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AKR1B10 promotes breast cancer cell proliferation and migration via the PI3K/AKT/NF-κB signaling pathway
Cell and Bioscience ( IF 7.5 ) Pub Date : 2021-08-21 , DOI: 10.1186/s13578-021-00677-3
Jiayao Qu 1, 2 , Jia Li 3 , Yaming Zhang 3 , Rongzhang He 3 , Xiangting Liu 3 , Ke Gong 3 , Lili Duan 3 , Weihao Luo 3 , Zheng Hu 3 , Gengsheng Wang 2, 4 , Chenglai Xia 5, 6 , Dixian Luo 1, 2
Affiliation  

Aberrant expression of Aldo-Keto reductase family 1 member B10 (AKR1B10) was associated with tumor size and metastasis of breast cancer in our published preliminary studies. However, little is known about the detailed function and underlying molecular mechanism of AKR1B10 in the pathological process of breast cancer. The relationship between elevated AKR1B10 expression and the overall survival and disease-free survival of breast cancer patients was analyzed by Kaplan–Meier Plotter database. Breast cancer cell lines overexpressing AKR1B10 (MCF-7/AKR1B10) and breast cancer cell lines with knockdown of AKR1B10 (BT-20/shAKR1B10) were constructed to analyze the impact of AKR1B10 expression on cell proliferation and migration of breast cancer. The expression levels of AKR1B10 were detected and compared in the breast cancer cell lines and tissues by RT-qPCR, western blot and immunohistochemistry. The proliferation of breast cancer cells was monitored by CCK8 cell proliferation assay, and the migration and invasion of breast cancer cells was observed by cell scratch test and transwell assay. The proliferation- and EMT-related proteins including cyclinD1, c-myc, Survivin, Twist, SNAI1, SLUG, ZEB1, E-cadherin, PI3K, p-PI3K, AKT, p-AKT, IKBα, p-IKBα, NF-κB p65, p-NF-κB p65 were detected by western blot in breast cancer cells. MCF-7/AKR1B10 cells were treated with LY294002, a PI3K inhibitor, to consider the impact of AKR1B10 overexpression on the PI3K/AKT/NF-κB signal cascade and the presence of NF-κB p65 in nuclear. In vivo tumor xenograft experiments were used to observe the role of AKR1B10 in breast cancer growth in mice. AKR1B10 expression was significantly greater in breast cancer tissue compared to paired non-cancerous tissue. The expression of AKR1B10 positively correlated with lymph node metastasis, tumor size, Ki67 expression, and p53 expression, but inversely correlated with overall and disease-free survival rates. Gene Ontology analysis showed that AKR1B10 activity contributes to cell proliferation. Overexpression of AKR1B10 facilitated the proliferation of MCF-7 cells, and induced the migration and invasion of MCF-7 cells in vitro in association with induction of epithelial-mesenchymal transition (EMT). Conversely, knockdown of AKR1B10 inhibited these effects in BT-20 cells. Mechanistically, AKR1B10 activated PI3K, AKT, and NF-κB p65, and induced nuclear translocation of NF-κB p65, and expression of proliferation-related proteins including c-myc, cyclinD1, Survivin, and EMT-related proteins including ZEB1, SLUG, Twist, but downregulated E-cadherin expression in MCF-7 cells. AKR1B10 silencing reduced the phosphorylation of PI3K, AKT, and NF-κB p65, the nuclear translocation of NF-κB p65, and the expression of proliferation- and migration-related proteins in BT-20 cells. LY294002, a PI3K inhibitor, attenuated the phosphorylation of PI3K, AKT, and NF-κB p65, and the nuclear translocation of NF-κB p65. In vivo tumor xenograft experiments confirmed that AKR1B10 promoted breast cancer growth in mice. AKR1B10 promotes the proliferation, migration and invasion of breast cancer cells via the PI3K/AKT/NF-κB signaling pathway and represents a novel prognostic indicator as well as a potential therapeutic target in breast cancer.

中文翻译:

AKR1B10通过PI3K/AKT/NF-κB信号通路促进乳腺癌细胞增殖和迁移

在我们发表的初步研究中,Aldo-Keto 还原酶家族 1 成员 B10 (AKR1B10) 的异常表达与乳腺癌的肿瘤大小和转移有关。然而,关于 AKR1B10 在乳腺癌病理过程中的详细功能和潜在分子机制知之甚少。通过Kaplan-Meier Plotter数据库分析AKR1B10表达升高与乳腺癌患者的总生存期和无病生存期之间的关系。构建过表达 AKR1B10 的乳腺癌细胞系 (MCF-7/AKR1B10) 和敲低 AKR1B10 的乳腺癌细胞系 (BT-20/shAKR1B10) 以分析 AKR1B10 表达对乳腺癌细胞增殖和迁移的影响。通过RT-qPCR、蛋白质印迹和免疫组织化学检测和比较乳腺癌细胞系和组织中AKR1B10的表达水平。通过CCK8细胞增殖试验监测乳腺癌细胞的增殖,通过细胞划痕试验和transwell试验观察乳腺癌细胞的迁移和侵袭。增殖和 EMT 相关蛋白,包括 cyclinD1、c-myc、Survivin、Twist、SNAI1、SLUG、ZEB1、E-钙粘蛋白、PI3K、p-PI3K、AKT、p-AKT、IKBα、p-IKBα、NF-κB p65、p-NF-κB p65 通过蛋白质印迹法在乳腺癌细胞中检测到。MCF-7/AKR1B10 细胞用 LY294002(一种 PI3K 抑制剂)处理,以考虑 AKR1B10 过表达对 PI3K/AKT/NF-κB 信号级联的影响和核中 NF-κB p65 的存在。体内肿瘤异种移植实验用于观察AKR1B10在小鼠乳腺癌生长中的作用。与配对的非癌组织相比,乳腺癌组织中 AKR1B10 的表达显着更高。AKR1B10 的表达与淋巴结转移、肿瘤大小、Ki67 表达和 p53 表达呈正相关,但与总体和无病生存率呈负相关。基因本体分析表明,AKR1B10 活性有助于细胞增殖。AKR1B10 的过表达促进了 MCF-7 细胞的增殖,并在体外诱导了 MCF-7 细胞的迁移和侵袭,并与上皮间质转化 (EMT) 的诱导相关。相反,敲除 AKR1B10 会抑制 BT-20 细胞中的这些作用。从机制上讲,AKR1B10 激活 PI3K、AKT 和 NF-κB p65,和诱导 NF-κB p65 的核易位,以及增殖相关蛋白(包括 c-myc、cyclinD1、Survivin 和 EMT 相关蛋白(包括 ZEB1、SLUG、Twist)的表达,但下调 MCF-7 细胞中 E-钙粘蛋白的表达。AKR1B10 沉默降低了 PI3K、AKT 和 NF-κB p65 的磷酸化、NF-κB p65 的核转位以及 BT-20 细胞中增殖和迁移相关蛋白的表达。LY294002 是一种 PI3K 抑制剂,可减弱 PI3K、AKT 和 NF-κB p65 的磷酸化以及 NF-κB p65 的核转位。体内肿瘤异种移植实验证实,AKR1B10 促进了小鼠乳腺癌的生长。AKR1B10 促进增殖,
更新日期:2021-08-21
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