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Phenotypic Heterogeneity Analysis of APC-Mutant Colon Cancer by Proteomics and Phosphoproteomics Identifies RAI14 as a Key Prognostic Determinant in East Asians and Westerners
Adenomatous polyposis coli (APC) is an important tumor suppressor and is mostly linked to the regulation of the Wnt/β-catenin signaling pathway. APC mutation has been identified as an early event in more than 80% of sporadic colorectal cancers (CRCs). Moreover, prognostic differences are observed in...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10148045/ https://www.ncbi.nlm.nih.gov/pubmed/36934880 http://dx.doi.org/10.1016/j.mcpro.2023.100532 |
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author | Zhang, Rou Hu, Meng Chen, Hai-Ning Wang, Xiuxuan Xia, Zhili Liu, Yu Wang, Rui Xia, Xuyang Shu, Yang Du, Dan Meng, Wenbo Qi, Shiqian Li, Yuan Xu, Heng Zhou, Zong-Guang Dai, Lunzhi |
author_facet | Zhang, Rou Hu, Meng Chen, Hai-Ning Wang, Xiuxuan Xia, Zhili Liu, Yu Wang, Rui Xia, Xuyang Shu, Yang Du, Dan Meng, Wenbo Qi, Shiqian Li, Yuan Xu, Heng Zhou, Zong-Guang Dai, Lunzhi |
author_sort | Zhang, Rou |
collection | PubMed |
description | Adenomatous polyposis coli (APC) is an important tumor suppressor and is mostly linked to the regulation of the Wnt/β-catenin signaling pathway. APC mutation has been identified as an early event in more than 80% of sporadic colorectal cancers (CRCs). Moreover, prognostic differences are observed in CRC patients with APC mutations. Although previous genomics studies have investigated the roles of concomitant gene mutations in determining the phenotypic heterogeneity of APC-mutant tumors, valuable prognostic determinants for APC-mutant CRC patients are still lacking. Based on the proteome and phosphoproteome data, we classified APC-mutant colon cancer patients and revealed genomic, proteomic, and phosphoproteomic heterogeneity in APC-mutant tumors. More importantly, we identified RAI14 as a key prognostic determinant for APC-mutant but not APC-wildtype colon cancer patients. The heterogeneity and the significance of prognostic biomarkers in APC-mutant tumors were further validated in the Clinical Proteomic Tumor Analysis Consortium (CPTAC) colon cancer cohort. In addition, we found that colon cancer patients with high expression of RAI14 were less responsive to chemotherapy. Knockdown of RAI14 in cell lines led to reduced cell migration and changes in epithelial-mesenchymal transition (EMT)–related markers. Mechanistically, knockdown of RAI14 remodeled the phosphoproteome associated with cell adhesion, which might affect EMT marker expression and promote F-actin degradation. Collectively, this work describes the phenotypic heterogeneity of APC-mutant tumors and identifies RAI14 as an important prognostic determinant for APC-mutant colon cancer patients. The prognostic utility of RAI14 in APC-mutant colon cancer will provide early warning and increase the chance of successful treatment. |
format | Online Article Text |
id | pubmed-10148045 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-101480452023-04-30 Phenotypic Heterogeneity Analysis of APC-Mutant Colon Cancer by Proteomics and Phosphoproteomics Identifies RAI14 as a Key Prognostic Determinant in East Asians and Westerners Zhang, Rou Hu, Meng Chen, Hai-Ning Wang, Xiuxuan Xia, Zhili Liu, Yu Wang, Rui Xia, Xuyang Shu, Yang Du, Dan Meng, Wenbo Qi, Shiqian Li, Yuan Xu, Heng Zhou, Zong-Guang Dai, Lunzhi Mol Cell Proteomics Research Article Collection: Cancer Proteomics Adenomatous polyposis coli (APC) is an important tumor suppressor and is mostly linked to the regulation of the Wnt/β-catenin signaling pathway. APC mutation has been identified as an early event in more than 80% of sporadic colorectal cancers (CRCs). Moreover, prognostic differences are observed in CRC patients with APC mutations. Although previous genomics studies have investigated the roles of concomitant gene mutations in determining the phenotypic heterogeneity of APC-mutant tumors, valuable prognostic determinants for APC-mutant CRC patients are still lacking. Based on the proteome and phosphoproteome data, we classified APC-mutant colon cancer patients and revealed genomic, proteomic, and phosphoproteomic heterogeneity in APC-mutant tumors. More importantly, we identified RAI14 as a key prognostic determinant for APC-mutant but not APC-wildtype colon cancer patients. The heterogeneity and the significance of prognostic biomarkers in APC-mutant tumors were further validated in the Clinical Proteomic Tumor Analysis Consortium (CPTAC) colon cancer cohort. In addition, we found that colon cancer patients with high expression of RAI14 were less responsive to chemotherapy. Knockdown of RAI14 in cell lines led to reduced cell migration and changes in epithelial-mesenchymal transition (EMT)–related markers. Mechanistically, knockdown of RAI14 remodeled the phosphoproteome associated with cell adhesion, which might affect EMT marker expression and promote F-actin degradation. Collectively, this work describes the phenotypic heterogeneity of APC-mutant tumors and identifies RAI14 as an important prognostic determinant for APC-mutant colon cancer patients. The prognostic utility of RAI14 in APC-mutant colon cancer will provide early warning and increase the chance of successful treatment. American Society for Biochemistry and Molecular Biology 2023-03-18 /pmc/articles/PMC10148045/ /pubmed/36934880 http://dx.doi.org/10.1016/j.mcpro.2023.100532 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Collection: Cancer Proteomics Zhang, Rou Hu, Meng Chen, Hai-Ning Wang, Xiuxuan Xia, Zhili Liu, Yu Wang, Rui Xia, Xuyang Shu, Yang Du, Dan Meng, Wenbo Qi, Shiqian Li, Yuan Xu, Heng Zhou, Zong-Guang Dai, Lunzhi Phenotypic Heterogeneity Analysis of APC-Mutant Colon Cancer by Proteomics and Phosphoproteomics Identifies RAI14 as a Key Prognostic Determinant in East Asians and Westerners |
title | Phenotypic Heterogeneity Analysis of APC-Mutant Colon Cancer by Proteomics and Phosphoproteomics Identifies RAI14 as a Key Prognostic Determinant in East Asians and Westerners |
title_full | Phenotypic Heterogeneity Analysis of APC-Mutant Colon Cancer by Proteomics and Phosphoproteomics Identifies RAI14 as a Key Prognostic Determinant in East Asians and Westerners |
title_fullStr | Phenotypic Heterogeneity Analysis of APC-Mutant Colon Cancer by Proteomics and Phosphoproteomics Identifies RAI14 as a Key Prognostic Determinant in East Asians and Westerners |
title_full_unstemmed | Phenotypic Heterogeneity Analysis of APC-Mutant Colon Cancer by Proteomics and Phosphoproteomics Identifies RAI14 as a Key Prognostic Determinant in East Asians and Westerners |
title_short | Phenotypic Heterogeneity Analysis of APC-Mutant Colon Cancer by Proteomics and Phosphoproteomics Identifies RAI14 as a Key Prognostic Determinant in East Asians and Westerners |
title_sort | phenotypic heterogeneity analysis of apc-mutant colon cancer by proteomics and phosphoproteomics identifies rai14 as a key prognostic determinant in east asians and westerners |
topic | Research Article Collection: Cancer Proteomics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10148045/ https://www.ncbi.nlm.nih.gov/pubmed/36934880 http://dx.doi.org/10.1016/j.mcpro.2023.100532 |
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