Infiltrated pre-adipocytes increase prostate cancer metastasis via modulation of the miR-301a/androgen receptor (AR)/TGF-β1/Smad/MMP9 signals
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Hongjun Xie1,2,*, Lei Li1,2,*, Guodong Zhu1,2, Qiang Dang1,2, Zhenkun Ma1, Dalin He1, Luke Chang1, Wenbing Song1,2, Hong-Chiang Chang2, John J. Krolewski3, Kent L. Nastiuk3, Shuyuan Yeh2, Chawnshang Chang2,4
1Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
2George Whipple Lab for Cancer Research, Departments of Pathology and Urology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, USA
3Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA
4Sex Hormone Research Center, China Medical University/Hospital, Taichung, Taiwan
*These authors have contributed equally to this work
Lei Li, e-mail: firstname.lastname@example.org
Chawnshang Chang, e-mail: email@example.com
Keywords: prostate cancer, pre-adipocyte, mirna-301a, androgen receptor
Received: February 15, 2015 Accepted: March 15, 2015 Published: April 8, 2015
High fat dietary intake may increase the risk of prostate cancer (PCa). Pre-adipocytes, one of the basic components in the tumor microenvironment (TME), are capable of differentiating into adipose tissues and play key roles to affect PCa progression. Here we found the pre-adipocytes could be recruited more easily to PCa than its surrounding normal prostate tissue. In vitro co-culture system also confirmed PCa has a better capacity than normal prostate to recruit pre-adipocytes. The consequences of recruiting more pre-adipocytes may then increase PCa cell invasion. Mechanism dissection revealed infiltrating pre-adipocytes might function through down-regulation of the androgen receptor (AR) via modulation of miR-301a, and then increase PCa cell invasion via induction of TGF-β1/Smad/MMP9 signals. The mouse model with orthotopically xenografted PCa CWR22Rv1 cells with pre-adipocytes also confirmed that infiltrating pre-adipocytes could increase PCa cell invasion via suppressing AR signaling. Together, our results reveal a new mechanism showing pre-adipocytes in the prostate TME can be recruited to PCa to increase PCa metastasis via modulation of the miR-301a/AR/TGF-β1/Smad/MMP9 signals. Targeting this newly identified signaling may help us to better inhibit PCa metastasis.
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