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.
Zhang
Shu-quan
SQ
Department of Obstetrics and Gynecology, Affiliated First People's Hospital, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
Cai
Bin
B
Liu
Ling
L
He
Yin-yan
YY
Yang
Yi-xia
YX
Wan
Xiao-ping
XP
D000328:Adult; D000368:Aged; D015153:Blotting, Western; D018269:Carcinoma, Endometrioid / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D004714:Endometrial Hyperplasia / Q000188:drug therapy / Q000378:metabolism*; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000378:metabolism* / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007124:Immunoenzyme Techniques; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D012333:RNA, Messenger; D004958:Estradiol; D020928:Mitogen-Activated Protein Kinases; D007610:Kallikreins; C120801:kallikrein 4