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Epigenetic Silencing of miR-33b Promotes Peritoneal Metastases of Ovarian Cancer by Modulating the TAK1/FASN/CPT1A/NF-κB Axis

SIMPLE SUMMARY: Omental metastasis and peritoneal dissemination are frequently observed in ovarian cancer peritoneal metastases and are associated with high mortality and poor prognosis. The tumor microenvironment is known to influence cancer epigenomics, which plays an essential role in promoting t...

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Autores principales: Wang, Xueyu, Yung, Mingo M. H., Sharma, Rakesh, Chen, Fushun, Poon, Ying-Tung, Lam, Wai-Yip, Li, Benjamin, Ngan, Hextan Y. S., Chan, Karen K. L., Chan, David W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508465/
https://www.ncbi.nlm.nih.gov/pubmed/34638280
http://dx.doi.org/10.3390/cancers13194795
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author Wang, Xueyu
Yung, Mingo M. H.
Sharma, Rakesh
Chen, Fushun
Poon, Ying-Tung
Lam, Wai-Yip
Li, Benjamin
Ngan, Hextan Y. S.
Chan, Karen K. L.
Chan, David W.
author_facet Wang, Xueyu
Yung, Mingo M. H.
Sharma, Rakesh
Chen, Fushun
Poon, Ying-Tung
Lam, Wai-Yip
Li, Benjamin
Ngan, Hextan Y. S.
Chan, Karen K. L.
Chan, David W.
author_sort Wang, Xueyu
collection PubMed
description SIMPLE SUMMARY: Omental metastasis and peritoneal dissemination are frequently observed in ovarian cancer peritoneal metastases and are associated with high mortality and poor prognosis. The tumor microenvironment is known to influence cancer epigenomics, which plays an essential role in promoting tumor development and metastatic progression. Therefore, investigation of the epigenetic mechanisms underlying the growth of ovarian cancer cells in the omental metastatic microenvironment is of great importance. Here, we report that miR-33b is significantly silenced by DNA hypermethylation in metastatic ovarian cancer cells to adapt to a lipid-rich microenvironment. Restoration of miR-33b was shown to impair lipid metabolic activities and reduce the oncogenic properties of ovarian cancer cells by negatively regulating the TAK1/FASN/CPT1A/NF-κB pathway, indicating that targeting this signaling cascade may be a molecular therapeutic choice for ovarian cancer metastatic progression. ABSTRACT: Peritoneal metastases are frequently found in high-grade serous carcinoma (HGSOC) patients and are commonly associated with a poor prognosis. The tumor microenvironment (TME) is a complex milieu that plays a critical role in epigenetic alterations driving tumor development and metastatic progression. However, the impact of epigenetic alterations on metastatic ovarian cancer cells in the harsh peritoneal microenvironment remains incompletely understood. Here, we identified that miR-33b is frequently silenced by promoter hypermethylation in HGSOC cells derived from metastatic omental tumor tissues. Enforced expression of miR-33b abrogates the oncogenic properties of ovarian cancer cells cocultured in omental conditioned medium (OCM), which mimics the ascites microenvironment, and in vivo tumor growth. Of note, restoration of miR-33b inhibited OCM-upregulated de novo lipogenesis and fatty acid β-oxidation in ovarian cancer cells, indicating that miR-33b may play a novel tumor suppressor role in the lipid-mediated oncogenic properties of metastatic ovarian cancer cells found in the omentum. Mechanistic studies demonstrated that miR-33b directly targets transforming growth factor beta-activated kinase 1 (TAK1), thereby suppressing the activities of fatty acid synthase (FASN) and carnitine palmitoyltransferase 1A (CPT1A) in modulating lipid metabolic activities and simultaneously inhibiting the phosphorylation of NF-κB signaling to govern the oncogenic behaviors of ovarian cancer cells. Thus, our data suggest that a lipid-rich microenvironment may cause epigenetic silencing of miR-33b, which negatively modulates ovarian cancer peritoneal metastases, at least in part, by suppressing TAK1/FASN/CPT1A/NF-κB signaling.
