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Kallikrein 4 Overexpression in Endometrial Carcinoma and Upregulation by Estrogen via Mitogen-Activated Protein Kinase Signal Pathway
  1. Shu-quan Zhang, MD, PhD*,
  2. Bin Cai, MD, PhD*,
  3. Ling Liu, PhD*,,
  4. Yin-yan He, MD, PhD*,
  5. Yi-xia Yang, MD* and
  6. Xiao-ping Wan, MD, PhD*
  1. *Department of Obstetrics and Gynecology, Affiliated First People's Hospital, Shanghai Jiao Tong University, Shanghai, People's Republic of China; and
  2. Department of Medicine and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  1. Address correspondence and reprint requests to Xiao-ping Wan, Department of Obstetrics and Gynecology, Affiliated First People's Hospital, Shanghai Jiao Tong University, No. 100 Haining Rd, Shanghai 200080, People's Republic of China. E-mail: wanxiaoping61{at}


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 17β-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 17β-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.

  • KLK4
  • Endometrial carcinoma
  • Signal pathway

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  • This work was supported by the Chinese National Natural Science Foundation (grant 30672236), the Key Project of the Shanghai Health Bureau (grant 2005ZD002), and the Shanghai National Natural Science Foundation (grant 06ZR14053).