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Exploration of the Proteomic Landscape of Small Extracellular Vesicles in Serum as Biomarkers for Early Detection of Colorectal Neoplasia
BACKGROUND: Patient participation in colorectal cancer (CRC) screening via a stool test and colonoscopy is suboptimal, but participation can be improved by the development of a blood test. However, the suboptimal detection abilities of blood tests for advanced neoplasia, including advanced adenoma (...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473825/ https://www.ncbi.nlm.nih.gov/pubmed/34589434 http://dx.doi.org/10.3389/fonc.2021.732743 |
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author | Chang, Li-Chun Hsu, Yi-Chiung Chiu, Han-Mo Ueda, Koji Wu, Ming-Shiang Kao, Chiun-How Shen, Tang-Long |
author_facet | Chang, Li-Chun Hsu, Yi-Chiung Chiu, Han-Mo Ueda, Koji Wu, Ming-Shiang Kao, Chiun-How Shen, Tang-Long |
author_sort | Chang, Li-Chun |
collection | PubMed |
description | BACKGROUND: Patient participation in colorectal cancer (CRC) screening via a stool test and colonoscopy is suboptimal, but participation can be improved by the development of a blood test. However, the suboptimal detection abilities of blood tests for advanced neoplasia, including advanced adenoma (AA) and CRC, limit their application. We aimed to investigate the proteomic landscape of small extracellular vesicles (sEVs) from the serum of patients with colorectal neoplasia and identify specific sEV proteins that could serve as biomarkers for early diagnosis. MATERIALS AND METHODS: We enrolled 100 patients including 13 healthy subjects, 12 non-AAs, 13 AAs, and 16 stage-I, 15 stage-II, 16 stage-III, and 15 stage-IV CRCs. These patients were classified as normal control, early neoplasia, and advanced neoplasia. The sEV proteome was explored by liquid chromatography-tandem mass spectrometry. Generalized association plots were used to integrate the clustering methods, visualize the data matrix, and analyze the relationship. The specific sEV biomarkers were identified by a decision tree via Orange3 software. Functional enrichment analysis was conducted by using the Ingenuity Pathway Analysis platform. RESULTS: The sEV protein matrix was identified from the serum of 100 patients and contained 3353 proteins, of which 1921 proteins from 98 patients were finally analyzed. Compared with the normal control, subjects with early and advanced neoplasia exhibited a distinct proteomic distribution in the data matrix plot. Six sEV proteins were identified, namely, GCLM, KEL, APOF, CFB, PDE5A, and ATIC, which properly distinguished normal control, early neoplasia, and advanced neoplasia patients from each other. Functional enrichment analysis revealed that APOF(+) and CFB(+) sEV associated with clathrin-mediated endocytosis signaling and the complement system, which have critical implications for CRC carcinogenesis. CONCLUSION: Patients with colorectal neoplasia had a distinct sEV proteome expression pattern in serum compared with those patients who were healthy and did not have neoplasms. Moreover, the six identified specific sEV proteins had the potential to discriminate colorectal neoplasia between early-stage and advanced neoplasia. Collectively, our study provided a six-sEV protein biomarker panel for CRC diagnosis at early or advanced stages. Furthermore, the implication of the sEV proteome in CRC carcinogenesis via specific signaling pathways was explored. |
format | Online Article Text |
id | pubmed-8473825 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-84738252021-09-28 Exploration of the Proteomic Landscape of Small Extracellular Vesicles in Serum as Biomarkers for Early Detection of Colorectal Neoplasia Chang, Li-Chun Hsu, Yi-Chiung Chiu, Han-Mo Ueda, Koji Wu, Ming-Shiang Kao, Chiun-How Shen, Tang-Long Front Oncol Oncology BACKGROUND: Patient participation in colorectal cancer (CRC) screening via a stool test and colonoscopy is suboptimal, but participation can be improved by the development of a blood test. However, the suboptimal detection abilities of blood tests for advanced neoplasia, including advanced adenoma (AA) and CRC, limit their application. We aimed to investigate the proteomic landscape of small extracellular vesicles (sEVs) from the serum of patients with colorectal neoplasia and identify specific sEV proteins that could serve as biomarkers for early diagnosis. MATERIALS AND METHODS: We enrolled 100 patients including 13 healthy subjects, 12 non-AAs, 13 AAs, and 16 stage-I, 15 stage-II, 16 stage-III, and 15 stage-IV CRCs. These patients were classified as normal control, early neoplasia, and advanced neoplasia. The sEV proteome was explored by liquid chromatography-tandem mass spectrometry. Generalized association plots were used to integrate the clustering methods, visualize the data matrix, and analyze the relationship. The specific sEV biomarkers were identified by a decision tree via Orange3 software. Functional enrichment analysis was conducted by using the Ingenuity Pathway Analysis platform. RESULTS: The sEV protein matrix was identified from the serum of 100 patients and contained 3353 proteins, of which 1921 proteins from 98 patients were finally analyzed. Compared with the normal control, subjects with early and advanced neoplasia exhibited a distinct proteomic distribution in the data matrix plot. Six sEV proteins were identified, namely, GCLM, KEL, APOF, CFB, PDE5A, and ATIC, which properly distinguished normal control, early neoplasia, and advanced neoplasia patients from each other. Functional enrichment analysis revealed that APOF(+) and CFB(+) sEV associated with clathrin-mediated endocytosis signaling and the complement system, which have critical implications for CRC carcinogenesis. CONCLUSION: Patients with colorectal neoplasia had a distinct sEV proteome expression pattern in serum compared with those patients who were healthy and did not have neoplasms. Moreover, the six identified specific sEV proteins had the potential to discriminate colorectal neoplasia between early-stage and advanced neoplasia. Collectively, our study provided a six-sEV protein biomarker panel for CRC diagnosis at early or advanced stages. Furthermore, the implication of the sEV proteome in CRC carcinogenesis via specific signaling pathways was explored. Frontiers Media S.A. 2021-09-13 /pmc/articles/PMC8473825/ /pubmed/34589434 http://dx.doi.org/10.3389/fonc.2021.732743 Text en Copyright © 2021 Chang, Hsu, Chiu, Ueda, Wu, Kao and Shen https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Chang, Li-Chun Hsu, Yi-Chiung Chiu, Han-Mo Ueda, Koji Wu, Ming-Shiang Kao, Chiun-How Shen, Tang-Long Exploration of the Proteomic Landscape of Small Extracellular Vesicles in Serum as Biomarkers for Early Detection of Colorectal Neoplasia |
title | Exploration of the Proteomic Landscape of Small Extracellular Vesicles in Serum as Biomarkers for Early Detection of Colorectal Neoplasia |
title_full | Exploration of the Proteomic Landscape of Small Extracellular Vesicles in Serum as Biomarkers for Early Detection of Colorectal Neoplasia |
title_fullStr | Exploration of the Proteomic Landscape of Small Extracellular Vesicles in Serum as Biomarkers for Early Detection of Colorectal Neoplasia |
title_full_unstemmed | Exploration of the Proteomic Landscape of Small Extracellular Vesicles in Serum as Biomarkers for Early Detection of Colorectal Neoplasia |
title_short | Exploration of the Proteomic Landscape of Small Extracellular Vesicles in Serum as Biomarkers for Early Detection of Colorectal Neoplasia |
title_sort | exploration of the proteomic landscape of small extracellular vesicles in serum as biomarkers for early detection of colorectal neoplasia |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473825/ https://www.ncbi.nlm.nih.gov/pubmed/34589434 http://dx.doi.org/10.3389/fonc.2021.732743 |
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