LPA1/3 signaling mediates tumor lymphangiogenesis through promoting CRT expression in prostate cancer |
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Authors: | Yueh-Chien Lin Chien-Chin Chen Wei-Min Chen Kuan-Ying Lu Tang-Long Shen Yeong-Chin Jou Cheng-Huang Shen Norihiko Ohbayashi Yasunori Kanaho Yuan-Li Huang Hsinyu Lee |
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Affiliation: | 1. Department of Life Sciences, National Taiwan University, Taipei 10617, Taiwan;2. Department of Physiological Chemistry, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan;3. Department of Pathology, Chia-Yi Christian Hospital, Chiayi 600, Taiwan;4. Department of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan;5. Department of Plant Pathology and Microbiology, National Taiwan University, Taipei 10617, Taiwan;6. Department of Urology, Chia-Yi Christian Hospital, Chiayi 600, Taiwan;7. Department of Biotechnology, Asia University, Taichung 41354, Taiwan;8. Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan;9. Department of Electrical Engineering, National Taiwan University, Taipei 10617, Taiwan;10. Institute of Biomedical Electronic and Bioinformatics, National Taiwan University, Taipei 10617, Taiwan;11. Center for Biotechnology, National Taiwan University, Taipei 10617, Taiwan |
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Abstract: | Lysophosphatidic acid (LPA) is a bioactive lipid growth factor which is present in high levels in serum and platelets. LPA binds to its specific G-protein-coupled receptors, including LPA1 to LPA6, thereby regulating various physiological functions, including cancer growth, angiogenesis, and lymphangiogenesis. Our previous study showed that LPA promotes the expression of the lymphangiogenic factor vascular endothelial growth factor (VEGF)-C in prostate cancer (PCa) cells. Interestingly, LPA has been shown to regulate the expression of calreticulin (CRT), a multifunctional chaperone protein, but the roles of CRT in PCa progression remain unclear. Here we investigated the involvement of CRT in LPA-mediated VEGF-C expression and lymphangiogenesis in PCa. Knockdown of CRT significantly reduced LPA-induced VEGF-C expression in PC-3 cells. Moreover, LPA promoted CRT expression through LPA receptors LPA1 and LPA3, reactive oxygen species (ROS) production, and phosphorylation of eukaryotic translation initiation factor 2α (eIF2α). Tumor-xenografted mouse experiments further showed that CRT knockdown suppressed tumor growth and lymphangiogenesis. Notably, clinical evidence indicated that the LPA-producing enzyme autotaxin (ATX) is related to CRT and that CRT level is highly associated with lymphatic vessel density and VEGF-C expression. Interestingly, the pharmacological antagonist of LPA receptors significantly reduced the lymphatic vessel density in tumor and lymph node metastasis in tumor-bearing nude mice. Together, our results demonstrated that CRT is critical in PCa progression through the mediation of LPA-induced VEGF-C expression, implying that targeting the LPA signaling axis is a potential therapeutic strategy for PCa. |
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Keywords: | LPA VEGF-C Prostate cancer CRT eIF2α Lymphangiogenesis |
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