Ginsenoside Rd attenuates breast cancer metastasis implicating derepressing microRNA-18a-regulated Smad2 expression.

Peiwei Wang,Yu Chen,Xiaoye Du,Wenjian Wang,Minqi Xiong,Teng Zhang,Qinbo Yang,Jingang Cui

doi:10.1038/srep33709

Peiwei Wang, Yu Chen + Show 6 more

Open Access

https://doi.org/10.1038/srep33709

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Abstract

Metastasis remains a major cause of mortality and poor prognosis in breast cancer patients. Anti-metastatic therapies are in great need to achieve optimal clinical outcome in breast cancer patients. Panax Notoginseng Saponins (PNS) has previously been shown to inhibit breast cancer metastasis in mouse. Here the potential anti-metastatic effect of one of the chemical compounds of PNS, ginsenoside Rd (Rd), was further evaluated in mouse mammary carcinoma 4T1 cells. The results revealed that Rd treatment dose-dependently suppressed cell migration and invasion in cultured 4T1 cells. In 4T1 cell-inoculated mice, Rd treatment led to decreased number of tumor lesions in lungs in both spontaneous and experimental metastasis models. Rd treatment resulted in increased expression of Smad2 in cultured 4T1 cells and in tumors grown from inoculated 4T1 cells. Rd treatment decreased the expression of microRNA (miR)-18a in cultured 4T1 cells and in tumors derived from inoculated 4T1 cells. Smad2 was further verified to be a direct target of miR-18a in 4T1 cells. The significant impact of Rd on counteracting miR-18a-medidated downregulation of Smad2 expression was also demonstrated. Together, the current work shows for the first time that Rd treatment attenuates breast cancer metastasis in part through derepressing miR-18a-mediated Smad2 expression regulation.

Highlights

Panax Notoginseng has been extensively used in China as a therapeutic agent to treat a wide range of diseases including cancer[20]
We have demonstrated that Panax Notoginseng Saponins (PNS) treatment suppresses the tumor growth and decreases miR-18a expression in tumors derived from Lewis lung carcinoma cells[22]
The current study demonstrates that Rd treatment inhibits 4T1 cell migration and invasion in vitro and breast cancer lung metastasis in 4T1 cell-inoculated mice

Summary

Introduction

Panax Notoginseng has been extensively used in China as a therapeutic agent to treat a wide range of diseases including cancer[20]. We have demonstrated that PNS treatment suppresses the tumor growth and decreases miR-18a expression in tumors derived from Lewis lung carcinoma cells[22]. Which chemical component of PNS is pharmacologically active in suppressing breast cancer metastasis and the possible implication of miR-18a-mediated Smad[2] expression regulation in this process remains to be investigated. Rd treatment decreased miR-18a expression and increased the level of Smad[2] in cultured 4T1 cells and in 4T1-derived tumors. Rd treatment increased the luciferase reporter activity of Smad2 3′-UTR containing miR-18a seed region, supporting the implication of miR-18a-mediated Smad[2] regulation in the anti-metastatic effect of Rd in 4T1 mammary carcinoma cells

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Conclusion