Overexpression of Oct4 suppresses the metastatic potential of breast cancer cells via Rnd1 downregulation

https://doi.org/10.1016/j.bbadis.2014.07.015Get rights and content
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Highlights

  • Ectopic expression of Oct4 suppresses migration and invasion capacity in breast cancer cell lines.

  • Forced Oct4 expression decreases the metastatic lung nodules in the mouse model of breast cancer.

  • The inhibitory effect of Oct4 on metastasis is partially mediated via the downregulation of Rnd1.

  • Ectopic expression of Oct4 induces E-cadherin and increases the capacity of cell adhesion.

  • Downregulation of Rnd1 mediates the effect of Oct4 on E-cadherin.

Abstract

Although Oct4 is known as a critical transcription factor involved in maintaining “stemness”, its role in tumor metastasis is still controversial. Herein, we overexpressed and silenced Oct4 expression in two breast cancer cell lines, MDA-MB-231 and 4T1, separately. Our data showed that ectopic overexpression of Oct4 suppressed cell migration and invasion in vitro and the formation of metastatic lung nodules in vivo. Conversely, Oct4 downregulation increased the metastatic potential of breast cancer cells both in vitro and in vivo. Furthermore, we identified Rnd1 as the downstream target of Oct4 by ribonucleic acid sequencing (RNA-seq) analysis, which was significantly downregulated upon Oct4 overexpression. Chromatin immunoprecipitation assays revealed the binding of Oct4 to the promoter region of Rnd1 by ectopic overexpression of Oct4. Dual luciferase assays indicated that Oct4 overexpression suppressed transcriptional activity of the Rnd1 promoter. Moreover, overexpression of Rnd1 partially rescued the inhibitory effects of Oct4 on the migration and invasion of breast cancer cells. Overexpression of Rnd1 counteracted the influence of Oct4 on the formation of cell adhesion and lamellipodia, which implied a potential underlying mechanism involving Rnd1. In addition, we also found that overexpression of Oct4 led to an elevation of E-cadherin expression, even in 4T1 cells that possess a relatively high basal level of E-cadherin. Rnd1 overexpression impaired the promoting effects of Oct4 on E-cadherin expression in MDA-MB-231 cells. These results suggest that Oct4 affects the metastatic potential of breast cancer cells through Rnd1-mediated effects that influence cell motility and E-cadherin expression.

Keywords

Oct4
Metastasis
Breast cancer
E-cadherin
Rnd1

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