Expression of MUC5AC, an early marker of pancreatobiliary cancer, is regulated by DNA methylation in the distal promoter region in cancer cells
Corresponding Author
Norishige Yamada
- [email protected]
- +81-99-2755270 | Fax: +81-99-2657235
Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
Laboratory for Cell Lineage Modulation, RIKEN Center for Developmental Biology, Kobe, Japan
Search for more papers by this authorYukari Nishida
Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
Search for more papers by this authorSeiya Yokoyama
Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
Search for more papers by this authorHideaki Tsutsumida
Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
Search for more papers by this authorIzumi Houjou
Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
Search for more papers by this authorSho Kitamoto
Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
Search for more papers by this authorMasamichi Goto
Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
National Sanatorium Hoshizuka-Keiaien, Kanoya, Kagoshima, Japan
Search for more papers by this authorMichiyo Higashi
Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
Search for more papers by this authorSuguru Yonezawa
Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
Search for more papers by this authorCorresponding Author
Norishige Yamada
- [email protected]
- +81-99-2755270 | Fax: +81-99-2657235
Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
Laboratory for Cell Lineage Modulation, RIKEN Center for Developmental Biology, Kobe, Japan
Search for more papers by this authorYukari Nishida
Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
Search for more papers by this authorSeiya Yokoyama
Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
Search for more papers by this authorHideaki Tsutsumida
Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
Search for more papers by this authorIzumi Houjou
Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
Search for more papers by this authorSho Kitamoto
Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
Search for more papers by this authorMasamichi Goto
Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
National Sanatorium Hoshizuka-Keiaien, Kanoya, Kagoshima, Japan
Search for more papers by this authorMichiyo Higashi
Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
Search for more papers by this authorSuguru Yonezawa
Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
Search for more papers by this authorAbstract
Background and purpose
High de novo expression of MUC5AC (a gastric-type secreted mucin) is observed in many types of pancreatobiliary neoplasms, including precursor lesions. In this study, we show that the DNA methylation pattern is intimately correlated with MUC5AC expression in ten cancer cell lines (breast, lung, pancreas, and colon).
Methods
The CpG methylation status of theMUC5AC promoter from −3855 to +321 was mapped using MassARRAY analysis, which utilizes base-specific cleavage of nucleic acids. ChIP assays and micro-RNA (miRNA) microarray expression profiling were also carried out in both MUC5AC-positive cells and in those with no or low MUC5AC expression.
Results
In the distal region from −3718 to −3670 of the promoter, MUC5AC-negative cancer cells (e.g., MDA-MB-453) were highly methylated, whereas MUC5AC-positive cells (e.g., MCF-7) had low methylation levels. The modification status of histone H3 lysine 9 (H3-K9) was also closely related toMUC5AC expression. Expression levels of miRNAs in the cancer cells were not correlated with MUC5AC expression.
Conclusion
Our results indicate thatMUC5AC is regulated by CpG methylation and histone H3-K9 modification of theMUC5AC promoter distal region, but not by miRNAs. An understanding of the epigenetic regulation ofMUC5AC may be of importance for the diagnosis of carcinogenic risk in the pancreatobiliary system.
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