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

摘要

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 Hepa1-6 hepatocellular carcinoma-bearing model in AQP1 knockout mice was used to evaluate the role of AQP1 in Hepa1-6 hepatocellular carcinoma angiogenesis and tumor growth. The results demonstrated remarkably retarded growth of subcutaneously inoculated Hepa1-6 cells in AQP1-knockout (AQP1-/-) mice compared to that in wild-type (AQP1+/+) mice. Morphology of Hepa1-6 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-/- mice coincident with larger necrotic area in outer layer of the islands. Blood vessel AQP1 immune staining of Hepa1-6 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-/- mice. These results provided direct evidence that AQP1 deletion results in defective Hepa1-6 hepatocellular carcinoma angiogenesis and retarded tumor growth that may be involved in insufficient blood supply and abnormal transendothelial fluid transport.