title: Regulation and clinical significance of the hypoxia-induced expression of ANGPTL4 in gastric cancer.
abstract: Solid tumors are often exposed to hypoxia. Hypoxia inducible factor (HIF)-1α upregulates numerous target genes associated with the malignant behavior of hypoxic cancer cells. A member of the angiopoietin family, angiopoietin-like protein 4 (ANGPTL4) is a hypoxia-inducible gene. The present study aimed to clarify whether ANGPTL4 is regulated by HIF-1α in gastric cancer cells. The study also assessed whether ANGPTL4 expression is associated with clinicopathological factors or HIF-1α expression in gastric cancer tissues. Hypoxia-induced ANGPTL4 expression was quantitatively analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in 10 gastric cancer cell lines. RT-qPCR was further employed to investigate the HIF-1α dependency of ANGPTL4 expression using HIF-1α-knockdown transfectant 58As9-KD and control 58As9-SC gastric cancer cells. The HIF-1α and ANGPTL4 expression levels were immunohistochemically analyzed in 170 gastric cancer tissue specimens and were assessed for any correlations with the clinicopathological factors and/or patient survival. Subsequently, hypoxia-induced ANGPTL4 expression was observed in 7 out of 10 gastric cancer cell lines. The hypoxic induction of ANGPTL4 was almost preserved in the 58As9-KD cells compared with that observed in the 58As9-SC cells, while the induction of known HIF-1α target gene, carbonic anhydrase 9, was completely suppressed in the 58As9-KD cells. In the gastric cancer tissues, ANGPTL4 expression was inversely correlated with the tumor depth, whereas HIF-1α expression was positively correlated with venous invasion. A survival analysis revealed that the expression of ANGPTL4 was significantly correlated with a longer survival time, whereas that of HIF-1α was correlated with a shorter survival time. In conclusion, the present findings indicate that hypoxia-induced ANGPTL4 expression is independent of HIF-1α in hypoxic gastric cancer cells. ANGPTL4 may be a favorable marker for predicting a long survival time, whereas HIF-1α predicts a poor prognosis, in gastric cancer patients. The hypoxic environment independently induces ANGPTL4 and HIF-1α, which are believed to exhibit adverse effects on tumor progression.
authors.affiliation: Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kubo
authors.affiliation: Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan; Department of Surgery, National Hospital Organization Higashisaga Hospital, Saga 849-0101, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kitajima
authors.affiliation: Department of Pathology and Biodefense, Saga University Faculty of Medicine, Saga 849-8501, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Kai
authors.affiliation: Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Nakamura
authors.affiliation: Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan.
authors.forename: Shuusuke
authors.initials: S
authors.lastname: Miyake
authors.affiliation: Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Yanagihara
authors.affiliation: Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan.
authors.forename: Kiyoto
authors.initials: K
authors.lastname: Morito
authors.affiliation: Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Shida
authors.affiliation: Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Noshiro
keywords: ANGPTL4; HIF-1; gastric cancer; hypoxia