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CD44ICD promotes breast cancer stemness via PFKFB4-mediated glucose metabolism

CD44 is a single-pass cell surface glycoprotein that is distinguished as the first molecule used to identify cancer stem cells in solid tumors based on its expression. In this regard, the CD44(high) cell population demonstrates not only the ability to regenerate a heterogeneous tumor, but also the a...

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Autores principales: Gao, Ruifang, Li, Dan, Xun, Jing, Zhou, Wei, Li, Jun, Wang, Juan, Liu, Chen, Li, Xiru, Shen, Wenzhi, Qiao, Huan, Stupack, Dwayne G., Luo, Na
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299690/
https://www.ncbi.nlm.nih.gov/pubmed/30613295
http://dx.doi.org/10.7150/thno.28721
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author Gao, Ruifang
Li, Dan
Xun, Jing
Zhou, Wei
Li, Jun
Wang, Juan
Liu, Chen
Li, Xiru
Shen, Wenzhi
Qiao, Huan
Stupack, Dwayne G.
Luo, Na
author_facet Gao, Ruifang
Li, Dan
Xun, Jing
Zhou, Wei
Li, Jun
Wang, Juan
Liu, Chen
Li, Xiru
Shen, Wenzhi
Qiao, Huan
Stupack, Dwayne G.
Luo, Na
author_sort Gao, Ruifang
collection PubMed
description CD44 is a single-pass cell surface glycoprotein that is distinguished as the first molecule used to identify cancer stem cells in solid tumors based on its expression. In this regard, the CD44(high) cell population demonstrates not only the ability to regenerate a heterogeneous tumor, but also the ability to self-regenerate when transplanted into immune-deficient mice. However, the exact role of CD44 in cancer stem cells remains unclear in part because CD44 exists in various isoforms due to alternative splicing. Methods: Gain- and loss-of-function methods in different models were used to investigate the effects of CD44 on breast cancer stemness. Cancer stemness was analyzed by detecting SOX2, OCT4 and NANOG expression, ALDH activity, side population (SP) and sphere formation. Glucose consumption, lactate secretion and reactive oxygen species (ROS) levels were detected to assess glycolysis. Western blot, immunohistochemical staining, ELISA and TCGA dataset analysis were performed to determine the association of CD44ICD and PFKFB4 with clinical cases. A PFKFB4 inhibitor, 5MPN, was used in a xenograft model to inhibit breast cancer development. Results: In this report, we found that the shortest CD44 isoform (CD44s) inhibits breast cancer stemness, whereas the cleaved product of CD44 (CD44ICD) promotes breast cancer stemness. Furthermore, CD44ICD interacts with CREB and binds to the promoter region of PFKFB4, thereby regulating PFKFB4 transcription and expression. The resultant PFKFB4 expression facilitates the glycolysis pathway (vis-à-vis oxidative phosphorylation) and promotes stemness of breast cancer. In addition, we found that CD44ICD and PFKFB4 expressions are generally up-regulated in the tumor portion of breast cancer patient samples. Most importantly, we found that 5MPN (a selective inhibitor of PFKFB4) suppresses CD44ICD-induced tumor development. Conclusion: CD44ICD promotes breast cancer stemness via PFKFB4-mediated glycolysis, and therapies that target PFKFB4 (e.g., 5MPN therapy) may lead to improved outcomes for cancer patients.
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spelling pubmed-62996902019-01-04 CD44ICD promotes breast cancer stemness via PFKFB4-mediated glucose metabolism Gao, Ruifang Li, Dan Xun, Jing Zhou, Wei Li, Jun Wang, Juan Liu, Chen Li, Xiru Shen, Wenzhi Qiao, Huan Stupack, Dwayne G. Luo, Na Theranostics Research Paper CD44 is a single-pass cell surface glycoprotein that is distinguished as the first molecule used to identify cancer stem cells in solid tumors based on its expression. In this regard, the CD44(high) cell population demonstrates not only the ability to regenerate a heterogeneous tumor, but also the ability to self-regenerate when transplanted into immune-deficient mice. However, the exact role of CD44 in cancer stem cells remains unclear in part because CD44 exists in various isoforms due to alternative splicing. Methods: Gain- and loss-of-function methods in different models were used to investigate the effects of CD44 on breast cancer stemness. Cancer stemness was analyzed by detecting SOX2, OCT4 and NANOG expression, ALDH activity, side population (SP) and sphere formation. Glucose consumption, lactate secretion and reactive oxygen species (ROS) levels were detected to assess glycolysis. Western blot, immunohistochemical staining, ELISA and TCGA dataset analysis were performed to determine the association of CD44ICD and PFKFB4 with clinical cases. A PFKFB4 inhibitor, 5MPN, was used in a xenograft model to inhibit breast cancer development. Results: In this report, we found that the shortest CD44 isoform (CD44s) inhibits breast cancer stemness, whereas the cleaved product of CD44 (CD44ICD) promotes breast cancer stemness. Furthermore, CD44ICD interacts with CREB and binds to the promoter region of PFKFB4, thereby regulating PFKFB4 transcription and expression. The resultant PFKFB4 expression facilitates the glycolysis pathway (vis-à-vis oxidative phosphorylation) and promotes stemness of breast cancer. In addition, we found that CD44ICD and PFKFB4 expressions are generally up-regulated in the tumor portion of breast cancer patient samples. Most importantly, we found that 5MPN (a selective inhibitor of PFKFB4) suppresses CD44ICD-induced tumor development. Conclusion: CD44ICD promotes breast cancer stemness via PFKFB4-mediated glycolysis, and therapies that target PFKFB4 (e.g., 5MPN therapy) may lead to improved outcomes for cancer patients. Ivyspring International Publisher 2018-11-29 /pmc/articles/PMC6299690/ /pubmed/30613295 http://dx.doi.org/10.7150/thno.28721 Text en © Ivyspring International Publisher This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Gao, Ruifang
Li, Dan
Xun, Jing
Zhou, Wei
Li, Jun
Wang, Juan
Liu, Chen
Li, Xiru
Shen, Wenzhi
Qiao, Huan
Stupack, Dwayne G.
Luo, Na
CD44ICD promotes breast cancer stemness via PFKFB4-mediated glucose metabolism
title CD44ICD promotes breast cancer stemness via PFKFB4-mediated glucose metabolism
title_full CD44ICD promotes breast cancer stemness via PFKFB4-mediated glucose metabolism
title_fullStr CD44ICD promotes breast cancer stemness via PFKFB4-mediated glucose metabolism
title_full_unstemmed CD44ICD promotes breast cancer stemness via PFKFB4-mediated glucose metabolism
title_short CD44ICD promotes breast cancer stemness via PFKFB4-mediated glucose metabolism
title_sort cd44icd promotes breast cancer stemness via pfkfb4-mediated glucose metabolism
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299690/
https://www.ncbi.nlm.nih.gov/pubmed/30613295
http://dx.doi.org/10.7150/thno.28721
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