title: Endoplasmic reticulum stress, unfolded protein response and development of colon adenocarcinoma.
abstract: When misfolded proteins accumulate in the endoplasmic reticulum (ER), the cell is said to experience ER stress. This triggers an unfolded protein response (UPR) to restore the balance between misfolded proteins and ER chaperones such as BiP. UPR signalling is required for the growth of many solid cancers. In chronic ER stress, factors including CHOP have been shown to mediate cell death. Colorectal adenocarcinoma arises due to progressive changes within pre-malignant lesions. Our aim was to test the hypothesis that the expression of BiP and CHOP correlates with the progression of those pre-malignant lesions.Eighty-one patients with colon neoplasms treated at Rouen University Hospital between January 1, 2003 and January 1, 2013 were randomly selected. The expression of BiP and CHOP was estimated by immunohistochemical staining of a tissue microarray generated from colon cores: normal tissue, low-grade and high-grade adenoma, invasive colon adenocarcinoma and lymph node metastasis of colon adenocarcinoma. In parallel, nine cases comprising areas from normal epithelium to dyplasia to invasive carcinoma and included in the TMA were analysed on whole sections.As colon epithelium shows increasing evidence of pre-malignant and then malignant changes, BiP expression significantly increases (p for trend < 0.001), whereas CHOP expression is attenuated (p for trend < 0.001).We identified a positive relationship between BiP expression and colon carcinogenesis, and a negative correlation for CHOP expression. These findings are consistent with a model in which ER stress accompanies oncogenesis and in which loss of proteins that mediate the toxicity of ER stress, such as CHOP, may facilitate tumorigenesis. This raises the exciting possibility that restoration of the negative feedback loop of UPR, if achievable, might antagonise the malignant process.
authors.affiliation: Department of Pathology, Rouen University Hospital, Rouen, France. nicolas.piton@chu-rouen.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Piton
authors.affiliation: MRC Biostatistics Unit, Institute of Public Health, Robinson Way, Cambridge, UK.
authors.forename: James
authors.initials: J
authors.lastname: Wason
authors.affiliation: Department of Pathology, Rouen University Hospital, Rouen, France.
authors.forename: Élodie
authors.initials: É
authors.lastname: Colasse
authors.affiliation: Department of Pathology, Henri Becquerel Cancer Care Centre, Rouen, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Cornic
authors.affiliation: Department of Pathology, Rouen University Hospital, Rouen, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Lemoine
authors.affiliation: Department of Pathology, Rouen University Hospital, Rouen, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Le Pessot
authors.affiliation: Department of Pathology, Rouen University Hospital, Rouen, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Marguet
authors.affiliation: Department of Pathology, Rouen University Hospital, Rouen, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Sabourin
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D014157:Transcription Factors / Q000235:genetics; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors
keywords: Colon adenocarcinoma; Colon premalignancy; Endoplasmic reticulum stress; Tissue microarray; Unfolded protein response