title: Fructose-bisphosphate aldolase A is a key regulator of hypoxic adaptation in colorectal cancer cells and involved in treatment resistance and poor prognosis.
abstract: Hypoxia is an essential feature of cancer malignancy, but there are no methods for the routine detection of hypoxia-inducible prognostic factors and potential therapeutic targets. We reported previously that the hypoxic tumor cells of metastatic liver tissue from patients with colorectal cancer (CRC) could be used as an 'in vivo' hypoxia culture model. Several potential hypoxia-inducible genes were identified using this model. Among them, one glycolytic enzyme was of special interest. There is currently increasing attention on glycolytic enzymes as potential therapeutic targets due to their association with cancer-specific metabolism. To better understand the molecular mechanisms of cancer malignancy, we investigated the expression of fructose-bisphosphate aldolase A (ALDOA) and its relationship with cancer metabolism. We found that ALDOA was induced by hypoxia in CRC-derived cell lines, and univariate and multivariate analyses of microarray data from the resected CRC samples of 222 patients revealed that ALDOA was an independent prognostic factor for CRC. We also analyzed the malignant potential of ALDOA in vitro using overexpression and knockdown assays. We found that ALDOA was negatively related to chemosensitivity and radiosensitivity and positively associated with proliferation, sphere formation and invasion in both normoxia and hypoxia. These associations were due to the roles of ALDOA in regulating glycolysis, the epithelial-mesenchymal transition and the cell cycle. These findings demonstrate that ALDOA is a hypoxia-inducible prognostic factor that is closely related to CRC malignancy, and also provide new insights into the importance of ALDOA and glycolysis in cancer and suggest new targets for anticancer therapies.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kawai
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Uemura
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Munakata
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan.
authors.forename: Naotsugu
authors.initials: N
authors.lastname: Haraguchi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Nishimura
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan.
authors.forename: Taishi
authors.initials: T
authors.lastname: Hata
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan.
authors.forename: Chu
authors.initials: C
authors.lastname: Matsuda
authors.affiliation: Department of Surgery, Higashi-osaka City General Hospital, Higashiosaka, Osaka 578-8588, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ikenaga
authors.affiliation: Department of Surgery, Suita Municipal Hospital, Suita, Osaka 564‑0082, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Murata
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan.
authors.forename: Tsunekazu
authors.initials: T
authors.lastname: Mizushima
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
mesh_terms: D000368:Aged; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005634:Fructose-Bisphosphate Aldolase / Q000235:genetics* / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D011379:Prognosis; D015854:Up-Regulation
chemical_list: C000618051:ALDOA protein, human; D005634:Fructose-Bisphosphate Aldolase