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Rapid xenograft tumor progression in beta-arrestin1 transgenic mice due to enhanced tumor angiogenesis

Lin Zou^*,, Rongxi Yang^*,, Jingjing Chai^* and Gang Pei^*,1

^* Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences and

Graduate School, Chinese Academy of Sciences, Shanghai, China; and

Clinical Molecular Medicine Center, Children Hospital, Chongqing University of Medical Sciences, Chongqing, China

¹Correspondence: No. 320 Yueyang Rd., Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. E-mail: gpei{at}sibs.ac.cn

β-arrestins (β-Arrs) are known to be associated with tumor signaling pathways such as transforming growth factor-β1 (TGF-β1), P53/Murine double minute (MDM2) and NF-B. To investigate the role of β-Arr in tumor progression in vivo, we generated β-Arr transgenic mice by subcutaneously inoculating tumor cells in them. We found that the xenograft tumor initiated earlier and grew more rapidly in β-Arr1 transgenic mice than in both the β-Arr2 transgenic and wild-type mice after inoculating murine liver cancer Hepa1–6 cells or lymphoma EL4 cells. Moreover, matrix metalloproteinase 9 (MMP9) activity, vascular endothelial growth factor (VEGF) concentration in plasma and new small blood vessel formation in tumor tissues were enhanced in β-Arr1 transgenic mice compared with those in control mice. In addition, injection of MMP9 inhibitors in β-Arr1 transgenic mice abrogated all these effects and suppressed rapid tumor progression. Similar results were observed in human microvascular endothelial cells, where overexpressed β-Arr1 did increase MMP9 activity and small blood vessel formation. Furthermore, phosphatidylinositol 3-kinase (PI3K) inhibitors could suppress β-Arr1-enhanced MMP9 activity and the C-terminal 181–418 amino acids (aa) of β-Arr1 was largely responsible for this effect. Our data reveal a functional role for β-arrestin1 in tumor progression in vivo, in which overexpression of β-Arr1 promotes MMP9 activity and tumor angiogenesis by providing a suitable microenvironment for tumor progression.—Zou, L., Yang, R., Chai, J., Gang Pei. Rapid xenograft tumor progression in beta-arrestin1 transgenic mice due to enhanced tumor angiogenesis.

Key Words: matrix metalloproteinase 9 • MMP9 • vascular endothelial growth factor • VEGF • phosphatidylinositol 3-kinase • PI3K