HOXB13 expression and promoter methylation as a candidate biomarker in gastric cancer

Abstract

Homeobox b13 (HOXB13) is considered to be a tumor suppressor gene in multiple types of human cancer. The present study aimed to identify the difference in expression of HOXB13 mRNA between gastric cancer (GC) tissues and corresponding non-malignant gastric tissues. The clinical significance of HOXB13 mRNA expression was also assessed in GC and a potential association between HOXB13 mRNA expression and DNA promoter methylation was observed. The expression of HOXB13 mRNA was assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and HOXB13 methylation status was assessed by methylation-specific PCR (MSP) in 5 GC cell lines and 85 paired GC and normal gastric tissues. Kaplan-Meier survival curves were used to assess the survival of patients with GC. HOXB13 mRNA expression was significantly lower in primary GC tissues than in corresponding nonmalignant gastric tissues, and decreased HOXB13 expression was associated with poorer differentiation, lymph node metastasis, invasion depth and Tumor-Node-Metastasis (TNM) stage. Kaplan-Meier survival analysis demonstrated that HOXB13 mRNA expression was a significant prognostic indicator of GC patient survival. Furthermore, MSP revealed that the proportion of GC samples with hypermethylated HOXB13 (60.0%, 51/85) was increased compared with the corresponding nonmalignant gastric tissues (11.8%, 10/85). Decreased HOXB13 mRNA expression was due to DNA hypermethylation as following treatment with the DNA methyltransferase inhibitor 5-Aza-dC, HOXB13 expression in the GC MKN-45 cell line was upregulated. The results of the present study indicate that decreased expression of HOXB13 mRNA was associated with tumor differentiation, depth of invasion, lymph node metastases and TNM stage in GC, and it was a significant poor prognostic factor for patients with GC. Aberrant DNA promoter methylation was a crucial reason for the downregulation of HOXB13 mRNA expression.

Paralogous HOX13 Genes in Human Cancers

“…The role of HOXB13 tumor suppressor has been also demonstrated in gastric cancer [114] in which HOXB13 mRNA is significantly lower in primary tumors and its de-regulation is associated with a poorer differentiation, lymph node metastases, invasion and TNM stage. HOX B13 expression is increased by the treatment of GC cells with DNA methyltransferase inhibitor 5-aza-dC[115]. In HCC patients, aberrant expression of HOXB13 is strongly associated with clinic-pathological features, such as vascular invasion, tumor grade, TNM stage and a poorer survival.…”

Tumor-suppressive function and mechanism of HOXB13 in right-sided colon cancer

“…14 Low HOXB13 expression is a poor prognostic factor in patients with gastric cancer. 15 Compared with its expression in normal colon tissue, HOXB13 expression in colorectal cancer (CRC) is downregulated, a common event in cancer progression. 16,17 A study based on tumor gene expression data showed that several homeobox genes are related to tumor location.…”

Quantitative Analysis of Differential Expression of HOX Genes in Multiple Cancers

“…The genes marked in * bold in Table 2 and in Table S3 are those that met these 2 criteria. These genes were already suggested for consideration as prognostic biomarkers in previous studies (selected references are listed in Table S12 [ 34 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ]).…”