Low ABCB1 gene expression is an early event in colorectal carcinogenesis

PLoS One. 2013 Aug 19;8(8):e72119. doi: 10.1371/journal.pone.0072119. eCollection 2013.

Abstract

The ABCB1/MDR1 gene product ABCB1/P-glycoprotein is implicated in the development of colorectal cancer (CRC). NFKB1 encodes transcription factors regulating expression of a number of genes including ABCB1. We have previously found association between the ABCB1 C-rs3789243-T polymorphism and CRC risk and interactions between the ABCB1 C-rs3789243-T and C3435T polymorphisms and meat intake in relation to CRC risk (Andersen, BMC Cancer, 2009, 9, 407). ABCB1 and NFKB1 mRNA levels were assessed in intestinal tissue from 122 CRC cases, 101 adenoma cases (12 with severe dysplasia, 89 with mild-moderate dysplasia) and from 18 healthy individuals, together with gene polymorphisms in ABCB1 and NFKB1. ABCB1 mRNA levels were highest in the healthy individuals and significantly lower in mild/moderate and severe dysplasia tissue (P<0.05 for both), morphologically normal tissues close to the tumour (P<0.05), morphologically normal tissue at a distance from the tumour (P<0.05) and CRC tissue (P<0.001). Furthermore, ABCB1 mRNA levels were lower in adenomas and carcinomas compared to morphologically normal tissue from the same individuals (P<0.01). The ABCB1 C-rs3789243-T and NFKB1 -94ins/del homozygous variant genotypes were associated with low ABCB1 mRNA levels in morphologically normal sigmoid tissue from adenoma cases (P<0.05 for both). NFKB1 mRNA levels were lower in both tumour and normal tissue from cancer patients (P<0.001) as compared to healthy individuals but we were unable to show association between NFKB1 -94ins/del genotype and NFKB1 mRNA levels. This study suggests that low ABCB1 mRNA levels are an early event in CRC development and that the two polymorphisms affect ABCB1 mRNA levels whereas low NFKB1 mRNA levels occur later in carcinogenesis. Low ABCB1 protein levels may promote colorectal carcinogenesis through increasing intracellular exposure to carcinogenic ABCB1 substrates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Adenoma / metabolism*
  • Adenoma / pathology
  • Carcinogenesis / metabolism*
  • Carcinoma / metabolism*
  • Carcinoma / pathology
  • Case-Control Studies
  • Colon / metabolism
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Female
  • Gene Expression
  • Humans
  • INDEL Mutation
  • Male
  • Middle Aged
  • NF-kappa B p50 Subunit / genetics
  • NF-kappa B p50 Subunit / metabolism
  • Polymorphism, Single Nucleotide
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • NF-kappa B p50 Subunit
  • NFKB1 protein, human
  • RNA, Messenger

Grants and funding

“Familien Erichsens Mindefond”, Viborg Regional Hospital (http://www.hospitalsenhedmidt.dk/regionshospitaletviborg), Hospital of Southern Jutland (http://www.sygehussonderjylland.dk/wm233821) and the Norwegian Colorectal Cancer Prevention (NORCCAP) study (Grants from the Norwegian Cancer Society (http://www.uicc.org/membership/norwegian-cancer-society) and the Department of Health and Social Affairs) have supported the study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.