Regulation and clinical significance of the hypoxia-induced expression of ANGPTL4 in gastric cancer

Kubo,Hiroshi; Kitajima,Yoshihiko; Kai,Keita; Nakamura,Jun; Miyake,Shuusuke; Yanagihara,Kazuyoshi; Morito,Kiyoto; Tanaka,Tomokazu; Shida,Masaaki; Noshiro,Hirokazu

doi:10.3892/ol.2015.4011

Regulation and clinical significance of the hypoxia-induced expression of ANGPTL4 in gastric cancer

Authors:
- Hiroshi Kubo
- Yoshihiko Kitajima
- Keita Kai
- Jun Nakamura
- Shuusuke Miyake
- Kazuyoshi Yanagihara
- Kiyoto Morito
- Tomokazu Tanaka
- Masaaki Shida
- Hirokazu Noshiro
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Affiliations: Department of Surgery, Saga University Faculty of Medicine, Saga 849‑8501, Japan, Department of Pathology and Biodefense, Saga University Faculty of Medicine, Saga 849‑8501, Japan, Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277‑8577, Japan
Published online on: December 8, 2015 https://doi.org/10.3892/ol.2015.4011
Pages: 1026-1034

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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.

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