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

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.