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Loss of cyclin A2 in murine colonic epithelial cells disrupts colon homeostasis by triggering DNA damage and dysplasia and high cyclin A2 expression is a good-prognosis factor in patients with colorectal cancer

By Yuchen Guo, Monica Gabola, Rossano Lattanzio, Conception Paul, Valérie Pinet, Ruizhi Tang, Hulya Tulari, Julie Bremond, Chloé Maurizy, Quentin Da Costa, Pascal Finetti, Florence Boissière-Michot, Céline Lemmers, Séverine Garnier, François Bertucci, Rania Azar, Jean-Marie Blanchard, Piotr Sicinski, Emilie Mamessier, Bénédicte Lemmers, Michael Hahne

Posted 03 Jul 2019
bioRxiv DOI: 10.1101/690404

To clarify the function of cyclin A2 in colon homeostasis and colorectal cancer (CRC) we generated mice deficient for cyclin A2 in colonic epithelial cells (CEC). Colons of those mice displayed architectural changes in the mucosa, and signs of inflammation as well as an increased proliferation of CEC associated with the appearance of low- and high-grade dysplasia. The main initial events triggering those alterations in cyclin A2 deficient CEC appear to be abnormal mitoses and DNA damage. Cyclin A2 deletion in CEC promoted the development of dysplasia and adenocarcinomas in the murine colitis-associated cancer model. We next explored the status of cyclin A2 expression in clinical CRC samples at the mRNA and protein level and found higher expression in tumors of stage I and II patients compared to those of stage III and IV. A meta-analysis of 11 transcriptome datasets comprising 2,239 primary CRC tumors displayed different CCNA2 (the mRNA coding for cyclin A2) expression levels among the CRC tumor subtypes with highest in CMS1 and lowest in CMS4. Moreover, high expression of CCNA2 was found to be a good prognosis factor independently from other prognostic factors for the CMS1, CMS3 and CMS4 subtypes.

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