Characterization of NOMO1 loss in early-onset colorectal cancer
Abel J. Martel Martel
Centro de Investigación del Cáncer-Hospital Universitario de Salamanca
Early-onset colorectal cancer (EOCRC; age younger than 50 years) incidence has been steadily increasing over the last decades worldwide with causes unexplained. A unique molecular feature of EOCRC is that these cases harbor a greater incidence of Nodal Modulator 1 (NOMO-1) somatic deletions compared with late-onset CRC. 50% of heterozygous NOMO1 deleted–EOCRCs present pathogenic mutations in this gene, suggesting that it can be inactivated by deletion or mutation in EOCRC. Yet the mechanisms of NOMO1 in early-onset colorectal carcinogenesis are currently unknown. To study the role of NOMO1 in EOCRC, CRISPR/cas9 technology was used to generate NOMO1 knockout HCT-116 (EOCRC) and HS-5 (bone marrow) cell lines. Loss of NOMO1 in these cell lines did not perturb Nodal pathway signaling and not modify cell viability. Importantly, NOMO1 inactivation increased the migration capacity of CRC cells. In addition, results of RNA sequencing, expression microarray and protein expression by LC-IMS/MS revealed that inactivation of NOMO1 gene deregulates other signaling pathways independent of the Nodal pathway. Additionally, a gut-specific conditional knockout mouse model of NOMO1 revealed no subsequent tumor development in mice. Overall, these findings suggest that NOMO1 is not a driver of early-onset colorectal carcinogenesis. Further study is warranted to explore other signaling pathways deregulated by the loss of NOMO-1 that may play a relevant role in the pathogenesis of the disease.