Heparanase promotes angiogenesis through Cox-2 and HIF1alpha.
Heparanase has been given attention for its role in the invasion and metastasis of various cancers for years. We have also investigated and reported the role of heparanase in several human cancers, including gastric, esophageal and colon carcinomas. Other than the critical role of heparanase in tumor invasion and metastasis, it is also believed that heparanase is involved in angiogenesis, another feature of tumor progression which is complicatedly mediated by many molecules, including cyclooxygenese-2 (Cox-2). Thus, our recent study elucidated a possible relationship of heparanase with Cox-2 upon tumor angiogenesis. Based upon our study, three major transcription factor binding sites containing NF-kappaB, NF-IL-6 and CRE sites seemed to have a compensative and cooperative role in heparanase-induced Cox-2 upregulation. On the other hand, tumor hypoxia often occurs in most tumors and Cox-2-induced HIF1alpha overexpression has recently been shown in various cancers. Here we believe that heparanase may also be involved in tumor hypoxia through the induction of HIFalpha either directly or indirectly through the Cox-2 pathway. This hypothesis indicates a possible novel function of heparanase and its link to HIF1alpha and Cox-2, and therefore this function would give us a clue about potential new strategies for cancer therapy.
Naomoto
Yoshio
Y
Department of Gastroenterological Surgery, Transplant and Surgical Oncology, Graduate School of Medicine and Dentistry, Okayama University, 2-5-1 Shikatacho, Okayama 700-8558, Japan. ynaomoto@md.okayama-u.ac.jp
Gunduz
Mehmet
M
Takaoka
Munenori
M
Okawa
Takaomi
T
Gunduz
Esra
E
Nobuhisa
Tetsuji
T
Kobayashi
Masahiko
M
Shirakawa
Yasuhiro
Y
Yamatsuji
Tomoki
T
Sonoda
Ryutaro
R
Matsuoka
Junji
J
Tanaka
Noriaki
N
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008954:Models, Biological; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D015398:Signal Transduction
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051546:Cyclooxygenase 2