title: Hypoxia-mediated CD24 expression is correlated with gastric cancer aggressiveness by promoting cell migration and invasion.
abstract: CD24 is a heavily glycosylated cell surface protein that is expressed in putative stem cells and is overexpressed in various human malignancies, yet the significant roles of CD24 in gastric cancer development are still elusive. We investigated the involvement of CD24 in gastric cancer aggressiveness, which is attributed to its heterogeneity. Cultured gastric cancer cells showed diverse expression patterns in CD24, whereas other defined cell surface markers, such as CD44 and CD133, were homogenous. Purely sorted CD24-negative gastric cancer cells showed strong alteration into the CD24-positive cell type in an autochthonous manner, and reached to steady expression levels. Our clinicopathological study revealed that CD24 positivity was an independent prognostic factor in both intestinal and diffuse types of gastric cancer. CD24 expression was correlated with the advanced stages, invasiveness, and lymph node metastasis of gastric cancer. Silencing of CD24 in cultured cells significantly decreased cell migration and invasion. Hypoxic treatment upregulated CD24 expression, and simultaneously induced cell motility and invasion of gastric cancer cells. Hypoxic treatment-induced CD24 expression was significantly attenuated by knockdown of hypoxia-inducible transcription factors. These data suggest that CD24-negative cells are capable of gaining cell motility and invasiveness through the induction of CD24, which is mediated by hypoxia. CD24 would be an attractive marker to define not only the heterogeneity but also the aggressiveness of gastric cancer cells. The mechanisms by which hypoxia induces CD24 expression would also be a potential therapeutic target for gastric cancer.
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Hiroshima University, Hiroshima, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Fujikuni
authors.forename: Hideki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Tanabe
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Naito
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
authors.forename: Yuka
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Yanagihara
authors.forename: Naohide
authors.initials: N
authors.lastname: Oue
authors.forename: Wataru
authors.initials: W
authors.lastname: Yasui
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohdan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D051927:CD24 Antigen / Q000235:genetics* / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D016017:Odds Ratio; D011379:Prognosis; D013274:Stomach Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology* / Q000601:surgery
chemical_list: D000954:Antigens, Surface; D051927:CD24 Antigen; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: CD24; gastric cancer; hypoxia; hypoxia inducible factor; invasion