Fatty acid binding protein 4 enhances prostate cancer progression by upregulating matrix metalloproteinases and stromal cell cytokine production
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Mingguo Huang1,3, Shintaro Narita1,3, Takamitsu Inoue1,3, Atsushi Koizumi1,3, Mitsuru Saito1, Hiroshi Tsuruta1, Kazuyuki Numakura1, Shigeru Satoh1, Hiroshi Nanjo4, Takehiko Sasaki2,3 and Tomonori Habuchi1,3
1Department of Urology, Akita University Graduate School of Medicine, Akita 010-8543, Japan
2Research Center for Biosignal, Akita University Graduate School of Medicine, Akita 010-8543, Japan
3AMED-CREST, Japan Agency for Medical Research and Development (AMED), Tokyo 102-0004, Japan
4Department of Clinical Pathology, Akita University Graduate School of Medicine, Akita 010-8543, Japan
Tomonori Habuchi, email: email@example.com
Keywords: fatty acid binding protein 4; cancer microenvironment; high-fat diet; prostate stromal cell; prostate cancer
Received: July 02, 2017 Accepted: November 20, 2017 Published: December 04, 2017
Fatty acid binding protein 4 (FABP4) is an abundant protein in adipocytes, and its production is influenced by high-fat diet (HFD) or obesity. The prostate stromal microenvironment induces proinflammatory cytokine production, which is key for the development and progression of prostate cancer (PCa). Here, we show that high FABP4 expression and its secretion by PCa cells directly stimulated PCa cell invasiveness by upregulating matrix metalloproteinases through phosphatidylinositol 3-kinase and mitogen-activated protein kinase signaling pathways. In addition, prostate stromal cells augmented PCa cell invasiveness by secreting interleukin-8 and -6 in response to FABP4. This was abrogated by the FABP4 specific inhibitor, BMS309403. Furthermore, a mouse xenograft experiment showed HFD enhanced PCa metastasis and invasiveness by the upregulation of FABP4 and interleukin-8. Clinically, the serum level of FABP4 was significantly associated with an aggressive type of PCa rather than obesity. Taken together, FABP4 may enhance PCa progression and invasiveness by upregulating matrix metalloproteinases and cytokine production in the PCa stromal microenvironment, especially under HFD or obesity.
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