HYAL1 hyaluronidase: a molecular determinant of bladder tumor growth and invasion.
Hyaluronic acid and HYAL1-type hyaluronidase show high accuracy in detecting bladder cancer and evaluating its grade, respectively. Hyaluronic acid promotes tumor progression; however, the functions of hyaluronidase in cancer are largely unknown. In this study, we stably transfected HT1376 bladder cancer cells with HYAL1-sense (HYAL1-S), HYAL1-antisense (HYAL1-AS), or vector cDNA constructs. Whereas HYAL1-S transfectants produced 3-fold more HYAL1 than vector transfectants, HYAL1-AS transfectants showed approximately 90% reduction in HYAL1 production. HYAL1-AS transfectants grew four times slower than vector and HYAL1-S transfectants and were blocked in the G2-M phase of the cell cycle. The expression of cdc25c and cyclin B1 and cdc2/p34-associated H1 histone kinase activity also decreased in HYAL1-AS transfectants. HYAL1-S transfectants were 30% to 44% more invasive, and HYAL1-AS transfectants were approximately 50% less invasive than the vector transfectants in vitro. In xenografts, there was a 4- to 5-fold delay in the generation of palpable HYAL1-AS tumors, and the weight of HYAL1-AS tumors was 9- to 17-fold less than vector and HYAL1-S tumors, respectively (P < 0.001). Whereas HYAL1-S and vector tumors infiltrated skeletal muscle and blood vessels, HYAL1-AS tumors resembled benign neoplasia. HYAL1-S and vector tumors expressed significantly higher amounts of HYAL1 (in tumor cells) and hyaluronic acid (in tumor-associated stroma) than HYAL1-AS tumors. Microvessel density in HYAL1-S tumors was 3.8- and 9.5-fold higher than that in vector and HYAL1-AS tumors, respectively. These results show that HYAL1 expression in bladder cancer cells regulates tumor growth and progression and therefore serves as a marker for high-grade bladder cancer.
Lokeshwar
Vinata B
VB
Department of Urology, University of Miami Miller School of Medicine, Miami, FL 33101, USA. vlokeshw@med.miami.edu
Cerwinka
Wolfgang H
WH
Lokeshwar
Bal L
BL
D017209:Apoptosis / Q000502:physiology; D002295:Carcinoma, Transitional Cell / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology*; D002453:Cell Cycle / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D006821:Hyaluronoglucosaminidase / Q000096:biosynthesis* / Q000235:genetics; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000473:pathology; D014162:Transfection; D014183:Transplantation, Heterologous; D001749:Urinary Bladder Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology*
D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase