Fructose-bisphosphate aldolase A is a key regulator of hypoxic adaptation in colorectal cancer cells and involved in treatment resistance and poor prognosis

Kawai,Kenji; Uemura,Mamoru; Munakata,Koji; Takahashi,Hidekazu; Haraguchi,Naotsugu; Nishimura,Junichi; Hata,Taishi; Matsuda,Chu; Ikenaga,Masakazu; Murata,Kohei; Mizushima,Tsunekazu; Yamamoto,Hirofumi; Doki,Yuichiro; Mori,Masaki

doi:10.3892/ijo.2016.3814

Fructose-bisphosphate aldolase A is a key regulator of hypoxic adaptation in colorectal cancer cells and involved in treatment resistance and poor prognosis

Authors:
- Kenji Kawai
- Mamoru Uemura
- Koji Munakata
- Hidekazu Takahashi
- Naotsugu Haraguchi
- Junichi Nishimura
- Taishi Hata
- Chu Matsuda
- Masakazu Ikenaga
- Kohei Murata
- Tsunekazu Mizushima
- Hirofumi Yamamoto
- Yuichiro Doki
- Masaki Mori
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Affiliations: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan, Department of Surgery, Higashi-osaka City General Hospital, Higashiosaka, Osaka 578-8588, Japan, Department of Surgery, Suita Municipal Hospital, Suita, Osaka 564‑0082, Japan
Published online on: December 20, 2016 https://doi.org/10.3892/ijo.2016.3814
Pages: 525-534

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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.

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