Overexpression of endogenous TIMP-2 increases the proliferation of BeWo choriocarcinoma cells through the MAPK-signaling pathway

Choriocarcinoma is a highly malignant form of trophoblastic tumor that is characterized by malignant placental tumors and rapid cell growth. In vivo and in vitro studies have demonstrated that tissue inhibitor of metalloproteinase 2 (TIMP-2) is present in choriocarcinoma. However, the role of TIMP-2 in cell proliferation in choriocarcinoma has not been investigated. Exogenous TIMP-2 is known to promote cell proliferation. During growth, cells are subjected to varied concentrations of TIMP-2, which depend on the amount of TIMP-2 produced by the cells themselves. Thus, the effect of gradually increasing endogenous TIMP-2 on the proliferation of choriocarcinoma cells needs to be examined. Proliferation of BeWo human choriocarcinoma cells was stimulated by transient transfection of a plasmid expressing TIMP-2. Overexpression of endogenous TIMP-2 also activated ERK1/2 and JNK1/2 of the MAPK-signaling pathway. Furthermore, inhibition of these proteins resulted in suppression of the cell proliferation-stimulating effect of TIMP-2. These results suggest that TIMP-2 plays an important role in tumor growth in the case of BeWo cells. Moreover, proliferation of BeWo cells due to TIMP-2 expression can be used as a model for fast-growing choriocarcinomas, and TIMP-2 could be used as a novel tumor marker of choriocarcinoma.