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Rho GTPases control a wide range of cellular processes, and their deregulation is associated with promotion of an aggressive and metastatic tumor phenotype in human cancers. Rho guanine nucleotide dissociation inhibitor 1 (RhoGDI1) plays a key role in regulating the activity of Rho GTPases. However, the underlying mechanisms are still unclear. In this study, we show that protein phosphatase 1B (PPM1B) interacts with RhoGDI1 and functions as its phosphatase. Ectopic expression of PPM1B results in dephosphorylation of RhoGDI1 and, thereby, abates the activation of RhoA, Rac1 and CDC42 by epidermal growth factor (EGF). PPM1B overexpression in Hs578T and SKBR3 human breast cancer cells decreases their motility and invasiveness in vitro and cancer metastasis in vivo. In contrast, knockdown of PPM1B in MCF-7 and MDA-MB-468 human breast cancer cells that express endogenous PPM1B enhances EGF-induced RhoGDI1 phosphorylation, activation of Rho GTPases, and cancer cell migration and invasion. Knockdown of RhoA or Rac1 by siRNA reverses the enhanced cell migration seen after PP1MB depletion. Collectively, these results indicate that PPM1B negatively regulates cancer cell motility and invasiveness through dephosphorylating RhoGDI1.

TGF-beta1 has been known to suppress the growth of gastric cancer cells. Interestingly, TGF-beta1 treatment increased the proliferation of human gastric cancer cell line, SNU-216 cells, while it reduced the proliferation of other tumor cells including SNU-620 cells. TGF-beta1-mediated down-regulation of c-Myc and induction of p21CIP1 were observed in SNU-620, but there was no change in SNU-216 in response to TGF-beta1. Similarly, TGF-beta1 receptors were upregulated by TGF-beta1 treatment in SNU-620, but they were not responded in SNU-216. By a single strand conformation polymorphism analysis, a repeated insertion of 37 nucleotides in the exon 8 of Smad4, resulting in premature termination at codon 362, was found in SNU-216. Furthermore, this truncated Smad4 functioned as a dominant negative form in TGF-beta1-mediated reporter activity and TGF-beta1 receptor expression. However, the proliferation of tumor cells was not affected by Smad4 mutation, but it was modulated by PD98059. Taken together, a mutation in Smad4 in addition to mitogen-activated protein kinase altered the TGF-beta1-mediated signaling, which is one of key events of gastric tumorigenesis.

As an effort to identify immune suppressive molecules in gastric cancer cells, a signal sequence trap was employed. Among the genes identified, 9-27 gene was highly expressed in gastric tumor tissues and in cancer cell lines. It was induced by IFN-γ treatment, but not by TNF-α or TGF-β1 treatment. The overexpression of 9-27 in the gastric cancer cells rendered tumor cells more resistant to natural killer cells. In addition, the 9-27-overexpressed cells showed an increased migration and an invasive capacity when compared with the control cells. Taken together, these data indicate that 9-27 plays a role in malignant progression by suppressing natural killer cells and by increasing the invasive potential of gastric cancer cells.