Downregulation of homeobox gene Barx2 increases gastric cancer proliferation and metastasis and predicts poor patient outcomes

Abstract

Barx2 is a Bar family homeodomain transcription factor shown to play a critical role in cell adhesion and cytoskeleton remodeling, key processes in carcinogenesis and metastasis. Using quantitative real-time PCR, Western blotting, and immunohistochemistry, we found that Barx2 is expressed at lower levels in human gastric cancer (GC) tissues than in adjacent normal mucosa. In a multivariate analysis, Barx2 expression emerged as an independent prognostic factor for disease-free and overall survival. Kaplan-Meier survival analysis showed a trend toward even shorter overall survival in the patient group with Barx2-negative tumors, independent of advanced UICC stage and tumor relapse. Using in vitro and in vivo assays, we demonstrated that under normal conditions Barx2 inhibited GC cell proliferation and invasiveness through inhibition of the Wnt/β-catenin signaling pathway. These findings indicate that reduction or loss of Barx2 dis-inhibits GC cell proliferation and invasion, and that reduction in Barx2 could serve as an independent prognostic biomarker for poor outcome in GC patients.

Downregulation of BarH‐like homeobox 2 promotes cell proliferation, migration and aerobic glycolysis through Wnt/β‐catenin signaling, and predicts a poor prognosis in non‐small cell lung carcinoma

“…A previous study revealed that Barx2 inhibited gastric cancer cell proliferation and invasiveness through inhibition of the Wnt/β‐catenin signaling pathway . In the present study, Barx2 overexpressing cells (A549‐pBarx2) reduced nuclear β‐catenin, c‐MYC, and HIF‐1α expression (Fig a).…”

“…β‐Catenin, as a central downstream effector of Wnt signaling, plays a critical role in the regulation of tumor growth and development . Because Barx2 has been reported to be involved in Wnt signaling, we explored the effect of Barx2 on the Wnt/β‐catenin signaling pathway in NSCLC carcinogenesis . Our results reveal that Barx2 inhibits Wnt/β‐catenin signaling in NSCLC cells.…”

“…Mi et al revealed that low Barx2 expression was associated with colorectal cancer progression and could serve as a potential independent prognostic biomarker for patients with colorectal cancer . In gastric cancer, Barx2 is expressed at lower levels than adjacent normal mucosa …”

“…BarH‐like homeobox 2 (Barx2), a homeodomain factor of the Bar family, regulates the expression of cell adhesion molecules and influences cellular differentiation in various developmental contexts . Recently, downregulation of Barx2 associated with a number of solid tumors, such as gastric cancer, ovarian cancer, and primary hepatocellular carcinoma, has correlated with poor prognosis. However, little is known about Barx2 in NSCLC.…”

High-throughput allelic expression imbalance analyses identify candidate breast cancer risk genes

“…BARX2 encodes a homeobox transcription factor that can function as a tumor suppressor and its down regulation is a predictor of poor prognosis in different cancer types [20][21][22] . BARX2 can bind the estrogen receptor (the target of tamoxifen) and influence estrogen-dependent growth and cellular invasion 23 .…”