Doxycycline inhibits breast cancer EMT and metastasis through PAR-1/NF-κB/miR-17/E-cadherin pathway.

Weilong Zhong,Hongzhi Wang,Yanrong Liu,Huijuan Liu,Honggang Zhou,Yueyang Lei,Jingxia Han,Tingting Yin,Jing Meng,Cheng Yang,Qiang Zhang,Lingfei He,Shuang Chen,Yuan Qin,Tao Sun,Longcong Huai,Bo Sun,Heng Zhang

doi:10.18632/oncotarget.20418

Abstract

Doxycycline displays high efficiency for cancer therapy. However, the molecular mechanism is poorly understood. In our previous study, doxycycline was found to suppress tumor progression by directly targeting proteinase-activated receptor 1 (PAR1). In this study, microRNAs were found to be involved in PAR1-mediated anti-tumor effects of doxycycline. Among these miRNAs, miR-17 was found to promote breast cancer cell metastasis both in vivo and in vitro. Moreover, miR-17 could reverse partial doxycycline inhibition effects on breast cancer. Employing luciferase and chromatin immunoprecipitation assays, nuclear factor-kappaB (NF-κB) was found to bind miR-17 promoters. Furthermore, E-cadherin was identified as the target gene of miR-17. These results showed that miR-17 can resist the inhibitory effects of doxycycline on breast cancer epithelial–mesenchymal transformation (EMT) by targeting E-cadherin.

Highlights

Breast cancer is a prevalent malignancy and the leading cause of cancer death among women worldwide [1]
These results showed that miR-17 can resist the inhibitory effects of doxycycline on breast cancer epithelial–mesenchymal transformation (EMT) by targeting E-cadherin
Previous study implied that doxycycline could induce EMT by regulating TMPRSS2 in LNCaP cells

Summary

Introduction

Breast cancer is a prevalent malignancy and the leading cause of cancer death among women worldwide [1]. Various therapies are used for breast cancer treatments; these interventions include surgery, chemotherapy and targeted therapy [2,3,4,5,6]. Researches studied important roles of doxycycline in breast cancer metastasis and tumor growth [9,10,11]. Successful breast cancer treatment relies on better understanding of molecular mechanisms involved in cancer progression. Protease-activated receptor 1 (PAR1) is a G protein-coupled receptor involved in metastatic and invasive cancer processes [12,13,14,15,16]. Our previous studies indicated that in PAR1-dependent manner, doxycycline possesses higher inhibition ability in lung cancer and breast cancer [8, 11]

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Results

Conclusion