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

• Published in: Oncology letters 2016-02, Vol.11 (2), p.1026-1034
• Main Authors: KUBO, HIROSHI, KITAJIMA, YOSHIHIKO, KAI, KEITA, NAKAMURA, JUN, MIYAKE, SHUUSUKE, YANAGIHARA, KAZUYOSHI, MORITO, KIYOTO, TANAKA, TOMOKAZU, SHIDA, MASAAKI, NOSHIRO, HIROKAZU
• Format: Article
• Language: English
• Subjects: Angiogenesis; ANGPTL4; Clinical significance; Development and progression; Gastric cancer; Gender; Genetic aspects; Genetic transcription; Health aspects; HIF-1; Histology; Hypoxia; Lymphatic system; Medical prognosis; Metabolism; Metastasis; Mortality; Multivariate analysis; Oncology; Patients; Prostate; Proteins; Rodents; Stomach cancer; Studies; Surgery; Transcription factors; Tumors
• ISSN: 1792-1074; 1792-1082
• DOI: 10.3892/ol.2015.4011

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.