Abstract
BackgroundInactivaion of tumor suppressor genes (TSGs) by promoter CpG methylation frequently occurs in tumorigenesis, even in the early stages, contributing to the initiation and progression of human cancers. Deleted in lung and esophageal cancer 1 (DLEC1), located at the 3p22-21.3 TSG cluster, has been identified frequently silenced by promoter CpG methylation in multiple carcinomas, however, no study has been performed for lymphomas yet.MethodsWe examined the expression of DLEC1 by semi-quantitative reverse transcription (RT)-PCR, and evaluated the promoter methylation of DLEC1 by methylation-specific PCR (MSP) and bisulfite genomic sequencing (BGS) in common lymphoma cell lines and tumors.ResultsHere we report that DLEC1 is readily expressed in normal lymphoid tissues including lymph nodes and PBMCs, but reduced or silenced in 70% (16/23) of non-Hodgkin and Hodgkin lymphoma cell lines, including 2/6 diffuse large B-cell (DLBCL), 1/2 peripheral T cell lymphomas, 5/5 Burkitt, 6/7 Hodgkin and 2/3 nasal killer (NK)/T-cell lymphoma cell lines. Promoter CpG methylation was frequently detected in 80% (20/25) of lymphoma cell lines and correlated with DLEC1 downregulation/silencing. Pharmacologic demethylation reversed DLEC1 expression in lymphoma cell lines along with concomitant promoter demethylation. DLEC1 methylation was also frequently detected in 32 out of 58 (55%) different types of lymphoma tissues, but not in normal lymph nodes. Furthermore, DLEC1 was specifically methylated in the sera of 3/13 (23%) Hodgkin lymphoma patients.ConclusionsThus, methylation-mediated silencing of DLEC1 plays an important role in multiple lymphomagenesis, and may serve as a non-invasive tumor marker for lymphoma diagnosis.
Highlights
Epigenetic silencing of tumor suppressor genes (TSGs) by promoter CpG methylation and histone modification has been widely recognized as one of the major causes of tumorigenesis including hematological malignancies [1,2]
Deleted in lung and esophageal cancer 1 (DLEC1) was downregulated by promoter CpG methylation in lymphoma cell lines We first examined the expression of DLEC1 mRNA in 25 non-Hodgkin and Hodgkin lymphoma cell lines by reverse transcription (RT)-PCR
DLEC1 was highly expressed in the normal lymph node, peripheral blood mononuclear cells (PBMC) samples, as well as human adult testis and bone marrow tissues (Figure 1A), but silenced or reduced in 33% (2/6) diffuse large B-cell (DLBCL), 50% (1/2) peripheral T cell lymphoma (PTCL), 100% (5/5) Burkitt lymphoma (BL), 86% (6/7) Hodgkin lymphoma (HL), and 67% (2/3) NL cell lines (Figure 1B), indicating that DLEC1 is a candidate TSG for lymphomas
Summary
Epigenetic silencing of tumor suppressor genes (TSGs) by promoter CpG methylation and histone modification has been widely recognized as one of the major causes of tumorigenesis including hematological malignancies [1,2]. Frequent inactivation of several 3p21.3 genes as functional TSGs, such as RASSF1 and BLU [14,19], by promoter CpG methylation had been identified associated with tumor initiation and progression. Inactivaion of tumor suppressor genes (TSGs) by promoter CpG methylation frequently occurs in tumorigenesis, even in the early stages, contributing to the initiation and progression of human cancers. Deleted in lung and esophageal cancer 1 (DLEC1), located at the 3p22-21.3 TSG cluster, has been identified frequently silenced by promoter CpG methylation in multiple carcinomas, no study has been performed for lymphomas yet
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