Stratification of Colorectal Patients Based on Survival Analysis Shows the Value of Consensus Molecular Subtypes and Reveals the CBLL1 Gene as a Biomarker of CMS2 Tumours
The consensus molecular subtypes (CMSs) classification of colorectal cancer (CRC) is a system for patient stratification that can be potentially applied to therapeutic decisions. Hakai (CBLL1) is an E3 ubiquitin–ligase that induces the ubiquitination and degradation of E-cadherin, inducing epithelia...
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| Format: | Article |
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MDPI AG
2024-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/3/1919 |
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| author | Gloria Alfonsín Alberto Berral-González Andrea Rodríguez-Alonso Macarena Quiroga Javier De Las Rivas Angélica Figueroa |
| author_facet | Gloria Alfonsín Alberto Berral-González Andrea Rodríguez-Alonso Macarena Quiroga Javier De Las Rivas Angélica Figueroa |
| author_sort | Gloria Alfonsín |
| collection | DOAJ |
| description | The consensus molecular subtypes (CMSs) classification of colorectal cancer (CRC) is a system for patient stratification that can be potentially applied to therapeutic decisions. Hakai (CBLL1) is an E3 ubiquitin–ligase that induces the ubiquitination and degradation of E-cadherin, inducing epithelial-to-mesenchymal transition (EMT), tumour progression and metastasis. Using bioinformatic methods, we have analysed CBLL1 expression on a large integrated cohort of primary tumour samples from CRC patients. The cohort included survival data and was divided into consensus molecular subtypes. Colon cancer tumourspheres were used to analyse the expression of stem cancer cells markers via RT-PCR and Western blotting. We show that CBLL1 gene expression is specifically associated with canonical subtype CMS2. WNT target genes LGR5 and c-MYC show a similar association with CMS2 as CBLL1. These mRNA levels are highly upregulated in cancer tumourspheres, while CBLL1 silencing shows a clear reduction in tumoursphere size and in stem cell biomarkers. Importantly, CMS2 patients with high CBLL1 expression displayed worse overall survival (OS), which is similar to that associated with CMS4 tumours. Our findings reveal CBLL1 as a specific biomarker for CMS2 and the potential of using CMS2 with high CBLL1 expression to stratify patients with poor OS. |
| first_indexed | 2024-03-08T03:54:54Z |
| format | Article |
| id | doaj.art-a6252408a17b445a9aa4755d4a764ddf |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T03:54:54Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a6252408a17b445a9aa4755d4a764ddf2024-02-09T15:15:10ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-02-01253191910.3390/ijms25031919Stratification of Colorectal Patients Based on Survival Analysis Shows the Value of Consensus Molecular Subtypes and Reveals the CBLL1 Gene as a Biomarker of CMS2 TumoursGloria Alfonsín0Alberto Berral-González1Andrea Rodríguez-Alonso2Macarena Quiroga3Javier De Las Rivas4Angélica Figueroa5Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006 A Coruña, SpainBioinformatics and Functional Genomics Group, Cancer Research Center (CiC-IBMCC, CSIC/USAL & IBSAL), Consejo Superior de Investigaciones Cientificas (CSIC), University of Salamanca (USAL) and Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, SpainEpithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006 A Coruña, SpainEpithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006 A Coruña, SpainBioinformatics and Functional Genomics Group, Cancer Research Center (CiC-IBMCC, CSIC/USAL & IBSAL), Consejo Superior de Investigaciones Cientificas (CSIC), University of Salamanca (USAL) and Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, SpainEpithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006 A Coruña, SpainThe consensus molecular subtypes (CMSs) classification of colorectal cancer (CRC) is a system for patient stratification that can be potentially applied to therapeutic decisions. Hakai (CBLL1) is an E3 ubiquitin–ligase that induces the ubiquitination and degradation of E-cadherin, inducing epithelial-to-mesenchymal transition (EMT), tumour progression and metastasis. Using bioinformatic methods, we have analysed CBLL1 expression on a large integrated cohort of primary tumour samples from CRC patients. The cohort included survival data and was divided into consensus molecular subtypes. Colon cancer tumourspheres were used to analyse the expression of stem cancer cells markers via RT-PCR and Western blotting. We show that CBLL1 gene expression is specifically associated with canonical subtype CMS2. WNT target genes LGR5 and c-MYC show a similar association with CMS2 as CBLL1. These mRNA levels are highly upregulated in cancer tumourspheres, while CBLL1 silencing shows a clear reduction in tumoursphere size and in stem cell biomarkers. Importantly, CMS2 patients with high CBLL1 expression displayed worse overall survival (OS), which is similar to that associated with CMS4 tumours. Our findings reveal CBLL1 as a specific biomarker for CMS2 and the potential of using CMS2 with high CBLL1 expression to stratify patients with poor OS.https://www.mdpi.com/1422-0067/25/3/1919cancer stem cellsCBL proteinscolon cancerconsensus molecular subtypesepithelial-to-mesenchymal transitionHakai |
| spellingShingle | Gloria Alfonsín Alberto Berral-González Andrea Rodríguez-Alonso Macarena Quiroga Javier De Las Rivas Angélica Figueroa Stratification of Colorectal Patients Based on Survival Analysis Shows the Value of Consensus Molecular Subtypes and Reveals the CBLL1 Gene as a Biomarker of CMS2 Tumours International Journal of Molecular Sciences cancer stem cells CBL proteins colon cancer consensus molecular subtypes epithelial-to-mesenchymal transition Hakai |
| title | Stratification of Colorectal Patients Based on Survival Analysis Shows the Value of Consensus Molecular Subtypes and Reveals the CBLL1 Gene as a Biomarker of CMS2 Tumours |
| title_full | Stratification of Colorectal Patients Based on Survival Analysis Shows the Value of Consensus Molecular Subtypes and Reveals the CBLL1 Gene as a Biomarker of CMS2 Tumours |
| title_fullStr | Stratification of Colorectal Patients Based on Survival Analysis Shows the Value of Consensus Molecular Subtypes and Reveals the CBLL1 Gene as a Biomarker of CMS2 Tumours |
| title_full_unstemmed | Stratification of Colorectal Patients Based on Survival Analysis Shows the Value of Consensus Molecular Subtypes and Reveals the CBLL1 Gene as a Biomarker of CMS2 Tumours |
| title_short | Stratification of Colorectal Patients Based on Survival Analysis Shows the Value of Consensus Molecular Subtypes and Reveals the CBLL1 Gene as a Biomarker of CMS2 Tumours |
| title_sort | stratification of colorectal patients based on survival analysis shows the value of consensus molecular subtypes and reveals the cbll1 gene as a biomarker of cms2 tumours |
| topic | cancer stem cells CBL proteins colon cancer consensus molecular subtypes epithelial-to-mesenchymal transition Hakai |
| url | https://www.mdpi.com/1422-0067/25/3/1919 |
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