Abstract

We have reported that hepatitis B X-interacting protein (HBXIP) promotes the proliferation and migration of breast cancer cells. However, the underlying mechanism is poorly understood. In this study, we report that HBXIP works in the event through up-regulating S100A4. We observed that HBXIP expression was positively correlated to that of S100A4 in 87 clinical breast cancer tissue samples. Then, we identified that HBXIP was able to up-regulate S100A4 expression in breast cancer cells. Notably, we observed the HBXIP nuclear localization, implying that HBXIP may be associated with the promoter of S100A4. Chromatin immunoprecipitation assay (ChIP) and electrophoretic mobility shift assay (EMSA) showed that HBXIP was able to bind to the nucleotides +200~+239 region of S100A4 promoter, containing two putative recognition motif of transcription factor STAT4 and GRβ. It suggests that HBXIP is able to activate S100A4 promoter via interacting with STAT4 in breast cancer cells, leading to the up-regulation of S100A4. In addition, we identified another pathway of S100A4 up-regulation mediated by HBXIP. We found that HBXIP activated the PTEN/PI3K/AKT signaling by inducing DNA methylation of PTEN, which subsequently boosted S100A4 expression. In function, we demonstrated that HBXIP enhanced the growth or migration of breast cancer cells through S100A4 in vivo and in vitro. Collectively, we conclude that HBXIP up-regulates S100A4 through activating S100A4 promoter involving STAT4 and inducing PTEN/PI3K/AKT signaling to promote growth and migration of breast cancer cells. Our finding provides new insight into the mechanism of HBXIP in promotion of the development of breast cancer.

Highlights

  • hepatitis B X-interacting protein (HBXIP) Up-regulates S100A4 in Breast Cancer Cells—Previously, we found that HBXIP expression was positively associated with the tumor carcinogenesis and metastasis

  • Our previous studies showed that HBXIP was highly expressed in breast cancer tissues and metastatic lymph node tissues and significantly associated with the growth and metastasis of breast cancer cells [4, 5]

  • We observed the HBXIP nuclear localization in breast cancer tissues and MCF-7 cells, implying that HBXIP may be involved in the transcriptional regulation of S100A4

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Summary

Background

Conclusion: HBXIP up-regulates S100A4 via two pathways to promote growth and migration of breast cancer cells. We have reported that hepatitis B X-interacting protein (HBXIP) promotes the proliferation and migration of breast cancer cells. It suggests that HBXIP is able to activate S100A4 promoter via interacting with STAT4 in breast cancer cells, leading to the up-regulation of S100A4. We conclude that HBXIP up-regulates S100A4 through activating S100A4 promoter involving STAT4 and inducing PTEN/PI3K/AKT signaling to promote growth. HBXIP Up-regulates S100A4 to Promote Cell Growth and Migration activation of PI3K/AKT signaling pathway which promotes the proliferation and growth of cancer cells [15]. Our data show that HBXIP promotes growth and migration of breast cancer cells through up-regulating S100A4 involving activating S100A4 promoter and inducing PTEN/PI3K/AKT signaling. Our finding provides new insight into the mechanism of HBXIP in promotion of the development of breast cancer

EXPERIMENTAL PROCEDURES
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