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MicroRNA-21 Plays Multiple Oncometabolic Roles in Colitis-Associated Carcinoma and Colorectal Cancer via the PI3K/AKT, STAT3, and PDCD4/TNF-α Signaling Pathways in Zebrafish
SIMPLE SUMMARY: The PI3K/AKT, STAT3, and PDCD4/TNF-α signaling networks, regulated by the microRNA (miR)-21, are critical for inflammatory regulation, tumor suppressor modulation, and oncogenic activation. We developed a zebrafish model (ImiR-21) with an inducible overexpression of miR-21, specifica...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583575/ https://www.ncbi.nlm.nih.gov/pubmed/34771727 http://dx.doi.org/10.3390/cancers13215565 |
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author | Lai, Chi-Yu Yeh, Kun-Yun Liu, Bi-Feng Chang, Tzu-Ming Chang, Chuan-Hsun Liao, Yung-Feng Liu, Yi-Wen Her, Guor Mour |
author_facet | Lai, Chi-Yu Yeh, Kun-Yun Liu, Bi-Feng Chang, Tzu-Ming Chang, Chuan-Hsun Liao, Yung-Feng Liu, Yi-Wen Her, Guor Mour |
author_sort | Lai, Chi-Yu |
collection | PubMed |
description | SIMPLE SUMMARY: The PI3K/AKT, STAT3, and PDCD4/TNF-α signaling networks, regulated by the microRNA (miR)-21, are critical for inflammatory regulation, tumor suppressor modulation, and oncogenic activation. We developed a zebrafish model (ImiR-21) with an inducible overexpression of miR-21, specifically in the intestine. The miR-21 overexpression resulted in the development of colorectal cancer (CRC) due to inflammatory bowel disease. Furthermore, the physiological, metabolic, and histological aspects of CRC were similar to those of colitis-associated cancer (CAC) induced by the intestinal carcinogens azoxymethane or dextran sodium sulfate in this model. Thus, miR-21 is critical to the pathogenesis of CRC/CAC and could serve as a novel therapeutic target to treat CRC/CAC. ABSTRACT: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Patients with inflammatory bowel disease (IBD) have a high risk of developing CRC. Inflammatory cytokines are regulated by complex gene networks and regulatory RNAs, especially microRNAs. MicroRNA-21 (miR-21) is amongst the most frequently upregulated microRNAs in inflammatory responses and cancer development. miR-21 has become a target for genetic and pharmacological regulation in various diseases. However, the association between inflammation and tumorigenesis in the gut is largely unknown. Hence, in this study, we generated a zebrafish model (ImiR-21) with inducible overexpression of miR-21 in the intestine. The results demonstrate that miR-21 can induce CRC or colitis-associated cancer (CAC) in ImiR-21 through the PI3K/AKT, PDCD4/TNF-α, and IL-6/STAT3 signaling network. miR-21 activated the PI3K/AKT and NF-κB signaling pathways, leading to initial inflammation; thereafter, miR-21 and TNF-α repressed PDCD4 and its tumor suppression activity. Eventually, active STAT3 stimulated a strong inflammatory response and activated the invasion/metastasis process of tumor cells. Hence, our findings indicate that miR-21 is critical for the development of CRC/CAC via the PI3K/AKT, STAT3, and PDCD4/TNF-α signaling networks. |
format | Online Article Text |
