激肽释放酶 4 在子宫内膜癌中的过表达及其通过丝裂原活化蛋白激酶信号通路被雌激素上调。

Kallikrein 4 overexpression in endometrial carcinoma and upregulation by estrogen via mitogen-activated protein kinase signal pathway.

机构信息

Department of Obstetrics and Gynecology, Affiliated First People's Hospital, Shanghai Jiao Tong University, Shanghai, People's Republic of China.

出版信息

Int J Gynecol Cancer. 2009 Nov;19(8):1377-83. doi: 10.1111/IGC.0b013e3181a83e1a.

DOI:10.1111/IGC.0b013e3181a83e1a

PMID:20009893

Abstract

OBJECTIVE

The aim of this study was to investigate the expression of kallikrein 4 (KLK4) and the potential signal pathway through which estrogen up-regulates KLK4 in endometrial cancer.

METHODS

The expression of KLK4 was analyzed in 15 human normal endometrium, 13 hyperplasia endometrium, and 68 endometrioid adenocarcinoma by immunohistochemistry. After exposure to 17beta-estradiol and/or to the mitogen-activated protein kinase (MAPK) inhibitor U0126 and to the PI3K inhibitor LY294002, the expression of KLK4 in the endometrial cancer cell lines KLE and RL95-2 was detected with quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot.

RESULTS

The expression of KLK4 protein was higher in endometroid endometrial cancer than in hyperplasia or normal endometrium (P < 0.001). Immunohistochemical staining revealed that 92.6% (63/68) of endometrial adenocarcinoma, 61.5% (8/13) of hyperplasia endometrium, and 26.7% (4/15) of normal endometrium were positive for KLK4 protein. The expression of KLK4 was significantly associated with tumor grade (P = 0.004), but not with ER status (P = 0.532). Quantitative reverse transcriptase PCR and Western blot analysis showed that estrogen can up-regulate the expression of KLK4 in endometrial cancer cell lines KLE and RL95-2, and the up-regulation effect of 17beta-estradiol on KLK4 can be inhibited by U0126 in the 2 endometrial cancer cell lines but not by LY294002.

CONCLUSIONS

Kallikrein 4 is a new nuclear protein, and estrogen up-regulates the expression of KLK4 by activating the MAPK pathway in endometrial cancer cell lines, which may play an important role in the development of endometrial cancer.

摘要

目的

本研究旨在探讨激肽释放酶 4（KLK4）的表达情况，以及雌激素通过何种潜在信号通路上调子宫内膜癌中 KLK4 的表达。

方法

采用免疫组织化学法分析 15 例正常子宫内膜、13 例子宫内膜增生和 68 例子宫内膜样腺癌组织中 KLK4 的表达。用 17β-雌二醇和/或丝裂原活化蛋白激酶（MAPK）抑制剂 U0126及 PI3K 抑制剂 LY294002 处理子宫内膜癌细胞系 KLE 和 RL95-2 后，用实时定量逆转录聚合酶链反应（qRT-PCR）和 Western blot 检测 KLK4 的表达。

结果

子宫内膜样腺癌中 KLK4 蛋白的表达高于增生或正常子宫内膜（P<0.001）。免疫组织化学染色显示，68 例子宫内膜腺癌中 92.6%（63/68）、13 例增生子宫内膜中 61.5%（8/13）和 15 例正常子宫内膜中 26.7%（4/15）的 KLK4 蛋白为阳性。KLK4 的表达与肿瘤分级显著相关（P=0.004），但与 ER 状态无关（P=0.532）。qRT-PCR 和 Western blot 分析表明，雌激素可上调子宫内膜癌细胞系 KLE 和 RL95-2 中 KLK4 的表达，17β-雌二醇对 KLK4 的上调作用可被 2 种子宫内膜癌细胞系中的 U0126 抑制，但不能被 LY294002 抑制。