Abstract
The loss of tumour suppressor gene function is a hallmark of malignant transformation and can occur by a variety of genetic and/or epigenetic alterations. We have previously characterised p38δ mitogen-activated protein kinase (MAPK) as a tumour suppressor in oesophageal squamous cell carcinoma (OESCC) and outlined how loss of p38δ MAPK expression promotes increased proliferation and migration, as well as reduced chemosensitivity. Our aim was to investigate the underlying molecular causes of loss of p38δ MAPK expression in OESCC. Sequence analysis of DNA from p38δ MAPK positive and p38δ MAPK negative OESCC cell lines was used to investigate potential loss of function causing mutations. Epigenetic control of p38δ expression in OESCC was examined using methylation-specific PCR and sequencing of bisulfite-converted DNA. We did not identify any mutations in the MAPK13 sequence in OESCC cell lines which lack p38δ MAPK expression. However, we identified a differential pattern of methylation between p38δ MAPK positive and p38δ MAPK negative cell lines. We outline here for the first time differential MAPK13 promoter methylation in OESCC. Our results suggest that epigenetic alterations are responsible, in part, for the suppression of p38δ MAPK expression and promotion of tumourigenesis in OESCC.
Highlights
We have previously documented the differential expression of p38δ mitogen activated protein kinase (MAPK) in oesophageal squamous cell carcinoma (OESCC) and the consequences of p38δ MAPK expression on OESCC tumourigenicity and response to cytotoxic drugs
We have previously reported that differential p38δ MAPK expression is only observed in OESCC and not adenocarcinoma cell lines [1]
These include somatic mutations, including insertions, deletions or point mutations, and/or epigenetic changes such as DNA methylation or histone deacetylation. p38δ MAPK displays tumour suppressor functions in OESCC—its loss promotes proliferation, migration, anchorage-independent growth, and resistance to conventional chemotherapy [1,2]. p38δ MAPK expression is absent at the protein level in OESCC cell lines KE-3, KE-8, KYSE-70, OE-21, and OC-1
Summary
We have previously documented the differential expression of p38δ mitogen activated protein kinase (MAPK) in oesophageal squamous cell carcinoma (OESCC) and the consequences of p38δ MAPK expression on OESCC tumourigenicity and response to cytotoxic drugs. Re-introduction of p38δ and p-p38δ MAPK expression resulted in a decrease in OESCC cell proliferation, migration and anchorage-independent growth [1]. These results demonstrated significant tumour suppressive functions for p38δ MAPK in OESCC. Loss or inactivation of tumour suppressor genes occurs via genetic changes, such as point mutations and deletions or by epigenetic regulation [3]. This new study sheds light on some mechanism(s) by which the loss of p38δ MAPK expression may occur in OESCC
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