Overexpression of Endogenous TIMP-2 Increases the Proliferation of BeWo Choriocarcinoma Cells Through the MAPK-Signaling Pathway

Abstract

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.

Integrated Analysis of Expression Profile Based on Differentially Expressed Genes in Middle Cerebral Artery Occlusion Animal Models

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Tissue inhibitor of metalloproteinase 2 inhibits activation of the β-catenin signaling in melanoma cells

“…Over-expression of TIMP-2 increases the proliferation of human choriocarcinoma cells through the mitogenactivated protein kinase (MAPK) signalling pathway. 37 TIMP-2 reduced tumor growth in diffuse-type gastric cancer cell lines through the transforming growth factor beta (TGF-β) pathway. 38 Our data suggest that TIMP-2 over-expression is able to enhance proliferation in human melanoma A2058 cells at the basal level when β-catenin activity is relative low.…”

TIMP-3 as a therapeutic target for cancer

“…Overexpression of TIMP-2 has been reported to increase proliferation of choriocarcinoma cells. 54 By contrast, TIMP-2 inhibits angiogenesis via an MMP-independent mechanism. 55 TIMP-4 is expressed in some cancers; however, its role in carcinogenesis remains unclear.…”