Cyclin A2 maintains colon homeostasis and is a prognostic factor in CRC

Colorectal cancer (CRC) is one of the leading causes of malignancy-related death worldwide with increasing incidence.

Although cyclin A2 is an established regulator of cell proliferation and has been used for molecular diagnostics as a proliferation marker, few studies investigated the role of cyclin A2 in tumor development in vivo. In collaboration with the group of E. Mamessier (CRCM, Marseille), we generated mice deficient for cyclin A2 in colonic epithelial cells (CEC) to characterize the function of cyclin A2 in colon homeostasis and CRC.

Our results reveal that colon 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 dysplasia and adenocarcinomas in the murine colitis-associated cancer model. We found that the main initial events triggering those alterations appear to be abnormal mitosis and DNA damage. Furthermore, by analyzing cyclinA2 mRNA and protein levels from clinical CRC samples, we found higher expression in tumors of stage I and II patients compared to those of stage III and IV. These data were supported by a meta-analysis of 11 transcriptome datasets comprising 2,239 primary CRC tumors.

Together, our study highlights that expression pattern of cyclin A2 in CRC tissues mirrors distinct roles during colon carcinogenesis, such as driving cell proliferation in early stages, when highly expressed, but promoting aggressiveness in later stages, when expression levels are lower. These results on cyclin A2 strikingly illustrate the complexity of CRC for developing therapeutic strategies.



Cyclin A2 maintains colon homeostasis and is a prognostic factor in CRC

Yuchen Guo,1 Monica Gabola,1 Rossano Lattanzio,2 Conception Paul,1 Valérie Pinet,1Ruizhi Tang,1 Hulya Turali,1 Julie Bremond,1 Ciro Longobardi,1 Chloé Maurizy,1 Quentin Da Costa,3 Pascal Finetti,3 Florence Boissière-Michot,4 Benjamin Rivière,1 Céline Lemmers,5 Séverine Garnier,3 François Bertucci,6 Inti Zlobec,7 Karim Chebli,1 Jamal Tazi,1Rania Azar,8 Jean-Marie Blanchard,1 Peter Sicinski,9 Emilie Mamessier,3 Bénédicte Lemmers,1 and Michael Hahne1

J Clin Invest. 2020 Dec 17:131517. doi: 10.1172/JCI131517. Online ahead of print.