title: High ABCC2 and low ABCG2 gene expression are early events in the colorectal adenoma-carcinoma sequence.
abstract: Development of colorectal cancer (CRC) may result from a dysfunctional interplay between diet, gut microbes and the immune system. The ABC transport proteins ABCB1 (P-glycoprotein, Multidrug resistance protein 1, MDR1), ABCC2 (MRP2) and ABCG2 (BCRP) are involved in transport of various compounds across the epithelial barrier. Low mRNA level of ABCB1 has previously been identified as an early event in colorectal carcinogenesis (Andersen et al., PLoS One. 2013 Aug 19;8(8):e72119). ABCC2 and ABCG2 mRNA levels were assessed in intestinal tissue from 122 CRC cases, 106 adenoma cases (12 with severe dysplasia, 94 with mild-moderate dysplasia) and from 18 controls with normal endoscopy. We found significantly higher level of ABCC2 in adenomas with mild to moderate dysplasia and carcinoma tissue compared to the levels in unaffected tissue from the same individual (P = 0.037, P = 0.037, and P<0.0001) and in carcinoma and distant unaffected tissue from CRC cases compared to the level in the healthy individuals (P = 0.0046 and P = 0.036). Furthermore, ABCG2 mRNA levels were significantly lower in adenomas and carcinomas compared to the level in unaffected tissue from the same individuals and compared to tissue from healthy individuals (P<0.0001 for all). The level of ABCB2 in adjacent normal tissue was significantly higher than in tissue from healthy individuals (P = 0.011). In conclusion, this study found that ABCC2 and ABCG2 expression levels were altered already in mild/moderate dysplasia in carcinogenesis suggesting that these ABC transporters are involved in the early steps of carcinogenesis as previously reported for ABCB1. These results suggest that dysfunctional transport across the epithelial barrier may contribute to colorectal carcinogenesis.
authors: Organ Center, Hospital of Southern Jutland, Aabenraa, Denmark; Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark; Medical Department, Regional Hospital Viborg, Viborg, Denmark.
authors: Vibeke
authors: V
authors: Andersen
authors: Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors: Lotte K
authors: LK
authors: Vogel
authors: National Food Institute, Technical University of Denmark, Søborg, Denmark.
authors: Tine Iskov
authors: TI
authors: Kopp
authors: Telemark University College, Faculty of Arts and Sciences, Department of Environmental and Health Studies, Telemark, Norway.
authors: Mona
authors: M
authors: Sæbø
authors: Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors: Annika W
authors: AW
authors: Nonboe
authors: Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors: Julian
authors: J
authors: Hamfjord
authors: Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors: Elin H
authors: EH
authors: Kure
authors: National Research Centre for the Working Environment, Copenhagen, Denmark.
authors: Ulla
authors: U
authors: Vogel
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human