title: ABCC11/MRP8 Expression in the Gastrointestinal Tract and a Novel Role for Pepsinogen Secretion.
abstract: ATP-binding cassette (ABC) transporters are involved in chemotherapy resistance. Multidrug-resistance protein 8 (ABCC11/MRP8) is also involved in 5-fluorouracil (5-FU) metabolism. 5-FU and its derivatives are widely used in the treatment of gastrointestinal tract cancers, but little is known about the contribution of ABCC11/MRP8 to gastrointestinal tract and related cancers. Here, we report our investigation of ABCC11/MRP8 expression in normal and cancerous gastrointestinal tract tissues and reveal its novel role in the gastric mucosa. In tissue microarray and surgically resected cancer specimens, immunohistochemical (IHC) staining revealed significantly reduced expression of ABCC11/MRP8 in gastrointestinal tract cancers compared with other cancers. In contrast, strong ABCC11/MRP8 expression was observed in normal gastric mucosa. Additional immuno-fluorescence assays revealed co-localization of ABCC11/MRP8 and pepsinogen I in normal gastric chief cells. Quantitative PCR and Western blot analysis also revealed significant expression of ABCC11/MRP8 in fundic mucosa where the chief cells are mainly located. Furthermore, the ABCC11 mRNA-suppressed NCI-N87 gastric cancer cell line failed to secret pepsinogen I extracellularly. Thus, low expression of ABCC11/MRP8 is consistent with chemotherapeutic regimens using 5-FU and its derivatives in gastrointestinal tract cancers. Our results indicated a novel function of ABCC11/MRP8 in the regulation of pepsinogen I secretion in the normal gastric chief cells.
authors.affiliation: Division of Surgical Oncology, Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Matsumoto
authors.affiliation: Division of Surgical Oncology, Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences.
authors.forename: Tomoshi
authors.initials: T
authors.lastname: Tsuchiya
authors.affiliation: Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences , 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
authors.forename: Koh-Ichiro
authors.initials: K
authors.lastname: Yoshiura
authors.affiliation: Department of Pathology, Nagasaki University Hospital , Nagasaki, Japan.
authors.forename: Tomayoshi
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Division of Surgical Oncology, Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences.
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Hidaka
authors.affiliation: Division of Surgical Oncology, Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nanashima
authors.affiliation: Division of Surgical Oncology, Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagayasu
keywords: ABC transporter; ABCC11/MRP8; gastric chief cells; gastrointestinal tract; pepsinogen I