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LKB1 Inhibits Breast Cancer Partially through Repressing the Hedgehog Signaling Pathway

Constitutive activation of the Hedgehog (Hh) signaling pathway has been implicated in the development of many human malignancies. Hh targets, such as Patched (PTCH), smoothened (SMO), Sonic hedgehog (SHH) and glioma-associated oncogene homologue 1 (GLI1), are markers of Hh signaling activation and e...

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Autores principales: Zhuang, Zhigang, Wang, Kai, Cheng, Xiaolin, Qu, Xueying, Jiang, Beiqi, Li, Zhengdong, Luo, Jianming, Shao, Zhiming, Duan, Tao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3701543/
https://www.ncbi.nlm.nih.gov/pubmed/23861764
http://dx.doi.org/10.1371/journal.pone.0067431
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author Zhuang, Zhigang
Wang, Kai
Cheng, Xiaolin
Qu, Xueying
Jiang, Beiqi
Li, Zhengdong
Luo, Jianming
Shao, Zhiming
Duan, Tao
author_facet Zhuang, Zhigang
Wang, Kai
Cheng, Xiaolin
Qu, Xueying
Jiang, Beiqi
Li, Zhengdong
Luo, Jianming
Shao, Zhiming
Duan, Tao
author_sort Zhuang, Zhigang
collection PubMed
description Constitutive activation of the Hedgehog (Hh) signaling pathway has been implicated in the development of many human malignancies. Hh targets, such as Patched (PTCH), smoothened (SMO), Sonic hedgehog (SHH) and glioma-associated oncogene homologue 1 (GLI1), are markers of Hh signaling activation and expressed in most Hh-associated tumors. The protein kinase LKB1 has been shown to slow proliferation and induce cell-cycle arrest in many cell lines. In this study, we observed that activated LKB1 decreased the expression of factors related to Hh reporter activity in MDA-MB-231 breast cancer cells, including of SMO, SHH and GLI1. In contrast, LKB1 siRNA increased the expression of these target genes. The same results were shown to inhibit the Hh factors Sufu and Hip. Furthermore, we also observed negative correlation between LKB1 and glioma-associated oncogene homologue 1 (GLI1) in three breast cancer cell lines. Meanwhile, LKB1 siRNA rescued the inhibition of cell growth by 3-Keto-N-(aminoethyl-N'-aminocaproyldihydrocinnamoyl) cyclopamine (KAAD-cyclopamine), an antagonist of the Hh element SMO, which suggests that LKB1 acts as the downstream of SMO. In vivo, LKB1 siRNA increased tumor growth in the mammary fat pad, and the expression levels of Hh displayed similar results in vitro. Overexpression of the LKB1 protein in human breast cancers is associated with the expression of Hh. We found that breast carcinomas with detectable Hh had weak or undetectable expression of LKB1, whereas tumors that expressed high levels of LKB1 had undetectable Hh signaling. In this study, we find that LKB1 are negatively correlated with the expression of Hh related transcription factors. These findings suggest that LKB1 may inhibit tumorigenesis by regulating Hh signaling in certain cancers.
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spelling pubmed-37015432013-07-16 LKB1 Inhibits Breast Cancer Partially through Repressing the Hedgehog Signaling Pathway Zhuang, Zhigang Wang, Kai Cheng, Xiaolin Qu, Xueying Jiang, Beiqi Li, Zhengdong Luo, Jianming Shao, Zhiming Duan, Tao PLoS One Research Article Constitutive activation of the Hedgehog (Hh) signaling pathway has been implicated in the development of many human malignancies. Hh targets, such as Patched (PTCH), smoothened (SMO), Sonic hedgehog (SHH) and glioma-associated oncogene homologue 1 (GLI1), are markers of Hh signaling activation and expressed in most Hh-associated tumors. The protein kinase LKB1 has been shown to slow proliferation and induce cell-cycle arrest in many cell lines. In this study, we observed that activated LKB1 decreased the expression of factors related to Hh reporter activity in MDA-MB-231 breast cancer cells, including of SMO, SHH and GLI1. In contrast, LKB1 siRNA increased the expression of these target genes. The same results were shown to inhibit the Hh factors Sufu and Hip. Furthermore, we also observed negative correlation between LKB1 and glioma-associated oncogene homologue 1 (GLI1) in three breast cancer cell lines. Meanwhile, LKB1 siRNA rescued the inhibition of cell growth by 3-Keto-N-(aminoethyl-N'-aminocaproyldihydrocinnamoyl) cyclopamine (KAAD-cyclopamine), an antagonist of the Hh element SMO, which suggests that LKB1 acts as the downstream of SMO. In vivo, LKB1 siRNA increased tumor growth in the mammary fat pad, and the expression levels of Hh displayed similar results in vitro. Overexpression of the LKB1 protein in human breast cancers is associated with the expression of Hh. We found that breast carcinomas with detectable Hh had weak or undetectable expression of LKB1, whereas tumors that expressed high levels of LKB1 had undetectable Hh signaling. In this study, we find that LKB1 are negatively correlated with the expression of Hh related transcription factors. These findings suggest that LKB1 may inhibit tumorigenesis by regulating Hh signaling in certain cancers. Public Library of Science 2013-07-04 /pmc/articles/PMC3701543/ /pubmed/23861764 http://dx.doi.org/10.1371/journal.pone.0067431 Text en © 2013 Zhuang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Zhuang, Zhigang
Wang, Kai
Cheng, Xiaolin
Qu, Xueying
Jiang, Beiqi
Li, Zhengdong
Luo, Jianming
Shao, Zhiming
Duan, Tao
LKB1 Inhibits Breast Cancer Partially through Repressing the Hedgehog Signaling Pathway
title LKB1 Inhibits Breast Cancer Partially through Repressing the Hedgehog Signaling Pathway
title_full LKB1 Inhibits Breast Cancer Partially through Repressing the Hedgehog Signaling Pathway
title_fullStr LKB1 Inhibits Breast Cancer Partially through Repressing the Hedgehog Signaling Pathway
title_full_unstemmed LKB1 Inhibits Breast Cancer Partially through Repressing the Hedgehog Signaling Pathway
title_short LKB1 Inhibits Breast Cancer Partially through Repressing the Hedgehog Signaling Pathway
title_sort lkb1 inhibits breast cancer partially through repressing the hedgehog signaling pathway
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3701543/
https://www.ncbi.nlm.nih.gov/pubmed/23861764
http://dx.doi.org/10.1371/journal.pone.0067431
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