Ubiquitin ligase Cbl-b represses IGF-I-induced epithelial mesenchymal transition via ZEB2 and microRNA-200c regulation in gastric cancer cells.
Ubiquitin ligase Cbl-b represses IGF-I-induced epithelial mesenchymal transition via ZEB2 and microRNA-200c regulation in gastric cancer cells.
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泛素连接酶 Cbl-b 通过 ZEB2 和 microRNA-200c 调节胃癌细胞抑制 IGF-I 诱导的上皮间质转化
DOI：
10.1186/1476-4598-13-136
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发表时间：
2014-06-02
期刊：
影响因子：
37.3
通讯作者：
Qu X
中科院分区：
文献类型：
--
作者：
Li H;Xu L;Li C;Zhao L;Ma Y;Zheng H;Li Z;Zhang Y;Wang R;Liu Y;Qu X
背景胰岛素样生长因子I（IGF-I）可诱导许多上皮性肿瘤发生上皮间质转化（EMT），但其分子机制尚不清楚。另外，IGF-I在胃癌中的作用还知之甚少。方法用IGF-I诱导两种胃癌细胞系EMT，检测转录因子ZEB 2和microRNA-200 c（miR-200 c）的表达水平。用Akt/ERK抑制剂处理细胞以研究这些途径在IGF-I介导的EMT中的作用。使用shRNA质粒的转染来沉默泛素连接酶Cbl-b，以评估其在该过程中的参与。结果IGF-I诱导胃癌细胞EMT的同时伴有ZEB 2的上调，IGF-IR与Cbl-b表达的相关性及两者对胃癌转移的影响。此外，Akt/ERK抑制剂和Akt/ERK基因敲除均通过上调miR-200 c逆转IGF-I诱导的ZEB 2上调和EMT，表明Akt/ERK-miR-200 c-ZEB 2轴参与IGF-I诱导的EMT。泛素连接酶Cbl-b也泛素化和降解IGF-IR，并抑制Akt/ERK-miR-200 c-ZEB 2轴，导致IGF-I诱导的EMT的抑制。胃癌组织中IGF-IR和Cbl-b的表达呈显著负相关（r =-0.265，p < 0.05）。结论泛素连接酶Cbl-b抑制IGF-I诱导的EMT，可能是通过靶向IGF-IR降解进而抑制Akt/ERK-miR-200 c-ZEB 2轴而实现的。
BackgroundInsulin-like growth factor I (IGF-I) can induce epithelial mesenchymal transition (EMT) in many epithelial tumors; however, the molecular mechanism by which this occurs is not clearly understood. Additionally, little is known about the involvement of IGF-I in gastric cancer.MethodsTwo gastric cancer cell lines were treated with IGF-I to induce EMT and levels of transcription factor ZEB2 and microRNA-200c (miR-200c) were measured. Cells were treated with Akt/ERK inhibitors to investigate the role of these pathways in IGF-I-mediated EMT. Transfection of shRNA plasmids was used to silence the ubiquitin ligase Cbl-b to assess its involvement in this process. The relationship between IGF-IR and Cbl-b expression, and the effect of IGF-IR and Cbl-b on metastasis were analyzed in primary gastric adenocarcinoma patients.ResultsIGF-I-induced gastric cancer cell EMT was accompanied by ZEB2 up-regulation. Furthermore, both Akt/ERK inhibitors and knockdown of Akt/ERK gene reversed IGF-I-induced ZEB2 up-regulation and EMT through up-regulation of miR-200c, suggesting the involvement of an Akt/ERK-miR-200c-ZEB2 axis in IGF-I-induced EMT. The ubiquitin ligase Cbl-b also ubiquitinated and degraded IGF-IR and inhibited the Akt/ERK-miR-200c-ZEB2 axis, leading to the repression of IGF-I-induced EMT. There was a significant negative correlation between the expression of IGF-IR and Cbl-b in gastric cancer patient tissues (r = -0.265, p < 0.05). More of patients with IGF-IR-positive expression and Cbl-b-negative expression were with lymph node metastasis (p < 0.001).ConclusionsTogether, these findings demonstrate that the ubiquitin ligase Cbl-b represses IGF-I-induced EMT, likely through targeting IGF-IR for degradation and further inhibiting the Akt/ERK-miR-200c-ZEB2 axis in gastric cancer cells.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
8.8
作者：
通讯作者：
--
泛素连接酶 Cbl 家族的上调参与 ATRA 和蟾蜍灵诱导的细胞粘附，但不参与细胞分化
DOI：
10.1016/j.bbrc.2007.12.120
发表时间：
2008-02-29
影响因子：
3.1
作者：
Qu, Xiujuan;Liu, Yunpeng;Hou, Kezou
通讯作者：
Hou, Kezou
影响因子：
11.4
作者：
Remacle, JE;Kraft, H;Huylebroeck, D
通讯作者：
Huylebroeck, D
影响因子：
11.2
作者：
Bracken, Cameron P.;Gregory, Philip A.;Goodall, Gregory J.
通讯作者：
Goodall, Gregory J.