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spelling pubmed-85084652021-10-13 Epigenetic Silencing of miR-33b Promotes Peritoneal Metastases of Ovarian Cancer by Modulating the TAK1/FASN/CPT1A/NF-κB Axis Wang, Xueyu Yung, Mingo M. H. Sharma, Rakesh Chen, Fushun Poon, Ying-Tung Lam, Wai-Yip Li, Benjamin Ngan, Hextan Y. S. Chan, Karen K. L. Chan, David W. Cancers (Basel) Article SIMPLE SUMMARY: Omental metastasis and peritoneal dissemination are frequently observed in ovarian cancer peritoneal metastases and are associated with high mortality and poor prognosis. The tumor microenvironment is known to influence cancer epigenomics, which plays an essential role in promoting tumor development and metastatic progression. Therefore, investigation of the epigenetic mechanisms underlying the growth of ovarian cancer cells in the omental metastatic microenvironment is of great importance. Here, we report that miR-33b is significantly silenced by DNA hypermethylation in metastatic ovarian cancer cells to adapt to a lipid-rich microenvironment. Restoration of miR-33b was shown to impair lipid metabolic activities and reduce the oncogenic properties of ovarian cancer cells by negatively regulating the TAK1/FASN/CPT1A/NF-κB pathway, indicating that targeting this signaling cascade may be a molecular therapeutic choice for ovarian cancer metastatic progression. ABSTRACT: Peritoneal metastases are frequently found in high-grade serous carcinoma (HGSOC) patients and are commonly associated with a poor prognosis. The tumor microenvironment (TME) is a complex milieu that plays a critical role in epigenetic alterations driving tumor development and metastatic progression. However, the impact of epigenetic alterations on metastatic ovarian cancer cells in the harsh peritoneal microenvironment remains incompletely understood. Here, we identified that miR-33b is frequently silenced by promoter hypermethylation in HGSOC cells derived from metastatic omental tumor tissues. Enforced expression of miR-33b abrogates the oncogenic properties of ovarian cancer cells cocultured in omental conditioned medium (OCM), which mimics the ascites microenvironment, and in vivo tumor growth. Of note, restoration of miR-33b inhibited OCM-upregulated de novo lipogenesis and fatty acid β-oxidation in ovarian cancer cells, indicating that miR-33b may play a novel tumor suppressor role in the lipid-mediated oncogenic properties of metastatic ovarian cancer cells found in the omentum. Mechanistic studies demonstrated that miR-33b directly targets transforming growth factor beta-activated kinase 1 (TAK1), thereby suppressing the activities of fatty acid synthase (FASN) and carnitine palmitoyltransferase 1A (CPT1A) in modulating lipid metabolic activities and simultaneously inhibiting the phosphorylation of NF-κB signaling to govern the oncogenic behaviors of ovarian cancer cells. Thus, our data suggest that a lipid-rich microenvironment may cause epigenetic silencing of miR-33b, which negatively modulates ovarian cancer peritoneal metastases, at least in part, by suppressing TAK1/FASN/CPT1A/NF-κB signaling. MDPI 2021-09-24 /pmc/articles/PMC8508465/ /pubmed/34638280 http://dx.doi.org/10.3390/cancers13194795 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
Wang, Xueyu
Yung, Mingo M. H.
Sharma, Rakesh
Chen, Fushun
Poon, Ying-Tung
Lam, Wai-Yip
Li, Benjamin
Ngan, Hextan Y. S.
Chan, Karen K. L.
Chan, David W.
Epigenetic Silencing of miR-33b Promotes Peritoneal Metastases of Ovarian Cancer by Modulating the TAK1/FASN/CPT1A/NF-κB Axis
title Epigenetic Silencing of miR-33b Promotes Peritoneal Metastases of Ovarian Cancer by Modulating the TAK1/FASN/CPT1A/NF-κB Axis
title_full Epigenetic Silencing of miR-33b Promotes Peritoneal Metastases of Ovarian Cancer by Modulating the TAK1/FASN/CPT1A/NF-κB Axis
title_fullStr Epigenetic Silencing of miR-33b Promotes Peritoneal Metastases of Ovarian Cancer by Modulating the TAK1/FASN/CPT1A/NF-κB Axis
title_full_unstemmed Epigenetic Silencing of miR-33b Promotes Peritoneal Metastases of Ovarian Cancer by Modulating the TAK1/FASN/CPT1A/NF-κB Axis
title_short Epigenetic Silencing of miR-33b Promotes Peritoneal Metastases of Ovarian Cancer by Modulating the TAK1/FASN/CPT1A/NF-κB Axis
title_sort epigenetic silencing of mir-33b promotes peritoneal metastases of ovarian cancer by modulating the tak1/fasn/cpt1a/nf-κb axis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508465/
https://www.ncbi.nlm.nih.gov/pubmed/34638280
http://dx.doi.org/10.3390/cancers13194795
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