NEDD4 promotes acquired erlotinib resistance in non-small cell lung cancer

Huake SUN; Jiang WANG; Fengyi ZHAO; Jing HAN; Jianguo SUN; Zhengtang CHEN

doi:10.16016/j.1000-5404.201701139

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NEDD4 promotes acquired erlotinib resistance in non-small cell lung cancer

Basic Medicine | 更新时间：2026-01-09

- NEDD4 promotes acquired erlotinib resistance in non-small cell lung cancer
- Journal of Third Military Medical University Vol. 39, Issue 15, Pages: 1543-1548(2017)
- 作者机构：
  
  400037 重庆，第三军医大学新桥医院全军肿瘤研究所
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(81672841);the Key Tackling Project of Chongqing Science and Technology Commission(2011AB5032)
- DOI：10.16016/j.1000-5404.201701139
  CLC： R734.2;R966;R979.19
- Received：24 January 2017，
  
  Revised：2017-03-07，
  
  Published：15 August 2017
- 稿件说明：
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Huake SUN, Jiang WANG, Fengyi ZHAO, et al. NEDD4 promotes acquired erlotinib resistance in non-small cell lung cancer[J]. Journal of Third Military Medical University, 2017, 39(15): 1543-1548.
DOI：

Huake SUN, Jiang WANG, Fengyi ZHAO, et al. NEDD4 promotes acquired erlotinib resistance in non-small cell lung cancer[J]. Journal of Third Military Medical University, 2017, 39(15): 1543-1548. DOI： 10.16016/j.1000-5404.201701139.

摘要

目的

探讨NEDD4(neural precursor cell expressed developmentally downregulated protein 4) 在非小细胞肺癌(non-small cell lung cancer，NSCLC)继发厄洛替尼耐药中的作用。

方法

以HCC827细胞及耐厄洛替尼的HCC827(HCC827/ER)细胞为工具，CCK-8法检测HCC827/ER细胞的耐药指数；实时荧光定量PCR(quantitative real-time，qPCR)及Western blot检测厄洛替尼处理48 h后，NEDD4 mRNA和蛋白在两种细胞中的表达及PI3K/AKT信号通路活化情况。NEDD4小干扰RNA(siNEDD4) 转染HCC827/ER细胞，比较处理前后HCC827/ER细胞的厄洛替尼IC

变化以及PI3K/AKT信号通路活化情况。裸鼠成瘤实验在活体水平上进一步验证NEDD4在NSCLC继发厄洛替尼耐药中的作用。

结果

HCC827/ER细胞的耐药指数为(118.23±23.77)；HCC827/ER细胞NEDD4 mRNA和蛋白以及PI3K/AKT信号通路活化水平均高于HCC827细胞；HCC827/ER细胞成功转染siNEDD4后，转染组的PI3K/AKT信号通路活化水平降低，且厄洛替尼IC

值明显低于对照组(

＜0.05)。裸鼠成瘤实验中转染组肿瘤对厄洛替尼的敏感性明显增加，与阴性对照组比较，药物处理组肿瘤生长受到明显的抑制。

结论

NEDD4通过激活PI3K/AKT信号通路促进NSCLC继发厄洛替尼耐药。

Abstract

Objective

To investigate the role of neural precursor cell expressed developmentally downregulated protein 4 (NEDD4) to erlotinib acquired resistance in non-small cell lung cancer (NSCLC).

Methods

HCC827 and HCC827/ER cells (erlotinib resistant cells induced from HCC827 cells) were sub-cultured to evaluate erlotinib resistance index using CCK-8 kit. After treated with erlotinib for 48 h

the mRNA and protein levels of NEDD4 in these cells were detected by quantitative real-time PCR (qPCR) and Western blotting respectively. The activity of PI3K/Akt signaling pathway was measured at the same time. After knocking down NEDD4 in HCC827/ER with si-NEDD4

changes of erlotinib IC

and PI3K/Akt signaling pathway activity were detected again.

In vivo

experiments were taken to further validate the role of NEDD4 in NSCLC acquired erlotinib resistance in nude mice.

Results

The resistance index of HCC827/ER to erlotinib was 118.23±23.77. Compared with the HCC827 cells

the HCC827/ER cells had higher mRNA and protein levels of NEDD4

and stronger activation of PI3K/Akt signaling pathway. NEDD4 knockdown by siNEDD4 transfection resulted in lowered activation of PI3K/Akt signaling pathway and reduced erlotinib IC

than the control cells (

0.05).

In vivo

experiments indicated that the nude mice bearing siNEDD4-transfected HCC827/ER cells had obviously enhanced sensitivity to erlotinib

and remarkably inhibited tumor growth when compared with the mice bearing the untrasfected cells.

Conclusion

NEDD4 promotes erlotinib acquired resistance in NSCLC through activation of PI3K/Akt signaling pathway.

关键词

Keywords

references

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