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Barx2

Official Full Name
BARX homeobox 2
Background
This gene encodes a member of the homeobox transcription factor family. A highly related protein in mouse has been shown to influence cellular processes that control cell adhesion and remodeling of the actin cytoskeleton in myoblast fusion and chondrogenesis. The encoded protein may also play a role in cancer progression.
Synonyms
BARX2; BARX homeobox 2; BarH like homeobox 2; homeobox protein BarH-like 2; BarX 2; BARX homeobox; BARX2_HUMAN; Homeobox protein BarH like 2; MGC133368; MGC133369; OTTHUMP00000230949; OTTHUMP00000244646; BarH-like homeobox 2; BARX2B; homeodomain transcription factor BARX2B

BARX2 is a member of the Bar class homeobox gene family, which also includes BarHI and BarH2 from Drosophila. The BARX2 gene is located on human chromosome 11q25; it has four exons ranging in size from 85 to 1099 bp, and is associated with the congenital disease Jacobson syndrome. BARX2 has 87% amino acid identity with BARX1 and they are all expressed in multiple epithelial tissues. Regarding the function of BARX2, it has been shown to play a key role in regulating cellular processes involved in cell adhesion and cytoskeletal remodeling in myoblast fusion, and is a key process for carcinogenesis and metastasis.

BARX2 and OSCC

Oral squamous cell carcinoma (OSCC) is one of the most common cancers in the world. Abnormalities in miRNA regulation are known to play an important role in the pathogenesis of OSCC. Further studies have found that miR-187 increases the carcinogenicity of OSCC cells, especially migration. The BARX2 gene has been identified as a target for miR-187. BARX2 expression inhibited migration, invasion, anchorage-independent colony formation and orthotopic tumorigenesis of OSCC cells. MiR-187-induced migration phenotype and neck metastasis were rescued by BARX2 expression. BARX2 expression was down-regulated in most OSCCs, and this down-regulation was particularly pronounced in tumors with advanced lymph node metastasis. In addition, plasma miR-187 was significantly higher in OSCC patients than in normal subjects. In conclusion, miR-187-BARX2 plays an important role in driving the progression of OSCC carcinogenesis.

BARX2 and CRC

Colorectal cancer (CRC) is a malignant tumor originating from the colorectal mucosal epithelium and is one of the most common malignant tumors in the clinic. It is reported that low expression of BARX2 was significantly associated with tumor node metastasis (TNM) staging, AJCC staging, differentiation and relapse in patients with CRC. Patients with lower BARX2 expression levels had reduced disease-free survival and overall survival. Furthermore, a trend toward shorter overall survival in the group of patients with BARX2-negative tumors independent of advanced AJCC stage and poor differentiation was determined by Kaplan-Meier survival analysis. Based on univariate and multivariate analysis, BARX2 expression was an independent prognostic factor for determining CRC prognosis. In conclusion, low BARX2 expression was associated with progression of CRC and could serve as a potential independent prognostic biomarker for CRC patients.

BARX2 and NSCLC

Epithelial-mesenchymal transition (EMT) has important functions in cancer. Recently, microRNAs have been reported to be involved in EMT by modulating target genes. Some studies have shown that miR-942 was relatively highly expressed in human non-small-cell lung cancer (NSCLC) tissues and cells. In vitro experiments have demonstrated that overexpression of miR-942 promoted cell migration, invasion and angiogenesis. Related experiments indicated that miR-942 contributed to NSCLC metastasis in vivo, and that BARX2 was predicted to be a downstream target of miR-942. Overexpression of BARX2 reverses the functional changes caused by miR-942. In addition, miR-942 increased EMT-related proteins N-cadherin and vimentin by inhibiting BARX2, while E-cadherin expression was reduced. In conclusion, miR-942 induces EMT-related metastasis by directly targeting BARX2, which may provide a potential therapeutic strategy for NSCLC.

BARX2 and GC

Recently, some studies have found that the expression level of BARX2 in human gastric cancer (GC) tissues was lower than that in adjacent normal mucosa. In 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 group of patients with BARX2-negative tumors. Using in vitro and in vivo assays, Mi et al. has demonstrated that under normal conditions, BARX2 inhibited GC cell proliferation and invasion by inhibiting the Wnt/β-catenin signaling pathway. These findings suggest that the reduction or loss of BARX2 inhibits proliferation and invasion of GC cells, and that the reduction of BARX2 could serve as an independent prognostic biomarker for poor prognosis in patients with GC.

BARX2 and HCC

Hepatocellular carcinoma (HCC) is a malignant tumor with an increasing incidence, making it the most common cancer in the world. Some studies have shown that BARX2 expression was lower in HCC tissues compared to matching adjacent non-cancerous tissues. The low expression level of BARX2 was significantly associated with tumor size, tumor differentiation, clinical stage, metastasis and recurrence. In addition, patients with low expression of BARX2 survived poorly. Importantly, multivariate Cox regression analysis showed that low BARX2 expression was an independent marker for lower overall survival. Furthermore, a significant negative correlation was observed between the expression of BARX2 and the EMT marker. These results provide evidence that low expression levels of BARX2 in HCC are significantly associated with tumor metastasis, and that BARX2 may be an independent prognostic biomarker for HCC patients.

In conclusion, BARX2 plays an important role in controlling the expression of cell adhesion molecules and has been reported to be associated with an increasing number of tumor types. Therefore, further study of the function of BARX2 and its important role in the mechanism of tumorigenesis is of great significance and value for the diagnosis and treatment of cancer.

References:

  1. Zhang Y, et al. Low expression of BARX2 in human primary hepatocellular carcinoma correlates with metastasis and predicts poor prognosis. Hepatology Research, 2015, 45: 228–237
  2. Lin SC, et al. Up-regulation of miR-187 modulates the advances of oral carcinoma by targeting BARX2 tumor suppressor. Oncotarget, 2016, 7(38): 61355-61365
  3. Mi YS, et al. Down-regulation of Barx2 predicts poor survival in colorectal cancer. Biochemical and Biophysical Research Communications, 2016, 478(1): 67-73
  4. Yang FM, et al. miR-942 promotes tumor migration, invasion, and angiogenesis by regulating EMT via BARX2 in non-small-cell lung cancer. Journal of cellular physiology, 2019
  5. Mi YS, et al. Down-regulation of homeobox gene Barx2 increases gastric cancer proliferation and metastasis and predicts poor patient outcomes. Oncotarget, 2016, 7(37): 60593-60608

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