Recurrent NOMO1 Gene Deletion Is a Potential Clinical Marker in Early-Onset Colorectal Cancer and Is Involved in the Regulation of Cell Migration

• Published in: Cancers 2022-08, Vol.14 (16), p.4029
• Main Authors: Pérez-García, Jésica, Martel-Martel, Abel, García-Vallés, Paula, Corchete, Luis A., García, Juan L., Gestoso-Uzal, Nerea, Vidal-Tocino, Rosario, Blanco, Óscar, Méndez, Lucía, Sánchez-Martín, Manuel, Fuentes, Manuel, Herrero, Ana B., Holowatyj, Andreana N., Perea, José, González-Sarmiento, Rogelio
• Format: Article
• Language: English
• Subjects: Age; Animal models; Bone marrow; Carcinogenesis; Cell adhesion & migration; Cell migration; Cell proliferation; Colon cancer; Colorectal cancer; Colorectal carcinoma; CRISPR; DNA microarrays; Enzymes; Gene amplification; Gene deletion; Genetic engineering; Medical prognosis; Mesenchyme; Mutation; Pathogenesis; Plasmids; Proteins; Signal transduction; Stem cells; Tumors
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers14164029

The incidence of early-onset colorectal cancer (EOCRC; age younger than 50 years) has been progressively increasing over the last decades globally, with causes unexplained. A distinct molecular feature of EOCRC is that compared with cases of late-onset colorectal cancer, in EOCRC cases, there is a higher incidence of Nodal Modulator 1 (NOMO1) somatic deletions. However, the mechanisms of NOMO1 in early-onset colorectal carcinogenesis are currently unknown. In this study, we show that in 30% of EOCRCs with heterozygous deletion of NOMO1, there were pathogenic mutations in this gene, suggesting that NOMO1 can be inactivated by deletion or mutation in EOCRC. To study the role of NOMO1 in EOCRC, CRISPR/cas9 technology was employed to generate NOMO1 knockout HCT-116 (EOCRC) and HS-5 (bone marrow) cell lines. NOMO1 loss in these cell lines did not perturb Nodal pathway signaling nor cell proliferation. Expression microarrays, RNA sequencing, and protein expression analysis by LC–IMS/MS showed that NOMO1 inactivation deregulates other signaling pathways independent of the Nodal pathway, such as epithelial–mesenchymal transition and cell migration. Significantly, NOMO1 loss increased the migration capacity of CRC cells. Additionally, a gut-specific conditional NOMO1 KO mouse model revealed no subsequent tumor development in mice. Overall, these findings suggest that NOMO1 could play a secondary role in early-onset colorectal carcinogenesis because its loss increases the migration capacity of CRC cells. Therefore, further study is warranted to explore other signalling pathways deregulated by NOMO1 loss that may play a significant role in the pathogenesis of the disease.