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.
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Nicolas Piton was funded for this work by the Société Française de Pathologie.
The authors would like to thank Doctor Doris M. Rassl (Papworth Hospital NHS Foundation Trust, Papworth Everard, Cambridge, UK) and Doctor Stefan J. Marciniak (University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK) for allowing the use of the cell clots made during the MPhil research project of Nicolas Piton whom they supervised. Cell clots and western blot analyses were made under the supervision of Doctor Lucy E. Dalton, Mrs Emily F.A. van’t Wout and Mrs Julia Knight.
The authors are indebted to Nikki Sabourin-Gibbs (Rouen University Hospital) for assistance with language editing.
Compliance with ethical standards
This research was approved by the local ethics committee of Rouen University Hospital.
This work was funded by the Société Française de Pathologie.
Conflict of interest
The authors declare that they have no competing interests.
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