ANGPTL4 overexpression is associated with progression and poor prognoses of olfactory neuroblastoma

OBJECTIVE: To analyze expression levels of angiopoietin‑like 4 (ANGPTL4) in olfactory neuroblastoma (ONB) to investigate the association between ANGPTL4 and ONB. METHODS: Immunohistochemistry was performed on 109 formalin‑fixed, paraffin‑embedded ONB tissue samples to detected the expression of ANGPTL4. Immunofluorescence co-localization was performed to detected the expression sites of ANGPTL4. Western blotting was used to measure the protein levels of ANGPTL4, Hypoxia-inducible factor (HIF-1α), and CD31 in tumor and Para tumoral tissues. The non‑parametric Kruskal-Wallis test was used to evaluate differential expression of ANGPTL4 and clinicopathological parameters of ONB. Cox regression analysis was used to evaluate the association between ANGPTL4 expression levels and ONB prognosis. RESULTS: Immunohistochemistry revealed that ANGPTL4 expression (moderately positive + strongly positive) was higher in high grade (Ⅲ+Ⅳ) ONB (98.2%; 55/56) compared with low grade (Ⅰ+Ⅱ) ONB (56.6%; 30/53). Immunofluorescence co-localization revealed that ANGPTL4 both focus on microvessel and macrophage, in addition, ANGPTL4 is co-located with HIF-1a. Western blotting showed that ANGPTL4, HIF-1α and CD31 expression was significantly increased in the tumor area compared with the paratumor area. The clinical significance of ANGPTL4 expression was analyzed in 109 ONB tissues, and high expression levels of ANGPTL4 were positively associated with the pathological grade (P < 0.001) and local recurrence (P < 0.001). Kaplan-Meier analysis revealed that patients with high ANGPTL4 expression had shorter disease‑free survival (DFS; P = 0.021, mean survival time: 93 ± 10.042 vs. 153 ± 13.835), but no difference in overall survival (P = 0.121). Multivariate Cox regression analysis revealed that ANGPTL4 was an independent prognostic factor for DFS (P = 0.028). CONCLUSIONS: These results demonstrated that ANGPTL4 might associated with a poor prognosis of ONB. ANGPTL4 expression were focus on CD34, macrophage and HIF-1α, suggesting that ANGPTL4 might associated with hypoxia and might play important role in angiogenesis and inflammatory. ANGPTL4 is a novel therapeutic target for ONB.