Sebastian C B Bremer1, Lena-Christin Conradi2, Nicolae-Catalin Mechie3, Ahmad Amanzada3, Eirini Mavropoulou3, Julia Kitz4, Michael Ghadimi2, Volker Ellenrieder3, Philipp Ströbel4, Elisabeth Hessmann3, Jochen Gaedcke2, Hanibal Bohnenberger4. 1. Clinic for Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Georg-August-University, Goettingen, Germany, sebastian.bremer@med.uni-goettingen.de. 2. Clinic for General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Georg-August-University, Goettingen, Germany. 3. Clinic for Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Georg-August-University, Goettingen, Germany. 4. Institute of Pathology, University Medical Center Goettingen, Georg-August-University, Goettingen, Germany.
Abstract
BACKGROUND: Colorectal cancer (CRC) is the leading gastrointestinal malignancy. The development from premalignant intraepithelial lesions leading to invasive cancer is paradigmatic for the stepwise carcinogenesis of epithelial cancers, but the knowledge of the underlying mechanism of carcinogenesis and progression of CRC is still incomplete. The understanding of epigenetic mechanisms of carcinogenesis has led to new therapeutic approaches during the last years. Enhancer of zeste homolog 2 (EZH2) is one central epigenetic silencer of the polycomb repressor complex 2 (PRC2) that is already in clinical use as a novel drug target and is associated with poorer prognosis in several cancer entities. PATIENTS AND METHODS: The protein expression of EZH2 and other members of the PRC2 as well as resulting posttranslational modifications were investigated by immunohistochemistry in 187 patients with CRC and in 94 patients with premalignant colorectal lesions and correlated with their clinical outcome. Furthermore, the corresponding mRNA expression levels were analyzed in 217 patients with rectal cancer that were enrolled in a prospective clinical trial. RESULTS: We found a weak expression of EZH2 in normal colon mucosa that increased in low grade, peaked in high grade intraepithelial neoplasia, and decreased again in invasive CRC. The posttranslational modification caused by EZH2 as a measure of EZH2 activity showed the same behavior. Strong protein and mRNA expression of EZH2 were significantly correlated with favorable prognosis in both investigated cohorts. CONCLUSION: The expression and activity of EZH2 are associated with colorectal carcinogenesis and most expressed in intraepithelial high-grade lesions. Strong expression of EZH2 is associated with a significantly favorable prognosis in patients suffering from CRC.
BACKGROUND:Colorectal cancer (CRC) is the leading gastrointestinal malignancy. The development from premalignant intraepithelial lesions leading to invasive cancer is paradigmatic for the stepwise carcinogenesis of epithelial cancers, but the knowledge of the underlying mechanism of carcinogenesis and progression of CRC is still incomplete. The understanding of epigenetic mechanisms of carcinogenesis has led to new therapeutic approaches during the last years. Enhancer of zeste homolog 2 (EZH2) is one central epigenetic silencer of the polycomb repressor complex 2 (PRC2) that is already in clinical use as a novel drug target and is associated with poorer prognosis in several cancer entities. PATIENTS AND METHODS: The protein expression of EZH2 and other members of the PRC2 as well as resulting posttranslational modifications were investigated by immunohistochemistry in 187 patients with CRC and in 94 patients with premalignant colorectal lesions and correlated with their clinical outcome. Furthermore, the corresponding mRNA expression levels were analyzed in 217 patients with rectal cancer that were enrolled in a prospective clinical trial. RESULTS: We found a weak expression of EZH2 in normal colon mucosa that increased in low grade, peaked in high grade intraepithelial neoplasia, and decreased again in invasive CRC. The posttranslational modification caused by EZH2 as a measure of EZH2 activity showed the same behavior. Strong protein and mRNA expression of EZH2 were significantly correlated with favorable prognosis in both investigated cohorts. CONCLUSION: The expression and activity of EZH2 are associated with colorectal carcinogenesis and most expressed in intraepithelial high-grade lesions. Strong expression of EZH2 is associated with a significantly favorable prognosis in patients suffering from CRC.
Authors: Sebastian C B Bremer; Gabi Bittner; Omar Elakad; Helen Dinter; Jochen Gaedcke; Alexander O König; Ahmad Amanzada; Volker Ellenrieder; Alexander Freiherr von Hammerstein-Equord; Philipp Ströbel; Hanibal Bohnenberger Journal: Cancers (Basel) Date: 2022-06-08 Impact factor: 6.575
Authors: Sandra Wiedenmann; Markus Breunig; Jessica Merkle; Christine von Toerne; Tihomir Georgiev; Michel Moussus; Lucas Schulte; Thomas Seufferlein; Michael Sterr; Heiko Lickert; Stephanie Ellen Weissinger; Peter Möller; Stefanie M Hauck; Meike Hohwieler; Alexander Kleger; Matthias Meier Journal: Nat Biomed Eng Date: 2021-07-08 Impact factor: 25.671
Authors: Sha Yao; Luogen Peng; Omar Elakad; Stefan Küffer; Marc Hinterthaner; Bernhard C Danner; Alexander von Hammerstein-Equord; Philipp Ströbel; Hanibal Bohnenberger Journal: Transl Lung Cancer Res Date: 2021-06