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LRP6 targeting suppresses gastric tumorigenesis via P14(ARF)–Mdm2–P53-dependent cellular senescence

NLRP6, a member of the Nod-like receptor family, protects against chemically induced intestinal injury and colitis-associated colon cancer. However, the cellular mechanisms involved in this NLRP6-mediated protection remain unclear. Here, we show that NLRP6 was down-regulated in approximately 75% of...

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Autores principales: Wang, Haibin, Xu, Guoxing, Huang, Zhengjie, Li, Weizheng, Cai, Huali, Zhang, Yunda, Xiong, Disheng, Liu, Gang, Wang, Shengjie, Xue, Zengfu, Luo, Qi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762345/
https://www.ncbi.nlm.nih.gov/pubmed/29340077
http://dx.doi.org/10.18632/oncotarget.22876
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author Wang, Haibin
Xu, Guoxing
Huang, Zhengjie
Li, Weizheng
Cai, Huali
Zhang, Yunda
Xiong, Disheng
Liu, Gang
Wang, Shengjie
Xue, Zengfu
Luo, Qi
author_facet Wang, Haibin
Xu, Guoxing
Huang, Zhengjie
Li, Weizheng
Cai, Huali
Zhang, Yunda
Xiong, Disheng
Liu, Gang
Wang, Shengjie
Xue, Zengfu
Luo, Qi
author_sort Wang, Haibin
collection PubMed
description NLRP6, a member of the Nod-like receptor family, protects against chemically induced intestinal injury and colitis-associated colon cancer. However, the cellular mechanisms involved in this NLRP6-mediated protection remain unclear. Here, we show that NLRP6 was down-regulated in approximately 75% of primary gastric cancer cases and exhibited significant associations with advanced clinical-stage lymph node metastasis and poor overall survival. Functional studies established that ectopic overexpression or down-regulation of NLRP6 inhibited cancer cell proliferation by inducing cell cycle arrest at the G1 phase via P21 and Cyclin D1 both in vitro and in vivo. Activation of the P14(ARF)-P53 pathway played a crucial role in the observed cellular senescence. We further demonstrated that ectopic overexpression of NLRP6 combined with inactivation of NF-κB(p65) and Mdm2 activates P14(ARF)-P53 to promote the senescence of gastric cancer cells. These findings indicate that NLRP6 functions as a negative regulator of gastric cancer and offer a potential new option for preventing gastric cancer.
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spelling pubmed-57623452018-01-16 LRP6 targeting suppresses gastric tumorigenesis via P14(ARF)–Mdm2–P53-dependent cellular senescence Wang, Haibin Xu, Guoxing Huang, Zhengjie Li, Weizheng Cai, Huali Zhang, Yunda Xiong, Disheng Liu, Gang Wang, Shengjie Xue, Zengfu Luo, Qi Oncotarget Research Paper NLRP6, a member of the Nod-like receptor family, protects against chemically induced intestinal injury and colitis-associated colon cancer. However, the cellular mechanisms involved in this NLRP6-mediated protection remain unclear. Here, we show that NLRP6 was down-regulated in approximately 75% of primary gastric cancer cases and exhibited significant associations with advanced clinical-stage lymph node metastasis and poor overall survival. Functional studies established that ectopic overexpression or down-regulation of NLRP6 inhibited cancer cell proliferation by inducing cell cycle arrest at the G1 phase via P21 and Cyclin D1 both in vitro and in vivo. Activation of the P14(ARF)-P53 pathway played a crucial role in the observed cellular senescence. We further demonstrated that ectopic overexpression of NLRP6 combined with inactivation of NF-κB(p65) and Mdm2 activates P14(ARF)-P53 to promote the senescence of gastric cancer cells. These findings indicate that NLRP6 functions as a negative regulator of gastric cancer and offer a potential new option for preventing gastric cancer. Impact Journals LLC 2017-12-04 /pmc/articles/PMC5762345/ /pubmed/29340077 http://dx.doi.org/10.18632/oncotarget.22876 Text en Copyright: © 2017 Wang et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Wang, Haibin
Xu, Guoxing
Huang, Zhengjie
Li, Weizheng
Cai, Huali
Zhang, Yunda
Xiong, Disheng
Liu, Gang
Wang, Shengjie
Xue, Zengfu
Luo, Qi
LRP6 targeting suppresses gastric tumorigenesis via P14(ARF)–Mdm2–P53-dependent cellular senescence
title LRP6 targeting suppresses gastric tumorigenesis via P14(ARF)–Mdm2–P53-dependent cellular senescence
title_full LRP6 targeting suppresses gastric tumorigenesis via P14(ARF)–Mdm2–P53-dependent cellular senescence
title_fullStr LRP6 targeting suppresses gastric tumorigenesis via P14(ARF)–Mdm2–P53-dependent cellular senescence
title_full_unstemmed LRP6 targeting suppresses gastric tumorigenesis via P14(ARF)–Mdm2–P53-dependent cellular senescence
title_short LRP6 targeting suppresses gastric tumorigenesis via P14(ARF)–Mdm2–P53-dependent cellular senescence
title_sort lrp6 targeting suppresses gastric tumorigenesis via p14(arf)–mdm2–p53-dependent cellular senescence
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762345/
https://www.ncbi.nlm.nih.gov/pubmed/29340077
http://dx.doi.org/10.18632/oncotarget.22876
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