Aquaporin-1 Deletion in Mice Inhibits Hepa1-6 Hepatocellular Carcinoma Growth

Aquaporin (AQP) has been reported to express in microvessels of many different type of tumor, indicating the possible involvement of AQP in tumor angiogenesis. Tumor angiogenesis is a mandatory step of tumor growth involving endothelial cell proliferation and migration from blood vessels in peritumoral tissues and formation of tubules. A murine Hepal-6 hepatocellular carcinoma-bearing model in AQP1 knockout mice was used to evaluate the role of AQP1 in Hepal-6 hepatocellular carcinoma angiogenesis and tumor growth. The results demonstrated remarkably retarded growth of subcutaneously inoculated Hepal-6 cells in AQPl-knockout (AQP1^-l-) mice compared to that in wild-type (AQP1^+/+) mice. Morphology of Hepal-6 hepatocellular carcinoma sections revealed tumor cells formed islands with microvessels in the center. Immunohistochemistry of tumor blood vessels demonstrated high-density and thin microvessels located in the center of tumor islands in AQP1^+/+ mice, whereas sparse and enlarged vessels were evident in tumor islands in AQP1^-l- mice coincident with larger necrotic area in outer layer of the islands. Blood vessel AQP1 immune staining of Hepal-6 hepatocellular carcinoma sections indicated that strong AQP1 protein labelling in vascular endothelium cells of hepatocellular carcinoma in AQP1^+/+ mice and negative labelling of AQP1 in the counterpart structures in AQP1^-l- mice. These results provided direct evidence that AQP1 deletion results in defective Hepal-6 hepatocellular carcinoma angiogenesis and retarded tumor growth that may be involved in insufficient blood supply and abnormal transendothelial fluid transport.