EMT and metastasis of pancreatic cancer cells via c-MYC/miR-9 signaling.
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eIF4A1通过c-MYC/miR-9信号通路靶向干预胰腺癌细胞EMT和转移
DOI：
10.1186/s12935-021-02390-0
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发表时间：
2021-12-14
影响因子：
5.8
通讯作者：
Luan Z
中科院分区：
文献类型：
--
作者：
Zhao Y;Wang Y;Chen W;Bai S;Peng W;Zheng M;Yang Y;Cheng B;Luan Z
由于缺乏有效的治疗方法，早期转移仍然是胰腺导管腺癌（PDAC）复发和死亡的主要原因。然而，早期转移的分子机制在很大程度上是未知的。我们的特点是真核翻译起始因子（eIFs）在上皮间质转化（EMT）和胰腺癌细胞转移的功能，以调查是否eIFs和下游c-MYC影响EMT和转移的联合干扰。我们使用癌症基因组图谱（TCGA）和基因组组织表达（GTEx）数据库来分析PDAC组织中eIF4A1的表达，并使用含有53个PDAC样本的微阵列进一步验证了研究结果。进行eIF4A1和c-MYC的表达调节和药理学抑制，以确定它们在胰腺癌细胞的体外和体内迁移、侵袭和转移中的作用。eIF4A1的高表达与淋巴结浸润、肿瘤大小呈正相关，提示预后不良。eIF4A1通过c-MYC/miR-9轴降低E-钙粘蛋白表达。eIF4A1和c-MYC的缺失降低了胰腺癌细胞的EMT和转移能力，而eIF4A1的上调减弱了c-MYC下调诱导的EMT和转移抑制。eIF4A1抑制剂罗格列胺（RocA）或c-MYC抑制剂Mycro 3单独或联合治疗显著降低了胰腺癌细胞体外EMT标志物的表达水平。然而，RocA单独使用的有效性和安全性并不劣于体内联合治疗的有效性和安全性。eIF4A1过表达通过c-MYC/miR-9轴下调E-cadherin表达，促进胰腺癌细胞EMT和转移。尽管eIF4A1和c-MYC之间存在潜在的反馈回路，但RocA单药治疗是一种有希望的抑制eIF4A1诱导的PDAC转移的治疗方法。在线版本包含补充材料，可通过10.1186/s12935 - 021 - 02390 - 0获得。
Owing to the lack of effective treatment options, early metastasis remains the major cause of pancreatic ductal adenocarcinoma (PDAC) recurrence and mortality. However, the molecular mechanism of early metastasis is largely unknown. We characterized the function of eukaryotic translation initiation factors (eIFs) in epithelial-mesenchymal-transition (EMT) and metastasis in pancreatic cancer cells to investigate whether eIFs and downstream c-MYC affect EMT and metastasis by joint interference. We used The Cancer Genome Atlas (TCGA) and Genome Tissue Expression (GTEx) databases to analyze eIF4A1 expression in PDAC tissues and further validated the findings with a microarray containing 53 PDAC samples. Expression regulation and pharmacological inhibition of eIF4A1 and c-MYC were performed to determine their role in migration, invasion, and metastasis in pancreatic cancer cells in vitro and in vivo. Elevated eIF4A1 expression was positively correlated with lymph node infiltration, tumor size, and indicated a poor prognosis. eIF4A1 decreased E-cadherin expression through the c-MYC/miR-9 axis. Loss of eIF4A1 and c-MYC decreased the EMT and metastasis capabilities of pancreatic cancer cells, whereas upregulation of eIF4A1 attenuated the inhibition of EMT and metastasis induced by c-MYC downregulation. Treatment with the eIF4A1 inhibitor rocaglamide (RocA) or the c-MYC inhibitor Mycro3 either alone or in combination significantly decreased the expression level of EMT markers in pancreatic cancer cells in vitro. However, the efficiency and safety of RocA alone were not inferior to those of the combination treatment in vivo. Overexpression of eIF4A1 downregulated E-cadherin expression through the c-MYC/miR-9 axis, which promoted EMT and metastasis of pancreatic cancer cells. Despite the potential feedback loop between eIF4A1 and c-MYC, RocA monotherapy is a promising treatment inhibiting eIF4A1-induced PDAC metastasis. The online version contains supplementary material available at 10.1186/s12935-021-02390-0.
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影响因子：
37.3
作者：
Madden SK;de Araujo AD;Gerhardt M;Fairlie DP;Mason JM
通讯作者：
Mason JM
影响因子：
64.8
作者：
Boussemart, Lise;Malka-Mahieu, Helene;Vagner, Stephan
通讯作者：
Vagner, Stephan
影响因子：
8
作者：
Doudican, N. A.;Orlow, S. J.
通讯作者：
Orlow, S. J.
影响因子：
21.3
作者：
Ma, Li;Young, Jennifer;Prabhala, Harsha;Pan, Elizabeth;Mestdagh, Pieter;Muth, Daniel;Teruya-Feldstein, Julie;Reinhardt, Ferenc;Onder, Tamer T.;Valastyan, Scott;Westermann, Frank;Speleman, Frank;Vandesompele, Jo;Weinberg, Robert A.
通讯作者：
Weinberg, Robert A.
影响因子：
11.2
作者：
Pelletier J;Graff J;Ruggero D;Sonenberg N
通讯作者：
Sonenberg N