醛酮还原酶1B10通过激活细胞外信号调节激酶信号通路促进乳腺癌细胞的迁移和侵袭。
AKR1B10 promotes breast cancer cell migration and invasion via activation of ERK signaling.
作者信息
Li Jia, Guo Yuanwei, Duan Lili, Hu Xinglin, Zhang Xi, Hu Jian, Huang Li, He Rongzhang, Hu Zheng, Luo Weihao, Tan Tan, Huang Renbin, Liao Duanfang, Zhu Yuan-Shan, Luo Di-Xian
机构信息
Translational Medicine Institute, National & Local Joint Engineering Laboratory for High-throughput Molecular Diagnosis Technology, Affiliated to The First People's Hospital of Chenzhou, University of South China, Chenzhou 423000, P.R. China.
Center for Clinical Pathology, Affiliated to The First People's Hospital of Chenzhou 423000, P.R. China.
出版信息
Oncotarget. 2017 May 16;8(20):33694-33703. doi: 10.18632/oncotarget.16624.
BACKGROUND
Aldo-keto reductase family 1, member B10 (AKR1B10), is known to be significantly induced in the cells of various cancers such as breast cancer. However, the mechanisms of AKR1B10 promoting tumorigenesis in breast cancer remain unclear. In the present study, we demonstrated the potential role and mechanism of AKR1B10 in the invasion and migration of breast cancer cells.
METHODS
The expression level of AKR1B10 in breast carcinoma, para-carcinoma and cancer tissues were detected by immunohistochemical evaluation and real-time polymerase chain reaction (RT-PCR), and the correlationships between AKR1B10 expression and clinicopathological features in breast cancer patients (n=131) were investigated. AKR1B10 was ectopically expressed in MCF-7 cells or silenced in BT-20 cells. The roles of AKR1B10 expression in the migration and invasion of MCF-7 cells and BT-20 cells were explored by wound healing assay, transwell migration assay and transwell matrigel invasion assay, and finally the activation level of extracellular signal-regulated kinase 1/2 (EKR1/2) activation and the expression level of matrix metalloproteinase-2 (MMP2) and vimentin in MCF-7 and BT-20 cells were measured by western blot.
RESULTS
We found that AKR1B10 expression was increased in malignant tissues, which was correlated positively with tumor size, lymph node metastasis (p<0.05). MCF-7/AKR1B10 cells displayed a higher ability of migration (43.57±1.04%) compared with MCF-7/vector cells (29.12±1.34%) in wound healing assay, and the migrated cell number of MCF-7/AKR1B10 was more (418.43±9.62) than that of MCF-7/vector (222.43±17.75) in transwell migration assay without matrigel. We furtherly confirmed MCF-7/AKR1B10 cells invaded faster compared with MCF-7/vector cells by transwell matrigel invasion assay. Finally, we found AKR1B10 induced the migration and invasion of MCF-7 and BT-20 cells by activating EKR signaling, which promoted the expressions of MMP2 and vimentin. PD98059, a specific inhibitor of the activation of MEK, blocked the migration and invasion by inhibiting the expression of MMP2 and vimentin.
CONCLUSIONS
AKR1B10 is overexpressed in breast cancer, and promotes the migration and invasion of MCF-7 and BT-20 cells by activating ERK signaling pathway.
背景
醛酮还原酶家族1成员B10（AKR1B10）在乳腺癌等多种癌症细胞中显著上调。然而，AKR1B10促进乳腺癌发生发展的机制尚不清楚。在本研究中，我们阐述了AKR1B10在乳腺癌细胞侵袭和迁移中的潜在作用及机制。
方法
采用免疫组化评估和实时聚合酶链反应（RT-PCR）检测AKR1B10在乳腺癌组织、癌旁组织和癌组织中的表达水平，并研究AKR1B10表达与131例乳腺癌患者临床病理特征之间的相关性。在MCF-7细胞中过表达AKR1B10，在BT-20细胞中沉默AKR1B10。通过划痕实验、Transwell迁移实验和Transwell基质胶侵袭实验探讨AKR1B10表达对MCF-7细胞和BT-20细胞迁移和侵袭的作用，最后通过蛋白质免疫印迹法检测细胞外信号调节激酶1/2（EKR1/2）的激活水平以及MCF-7和BT-20细胞中基质金属蛋白酶-2（MMP2）和波形蛋白的表达水平。
结果
我们发现恶性组织中AKR1B10表达增加，且与肿瘤大小、淋巴结转移呈正相关（p<0.05）。在划痕实验中，与MCF-7/载体细胞（29.12±1.34%）相比，MCF-7/AKR1B10细胞表现出更高的迁移能力（43.57±1.04%）；在无基质胶的Transwell迁移实验中，MCF-7/AKR1B10细胞的迁移细胞数（418.43±9.62）多于MCF-7/载体细胞（222.43±17.75）。通过Transwell基质胶侵袭实验，我们进一步证实MCF-7/AKR1B10细胞比MCF-7/载体细胞侵袭更快。最后，我们发现AKR1B10通过激活EKR信号通路诱导MCF-7和BT-20细胞的迁移和侵袭，促进了MMP2和波形蛋白的表达。MEK激活的特异性抑制剂PD98059通过抑制MMP2和波形蛋白的表达来阻断迁移和侵袭。
结论
AKR1B10在乳腺癌中过表达，并通过激活ERK信号通路促进MCF-7和BT-20细胞的迁移和侵袭。
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