Adele Aronica1, Laura Avagliano1, Anna Caretti1, Delfina Tosi1, Gaetano Pietro Bulfamante2, Marco Trinchera3. 1. Department of Health Sciences, San Paolo Hospital Medical School, University of Milan, 20142 Milano, Italy. 2. Department of Health Sciences, San Paolo Hospital Medical School, University of Milan, 20142 Milano, Italy; Unit of Human Pathology, Cytogenetics and Molecular Biology, ASST Santi Paolo e Carlo, 20142 Milano, Italy. 3. Department of Medicine Clinical and Experimental (DMCS), University of Insubria Medical School, 21100 Varese, Italy. Electronic address: marco.trinchera@uninsubria.it.
Abstract
BACKGROUND: CA19.9 antigen has been assumed as an abundant product of cancer cells, due to the reactivity found by immunohistochemical staining of cancer tissues with anti-CA19.9 antibody. METHODS: Expression and biosynthesis of type 1 chain Lewis antigens in the colon and the pancreas were studied by immunodetection in tissue sections and lysates, quantification of glycosyltransferase transcripts, bisulfite sequencing, and chromatin immunoprecipitation assays. RESULTS: CA19.9 was poorly detectable in normal colon mucosa and almost undetectable in colon cancer, while it was easily detected in the pancreatic ducts, together with Lewis b antigen, under both normal and cancer conditions. B3GALT5 transcripts were down-regulated in colon cancer, while they remained expressed in pancreatic cancer. Even ST3GAL3 transcript appeared well expressed in the pancreas but poorly in the colon, irrespective of normal or cancer conditions. CpG islands flanking B3GALT5 native promoter presented an extremely low degree of methylation in pancreatic cancer with respect to colon cancer. In a DNA region about 1kb away from the B3GALT5 retroviral promoter, a stretch of CG dinucleotides presented a methylation pattern potentially associated with transcription. Such a DNA region and the transcription factor binding site provided overlapping results by chromatin immunoprecipitation assays, corroborating the hypothesis. CONCLUSIONS: CA19.9 appears as a physiological product whose synthesis strongly depends on the tissue specific and epigenetically-regulated expression of B3GALT5 and ST3GAL3. GENERAL SIGNIFICANCE: CA19.9 and other Lewis antigens acquire tumor marker properties in the pancreas due to mechanisms giving rise to reabsorption into vessels and elevation in circulating levels. Copyright Â
BACKGROUND: CA19.9 antigen has been assumed as an abundant product of cancer cells, due to the reactivity found by immunohistochemical staining of cancer tissues with anti-CA19.9 antibody. METHODS: Expression and biosynthesis of type 1 chain Lewis antigens in the colon and the pancreas were studied by immunodetection in tissue sections and lysates, quantification of glycosyltransferase transcripts, bisulfite sequencing, and chromatin immunoprecipitation assays. RESULTS: CA19.9 was poorly detectable in normal colon mucosa and almost undetectable in colon cancer, while it was easily detected in the pancreatic ducts, together with Lewis b antigen, under both normal and cancer conditions. B3GALT5 transcripts were down-regulated in colon cancer, while they remained expressed in pancreatic cancer. Even ST3GAL3 transcript appeared well expressed in the pancreas but poorly in the colon, irrespective of normal or cancer conditions. CpG islands flanking B3GALT5 native promoter presented an extremely low degree of methylation in pancreatic cancer with respect to colon cancer. In a DNA region about 1kb away from the B3GALT5 retroviral promoter, a stretch of CG dinucleotides presented a methylation pattern potentially associated with transcription. Such a DNA region and the transcription factor binding site provided overlapping results by chromatin immunoprecipitation assays, corroborating the hypothesis. CONCLUSIONS: CA19.9 appears as a physiological product whose synthesis strongly depends on the tissue specific and epigenetically-regulated expression of B3GALT5 and ST3GAL3. GENERAL SIGNIFICANCE: CA19.9 and other Lewis antigens acquire tumor marker properties in the pancreas due to mechanisms giving rise to reabsorption into vessels and elevation in circulating levels. Copyright Â
Authors: Jingjing Zhu; Yaohua Yang; John B Kisiel; Douglas W Mahoney; Dominique S Michaud; Xingyi Guo; William R Taylor; Xiao-Ou Shu; Xiang Shu; Duo Liu; Bingshan Li; Ran Tao; Qiuyin Cai; Wei Zheng; Jirong Long; Lang Wu Journal: Cancer Epidemiol Biomarkers Prev Date: 2021-09-08 Impact factor: 4.254