PRL-3 siRNA Inhibits the Metastasis of B16-BL6 Mouse Melanoma Cells In Vitro and In Vivo

Abstract

Phosphatase of regenerating liver-3 (PRL-3) has been proposed to promote the invasion of tumor cells to metastasis sites. However, the effect of PRL-3 on spontaneous metastasis has not been clearly demonstrated, and whether PRL-3 could become a new therapeutic target in malignant tumor is still unknown. In this study, we used PRL-3 siRNA as a molecular medicine to specifically reduce the expression of PRL-3 in B16-BL6 cells, a highly metastatic melanoma cell line. In vitro, PRL-3 siRNA significantly inhibited cell adhesion and migration, but had no effect on cell proliferation. In the spontaneous metastatic tumor model in vivo, PRL-3 siRNA treatment remarkably inhibited the proliferation of primary tumor, prevented tumor cells from invading the draining lymph nodes, and prolonged the life span of mice. Therefore, our results indicate that PRL-3 plays a critical role in promoting the whole process of spontaneous metastasis and tumor growth initiation, and that inhibiting PRL-3 will improve malignant tumor therapy.

PRL PTPs: mediators and markers of cancer progression

“…In certain cell lines, proliferative rates were not always altered following changes in either PRL-1 or -3 levels, even though robust changes occurred with respect to other endpoints in the same cells [23,25,45,46]. This suggests that PRL-1 and -3 may not be essential regulators of cell cycle progression [15,45] and that their ability to promote tumor formation and metastasis may be due to other cellular effects. These are most likely related to endpoints such as cell migration and invasion, that can affect the interactions of cancer cells with their local environment.…”

“…In addition, the ablation of PRL-3 expression in the transfected B16-PRL-3 cells by treatment with an antisense oligodeoxynucleotide eliminated the increased migration, adhesion, and proliferation of these cells. The ability to reverse the PRL-3-dependent effects was extended in a subsequent study in which siRNA-mediated knockdown of endogenous PRL-3 expression in metastatic B16-BL6 melanoma cells decreased cell migration and invasion, inhibited tumor formation, prevented lymph node metastasis and significantly prolonged the survival of mice after injection of the cells [45]. This demonstrates the exciting possibility that specific targeting of PRL-3 may prove to be an effective treatment option for PRL-3-expressing human tumors.…”

“…In accordance with these results, the downregulation of PRL-3 expression abrogates or reduces several of these properties in melanoma, gastric carcinoma, breast carcinoma, and colon carcinoma cell lines (Table 2). Notably, the ability of some of these cell lines to form metastases in mice is significantly reduced upon PRL-3 knockdown, and survival of the animals is prolonged [23,45,46]. No studies of the effects of PRL-2 knockdown, and only a few that investigate the effects of PRL-1 knockdown, have been reported (Table 2).…”

Prognostic and metastatic value of phosphatase of regenerating liver-3 in invasive breast cancer

“…PRL-3 has at least 75% amino-acid sequence similarity with PRL-1 and PRL-2, the other two members of the PRL family (Diamond et al 1994;Zeng et al 2000). Overexpression of PRL-3 has been identiWed in several human cancers including colorectal, gastric, ovarian cancer as compared with their normal tissues Miskad et al 2004;Peng et al 2004;Polato et al 2005), and there are several reports showing its importance in cancer cells invasion and migration (Matter et al 2001;Qian et al 2007;Wu et al 2004;Zeng et al 2003). Recently, more and more Wndings strongly suggest that an excess of PRL-3 expression may play a key role in the acquisition of metastatic potential of tumor cells Liu et al 2008;Rouleau et al 2006;Wang et al 2007bWang et al , 2008, and in several studies, it has also been associated with poor prognosis.…”

Expression and Prognostic Value of PRL-3 in Human Intrahepatic Cholangiocarcinoma

“…Stable expression of wild-type PRL-3 could enhance cell motility and invasive ability in vitro, and promote metastasis in mouse model systems [21,23]. Oppositely, downregulation of PRL-3 expression by interfering RNA could attenuate the ability of motility and invasion in vitro and suppress metastasis in nude mice [24,25]. High expression of PRL-3 has been reported in a variety of cancer cell lines and tissues [26], including gastric cancer [27,28], breast cancer [29] and ovarian cancer [30,31].…”