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Activation of Mitogen-Activated Protein Kinase Pathway by Keratinocyte Growth Factor or Fibroblast Growth Factor-10 Promotes Cell Proliferation in Human Endometrial Carcinoma Cells

Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago 683-8504, Japan

Address all correspondence and requests for reprints to: Fuminori Taniguchi, M.D., Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago 683-8504, Japan. E-mail: tani4327{at}grape.med.tottori-u.ac.jp.

Fibroblast growth factors (FGFs) exert diverse effects resulting from their interaction with cognate receptors on target cells. Our current study was designed to examine the local production and action of two specific stromal-epithelial cell mediatory factors, keratinocyte growth factor (KGF) and FGF-10, in human endometrial carcinoma cells. The RT-PCR method was used to determine gene expression of KGF, FGF-10, and KGF receptor in human endometrial carcinoma cells (HEC-1) and human endometrial stromal cells. KGF mRNAs were expressed in both of these cell types. On the other hand, FGF-10 mRNA was detected only in the endometrial stromal cells, and KGF receptor mRNA was observed in the HEC-1 cells. The novel finding of the present study is that KGF is expressed in carcinoma cells and FGF-10 is expressed in human endometrial stromal cells. The distinct phosphorylation of ERK-1 and -2 (ERK1/2), which are members of the MAPK family, was observed when HEC-1 cells were treated with KGF or FGF-10. KGF and FGF-10 could induce the prompt phosphorylation of ERK1/2 and consequently stimulate DNA synthesis. KGF and FGF-10 did not activate the phosphorylation of Akt, protein kinase C, or signal transducer and activator of transcription-3. Blocking the MAPK pathway with the specific methyl ethyl ketone 1/2 inhibitor (U0126) completely neutralized the enhancement of cell proliferation induced by KGF and FGF-10. In addition, KGF and FGF-10 activated expressions of downstream nuclear transcription factors, such as Elk-1 and c-myc, but not c-fos. These results demonstrate for the first time that KGF and FGF-10 are capable of stimulating the growth of endometrial carcinoma cells via activating MAPK pathway through autocrine/paracrine fashion.

Abbreviations: BrdU, 5-Bromo-2'-deoxyuridine; FGF, fibroblast growth factor; FGFR, FGF receptor; G3PDH, glycerol-3-phosphate dehydrogenase; HEC, human endometrial carcinoma; KGF, keratinocyte growth factor; KGFR, KGF receptor; PKC, protein kinase C; RT, reverse transcription; STAT, signal transducers and activators of transcription.

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