Background/Aims: The invasion of trophoblast cells into the maternal uterine decidua is critical for normal placentation, establishment of pregnancy and maintenance of fetal growth in humans. Several growth factors and cytokines have been implicated in trophoblast invasion, but the underlying regulatory mechanisms of invasion are not fully understood. Our earlier studies have found that caudal related homeobox transcription factor 2 (CDX2) is hypomethylated in human pre-eclampsia placental tissues. However, whether CDX2 is involved in trophoblast invasion was unclear. Methods and Results: In this study, we investigated CDX2 function using a human HTR-8/SVneo cell line that overexpressed CDX2. Cell invasion assays demonstrated that CDX2 enhanced trophoblast cell invasiveness. Meanwhile, MTT assays revealed that CDX2 did not affect cell proliferation. Western blot analysis and quantitative real-time PCR demonstrated that the expression level of matrix metalloproteinase-9 (MMP-9) was significantly increased, whereas the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) was markedly suppressed in the CDX2-overexpressing trophoblast cells. The phosphoinositide-3-kinase (PI3K)/Akt signaling pathway is involved in proliferation, migration, metastasis and invasion. Our study showed that inhibition of PI3K/Akt signaling led to decreased expression of CDX2. Conclusion: We concluded that CDX2 is likely regulated by the PI3K/Akt signaling pathway during trophoblast cell invasion. Our findings may reveal new insights into the regulatory mechanisms of trophoblast cell invasion and may be an important contributor to the pathogenesis of pregnancy related diseases. Copyright (C) 2014 S. Karger AG, Basel