Arrestin Domain Containing 3 Reverses Epithelial to Mesenchymal Transition and Chemo-Resistance of TNBC Cells by Up-Regulating Expression of miR-200b.

Jun Chung,Jingfang Ju,Young Hwa Soung,Cecilia Yan,Heesung Chung

doi:10.3390/cells8070692

Jun Chung, Jingfang Ju

Open Access

https://doi.org/10.3390/cells8070692

Copy DOI

Journal: Cells	Publication Date: Jul 10, 2019
Citations: 18	License type: CC BY 4.0

Affiliation: Stony Brook Medicine, Ewha Womans University

Abstract

Our previous studies demonstrated the importance of arrestin domain containing 3 (ARRDC3), a metastasis suppressor, in inhibiting invasive and metastatic potential of triple negative breast cancer (TNBC) in vitro and in vivo. However, little is known about ARRDC3 mediated transcriptional control and its target genes that are implicated in its metastatic suppressing activity. In this study, we used miRNA array and subsequent functional analyses to identify miRNAs whose expression are significantly regulated by ARRDC3 in TNBC cells. We identified miR-200b as a major target gene of ARRDC3. miR-200b played an essential role in mediating ARRDC3 dependent reversal of EMT phenotypes and chemo-resistance to DNA damaging agents in TNBC cells. Expression of miR-200b also increased the expression of ARRDC3 as well in TNBC cells, suggesting a positive feedback loop between these two molecules. In addition, we combined the therapeutic powers of miR-200b and 5-fluorourancil (5-FU) into a single compound (5-FU-miR-200b) to maximize the synergistic effects of these compounds. Chemically modified miR-200b (5-FU-miR-200b mimic) was more effective in inhibiting metastatic potentials of TNBC cells than unmodified miR-200b and does not require transfection reagents, implying its therapeutic potential in TNBC. Our studies showed the importance of therapeutic targeting ARRDC3/miR-200b pathway in TNBC.

Highlights

Breast cancer is the most common type of cancer in women globally [1]
As epigenetic changes including miRNA expression has been implicated in aggressive nature of cancers [12,13,14], we explored the relationship between arrestin domain containing 3 (ARRDC3) and specific miRNAs important in controlling invasive and chemo-resistant potentials of triple negative breast cancer (TNBC). miRNA array based screening and subsequent functional analysis of target miRNAs whose expression are regulated by ARRDC3 expression in TNBC cells led to the finding that miR-200b-3p is an important target gene of ARRDC3 in mediating its metastatic suppressing and chemo-sensitizing functions
Our previous studies demonstrated that a metastasis suppressor, ARRDC3 is epigenetically silenced in TNBC cells [8], and that restoring ARRDC3 expression represents an important anti-cancer mechanism of selective inhibitors of nuclear exporters (SINEs) that effectively inhibits TNBC functions in vitro and in vivo [9]

Summary

Introduction

Significant advances in the treatment and detection of breast cancer have been made in recent years, the survival rate of patients with metastatic breast cancer has been dropping [1,2]. The treatment of TNBC patients is limited to cytotoxic drugs such as 5-fluorourancil (5-FU), paclitaxel, doxorubicin, but chemoresistance is the major reason for failure of chemotherapy and mortality in TNBC [5,6,7]. The molecular mechanism(s) involved in chemoresistance and strategies to resensitize chemoresistant cancer cells to chemotherapy remain to be determined in TNBC. We previously demonstrated that expression of arrestin domain containing 3 (ARRDC3), a potential metastatic suppressor, is suppressed in metastatic TNBC cells due to epigenetic silencing [8]. Our subsequent study showed that either a forced expression of ARRDC3 or treatment of small molecule

Methods

Results

Discussion

Conclusion