Strongly positive ANGPTL4 expression in gastric cancer tissues was associated with a more favorable disease-specific survival (HR 0.142) and significantly less tumor invasion.
Observational (n=170)
No
In gastric cancer, hypoxia-induced ANGPTL4 expression is independent of HIF-1α and serves as a favorable prognostic marker, contrasting with the poor prognosis associated with HIF-1α.
Hazard Ratio: 0.142 (95% CI 0.019–1.034)
p-value: p=0.054
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.
Kubo et al. (Tue,) conducted a observational in Advanced gastric cancer (n=170). Strongly positive ANGPTL4 expression vs. Weakly positive or negative ANGPTL4 expression was evaluated on Disease-specific survival (HR 0.142, 95% CI 0.019-1.034, p=0.054). Strongly positive ANGPTL4 expression in gastric cancer tissues was associated with a more favorable disease-specific survival (HR 0.142) and significantly less tumor invasion.