PRL-3 promotes the motility, invasion, and metastasis of LoVo colon cancer cells through PRL-3-integrin beta1-ERK1/2 and-MMP2 signaling
Phosphatase of regenerating liver-3 (PRL-3) plays a causative role in tumor metastasis, but the underlying mechanisms are not well understood. In our previous study, we observed that PRL-3 could decrease tyrosine phosphorylation of integrin beta1 and enhance activation of ERK1/2 in HEK293 cells.
Herein we aim to explore the association of PRL-3 with integrin beta1 signaling and its functional implications in motility, invasion, and metastasis of colon cancer cell LoVo.
Methods: Transwell chamber assay and nude mouse model were used to study motility and invasion, and metastsis of LoVo colon cancer cells, respectively. Knockdown of integrin beta1 by siRNA or lentivirus-mediated shRNA were detected with Western blot and RT-PCR.
The effect of PRL-3 on integrin beta1, ERK1/2, and MMPs that mediate motility, invasion, and metastasis were measured by Western blot, immunofluorencence, co-immunoprecipitation and zymographic assays.
Results: We demonstrated that PRL-3 associated with integrin beta1 and its expression was positively correlated with ERK1/2 phosphorylation in colon cancer tissues. Depletion of integrin beta1 with siRNA, not only abrogated the activation of ERK1/2 stimulated by PRL-3, but also abolished PRL-3-induced motility and invasion of LoVo cells in vitro.
Similarly, inhibition of ERK1/2 phosphorylation with U0126 or MMP activity with GM6001 also impaired PRL-3-induced invasion. In addition, PRL-3 promoted gelatinolytic activity of MMP2, and this stimulation correlated with decreased TIMP2 expression.
Moreover, PRL-3-stimulated lung metastasis of LoVo cells in a nude mouse model was inhibited when integrin beta1 expression was interfered with shRNA.
Conclusion: Our results suggest that PRL-3's roles in motility, invasion, and metastasis in colon cancer are critically controlled by the integrin beta1-ERK1/2 and -MMP2 signaling.
Author: Lirong PengXiaofang XingWeijun LiLike QuLin MengShenyi LianBeihai JiangJian WuChengchao Shou
Credits/Source: Molecular Cancer 2009, 8:110
Published on: 2009-11-25
Copyright by the authors listed above - made available via BioMedCentral (Open Access). Please
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