Xie Chuan-Gao, Sun Shi-Long, Wei Shu-Mei, Xu Xiao-Ming, Shao Li-Ming, Chen Jia-Min, Cai Jian-Ting
From the Departments of Gastroenterology and.
Pathology, the Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, China.
Pancreas. 2018 Jul;47(6):732-737. doi: 10.1097/MPA.0000000000001076.
The epidermal growth factor receptor is overexpressed in the majority of pancreatic cancer. Epidermal growth factor receptor tyrosine kinase inhibitor erlotinib was approved to treat patients combining with gemcitabine. However, the sensitivity is low. Here, we try to reveal the regulatory role of guanine nucleotide exchange protein 100 (GEP100) in erlotinib sensitivity.
We investigated the correlation between GEP100 expression and sensitivity to erlotinib in different pancreatic cancer cell lines, followed by examination of the effect of GEP100 on erlotinib sensitivity by establishing the stable knocked-down cell line. The expression level of epithelial mesenchymal transition-related protein was examined by Western blot, and the regulatory mechanism was investigated by short hairpin RNA. Xenograft experiment was also performed in nude mice.
We identified a significant correlation between sensitivity to erlotinib and expression of GEP100. GEP100 downregulation increased its sensitivity to erlotinib. E-cadherin short hairpin RNA treatment inhibited this sensitivity. Immunohistochemical staining showed a mutual exclusive expression pattern of GEP100 and E-cadherin in human pancreatic cancer tissues. Xenograft showed that downregulation of GEP100 enhanced the growth inhibition of erlotinib in nude mice.
Our results suggested that GEP100 and E-cadherin have the predictive value for responsiveness to erlotinib in pancreatic cancer.
表皮生长因子受体在大多数胰腺癌中过表达。表皮生长因子受体酪氨酸激酶抑制剂厄洛替尼已被批准与吉西他滨联合用于治疗患者。然而，其敏感性较低。在此，我们试图揭示鸟嘌呤核苷酸交换蛋白100（GEP100）在厄洛替尼敏感性中的调节作用。
我们研究了不同胰腺癌细胞系中GEP100表达与对厄洛替尼敏感性之间的相关性，随后通过建立稳定的敲低细胞系来检测GEP100对厄洛替尼敏感性的影响。通过蛋白质免疫印迹法检测上皮间质转化相关蛋白的表达水平，并通过短发夹RNA研究其调节机制。还在裸鼠中进行了异种移植实验。
我们发现对厄洛替尼的敏感性与GEP100的表达之间存在显著相关性。GEP100的下调增加了其对厄洛替尼的敏感性。E-钙黏蛋白短发夹RNA处理抑制了这种敏感性。免疫组织化学染色显示在人胰腺癌组织中GEP100和E-钙黏蛋白呈相互排斥的表达模式。异种移植实验表明，GEP100的下调增强了厄洛替尼对裸鼠的生长抑制作用。
我们的结果表明，GEP100和E-钙黏蛋白对胰腺癌中厄洛替尼的反应性具有预测价值。
