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This study was supported in part by the Japan Society for the Promotion of Science JSPS KAKENHI Grant (Nos. JP24249080, JP25462557, JP16K11086). The authors declare no conflict of interest.

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.