Hypermethylation‐mediated reduction of LMX1A expression in gastric cancer

Abstract

LMX1A is epigenetically inactivated in cervical cancer. However, the expression and methylation status of LMX1A in gastric cancer tissues remains unknown. In the present study, we found that the expression of LMX1A was significantly decreased in gastric cancer tissues compared with normal tissues. A statistically significant inverse association was found between the LMX1A methylation status and expression of LMX1A in tumor tissues (P = 0.008). Restoration of LMX1A induced cell apoptosis and suppressed anchorage-independent growth, suggesting LMX1A may be a potential biomarker for gastric cancer. (Cancer Sci 2011; 102: 361-366) T he LIM homeobox transcription factor 1, alpha (LMX1A) gene maps to 1q24.1 and is one of the group of LIM homeobox-containing genes that encode LIM-homeodomain (LIM-HD).(1,2) It is proven that LMX1A is a critical regulator of cell-fate decisions using genetic fate mapping in wild-type and LMX1A () ⁄ )) mice.(3) LMX1A also plays a pivotal role in the mDA differentiation of human embryonic stem (hES) cells. In the developing cerebellum, loss of LMX1A completely abolishes roof plate induction in the spinal cord.(4) Recently, evidence for the role of LMX1A in cancers has been found. For example, LMX1A was identified as a metastasis suppressor in cervical cancer.(5) It is well known that hypermethylation of CpG islands in their promoter regions is an important mechanism for loss of function of several tumor suppressor genes. (6,7) Like most tumor suppressors, LMX1A is methylated more frequently in squamous cell carcinoma tissues than in the normal cervix.(8) It was also reported that the methylation of LMX1A genes correlated with recurrence and overall survival of ovarian cancer patients.(8) Methylation of LMX1A was observed in a colon cancer cell line (HCT-116), and was demethylated in the DKO cell line genetically disrupted in DNMT1 and DNMT3B. (9) To characterize the role of LMX1A in gastric cancer, we examined a series of primary gastric cancers and control tissues for LMX1A expression and promoter methylation. Our results confirm frequent downregulation of LMX1A expression in primary gastric cancers and identify hypermethylation of the LMX1A gene as a common epigenetic aberration in these tumors. Materials and MethodsPatient samples and cell lines. Tumor samples were collected from surgical specimens from 50 patients with gastric cancer at the Department of Pathology, Minhang District Central Hospital, Shanghai, China. Non-tumor samples from the macroscopic tumor margin were isolated at the same time and used as the matched adjacent non-neoplastic tissues (>5 cm). Tissue samples were collected, immediately snap frozen in liquid nitrogen and stored at )80°C until RNA extraction. Informed consent was obtained for all samples and the institutional review board of Minhang District Central Hospital approved the study. All patients obtained a confirmed diagnosis of gastric carcinoma after resection. The five different established human gastric cancer cell lines used in the present study (AGS...

The Correlations of LMX1A and Osteopontin Expression to the Clinicopathologic Stages in Pancreatic Adenocarcinoma

“…8,21 Hypermethylation of LMX1A silences gene expression and induces carcinogenesis. 4 However, overexpression of LMX1A does not affect cell proliferation, but inhibits tumor invasion in cervical cancer. 8 On the contrary, Dong et al 4 demonstrated that silencing LMX1A expression indeed alters gastric cancer cell growth and apoptosis.…”

“…4 Suppression of LMX1A may impair roof plate development in the spinal cord. 5 Hypermethylation can silence LMX1A gene expression.…”

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Methylcap-Seq Reveals Novel DNA Methylation Markers for the Diagnosis and Recurrence Prediction of Bladder Cancer in a Chinese Population

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Quantitative DNA methylation analysis of paired box gene 1 and LIM homeobox transcription factor 1 α genes in cervical cancer

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