id | pubmed-8583575 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-85835752021-11-12 MicroRNA-21 Plays Multiple Oncometabolic Roles in Colitis-Associated Carcinoma and Colorectal Cancer via the PI3K/AKT, STAT3, and PDCD4/TNF-α Signaling Pathways in Zebrafish Lai, Chi-Yu Yeh, Kun-Yun Liu, Bi-Feng Chang, Tzu-Ming Chang, Chuan-Hsun Liao, Yung-Feng Liu, Yi-Wen Her, Guor Mour Cancers (Basel) Article SIMPLE SUMMARY: The PI3K/AKT, STAT3, and PDCD4/TNF-α signaling networks, regulated by the microRNA (miR)-21, are critical for inflammatory regulation, tumor suppressor modulation, and oncogenic activation. We developed a zebrafish model (ImiR-21) with an inducible overexpression of miR-21, specifically in the intestine. The miR-21 overexpression resulted in the development of colorectal cancer (CRC) due to inflammatory bowel disease. Furthermore, the physiological, metabolic, and histological aspects of CRC were similar to those of colitis-associated cancer (CAC) induced by the intestinal carcinogens azoxymethane or dextran sodium sulfate in this model. Thus, miR-21 is critical to the pathogenesis of CRC/CAC and could serve as a novel therapeutic target to treat CRC/CAC. ABSTRACT: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Patients with inflammatory bowel disease (IBD) have a high risk of developing CRC. Inflammatory cytokines are regulated by complex gene networks and regulatory RNAs, especially microRNAs. MicroRNA-21 (miR-21) is amongst the most frequently upregulated microRNAs in inflammatory responses and cancer development. miR-21 has become a target for genetic and pharmacological regulation in various diseases. However, the association between inflammation and tumorigenesis in the gut is largely unknown. Hence, in this study, we generated a zebrafish model (ImiR-21) with inducible overexpression of miR-21 in the intestine. The results demonstrate that miR-21 can induce CRC or colitis-associated cancer (CAC) in ImiR-21 through the PI3K/AKT, PDCD4/TNF-α, and IL-6/STAT3 signaling network. miR-21 activated the PI3K/AKT and NF-κB signaling pathways, leading to initial inflammation; thereafter, miR-21 and TNF-α repressed PDCD4 and its tumor suppression activity. Eventually, active STAT3 stimulated a strong inflammatory response and activated the invasion/metastasis process of tumor cells. Hence, our findings indicate that miR-21 is critical for the development of CRC/CAC via the PI3K/AKT, STAT3, and PDCD4/TNF-α signaling networks. MDPI 2021-11-06 /pmc/articles/PMC8583575/ /pubmed/34771727 http://dx.doi.org/10.3390/cancers13215565 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lai, Chi-Yu Yeh, Kun-Yun Liu, Bi-Feng Chang, Tzu-Ming Chang, Chuan-Hsun Liao, Yung-Feng Liu, Yi-Wen Her, Guor Mour MicroRNA-21 Plays Multiple Oncometabolic Roles in Colitis-Associated Carcinoma and Colorectal Cancer via the PI3K/AKT, STAT3, and PDCD4/TNF-α Signaling Pathways in Zebrafish |
title | MicroRNA-21 Plays Multiple Oncometabolic Roles in Colitis-Associated Carcinoma and Colorectal Cancer via the PI3K/AKT, STAT3, and PDCD4/TNF-α Signaling Pathways in Zebrafish |
title_full | MicroRNA-21 Plays Multiple Oncometabolic Roles in Colitis-Associated Carcinoma and Colorectal Cancer via the PI3K/AKT, STAT3, and PDCD4/TNF-α Signaling Pathways in Zebrafish |
title_fullStr | MicroRNA-21 Plays Multiple Oncometabolic Roles in Colitis-Associated Carcinoma and Colorectal Cancer via the PI3K/AKT, STAT3, and PDCD4/TNF-α Signaling Pathways in Zebrafish |
title_full_unstemmed | MicroRNA-21 Plays Multiple Oncometabolic Roles in Colitis-Associated Carcinoma and Colorectal Cancer via the PI3K/AKT, STAT3, and PDCD4/TNF-α Signaling Pathways in Zebrafish |
title_short | MicroRNA-21 Plays Multiple Oncometabolic Roles in Colitis-Associated Carcinoma and Colorectal Cancer via the PI3K/AKT, STAT3, and PDCD4/TNF-α Signaling Pathways in Zebrafish |
title_sort | microrna-21 plays multiple oncometabolic roles in colitis-associated carcinoma and colorectal cancer via the pi3k/akt, stat3, and pdcd4/tnf-α signaling pathways in zebrafish |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583575/ https://www.ncbi.nlm.nih.gov/pubmed/34771727 http://dx.doi.org/10.3390/cancers13215565 |
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