High HOXD4 protein expression in gastric adenocarcinoma tissues indicates unfavorable clinical outcomes.

Background/Aim: Homeobox D4 (HOXD4) belongs to the homeobox (HOX) family, which plays a crucial role in the early embryo development and cell differentiation. The role of HOXD4 in human gastric adenocarcinoma has not been elucidated. In the present study, we aimed to examine the expression levels of HOXD4 and dissect whether the HOXD4 expression is associated with aggressive clinicopathological outcomes of patients with gastric adenocarcinoma.

Patients and Methods: Clinicopathological analyses were performed in 127 patients with gastric adenocarcinoma. Expression of HOXD4 was tested by immunohistochemistry staining and quantitative RT-PCR. Clinical outcomes were evaluated by the Kaplan-Meier method and log-rank test. The prognostic role of HOXD4 in gastric adenocarcinoma patients was assessed by univariate and multivariate analyses. The effects and mechanisms of HOXD4 on cell proliferation, migration and invasion were explored through cellular experiments.

Results: HOXD4 expression was elevated in gastric adenocarcinoma tissues compared to non-tumorous gastric tissues (P = 0.018). High expression of HOXD4 was significantly associated with larger tumor size (P = 0.008), advanced tumor invasion depth (P = 0.014), and positive lymph node metastasis (P < 0.001). Moreover, patients with high HOXD4 expression had poorer overall survival (P = 0.001), and HOXD4 was identified as an independent prognosis factor according to multivariate analysis [hazard ratio (HR) =2.253, 95% confident interval (CI) 1.028-4.979, P = 0.044]. Cellular results revealed that HOXD4 can promote tumor cell proliferation by upregulating c-Myc and cyclin D1.

Conclusions: Our study demonstrated that overexpression of HOXD4 was significantly correlated with poorer prognosis of gastric adenocarcinoma patients, indicating the potential of HOXD4 as a novel clinical predictive biomarker and drug target.