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A stop-gain mutation in GXYLT1 promotes metastasis of colorectal cancer via the MAPK pathway

Genomic instability plays a key role in the initiation and progression of colorectal cancer (CRC). Although cancer driver genes in CRC have been well characterized, identifying novel genes associated with carcinogenesis and treatment remains challenging because of tumor heterogeneity. Here, we analy...

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Autores principales: Peng, Lin, Zhao, Min, Liu, Tianqi, Chen, Jiangbo, Gao, Pin, Chen, Lei, Xing, Pu, Wang, Zaozao, Di, Jiabo, Xu, Qiang, Qu, Hong, Jiang, Beihai, Su, Xiangqian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9033806/
https://www.ncbi.nlm.nih.gov/pubmed/35459861
http://dx.doi.org/10.1038/s41419-022-04844-3
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author Peng, Lin
Zhao, Min
Liu, Tianqi
Chen, Jiangbo
Gao, Pin
Chen, Lei
Xing, Pu
Wang, Zaozao
Di, Jiabo
Xu, Qiang
Qu, Hong
Jiang, Beihai
Su, Xiangqian
author_facet Peng, Lin
Zhao, Min
Liu, Tianqi
Chen, Jiangbo
Gao, Pin
Chen, Lei
Xing, Pu
Wang, Zaozao
Di, Jiabo
Xu, Qiang
Qu, Hong
Jiang, Beihai
Su, Xiangqian
author_sort Peng, Lin
collection PubMed
description Genomic instability plays a key role in the initiation and progression of colorectal cancer (CRC). Although cancer driver genes in CRC have been well characterized, identifying novel genes associated with carcinogenesis and treatment remains challenging because of tumor heterogeneity. Here, we analyzed the genomic alterations of 45 samples from CRC patients in northern China by whole-exome sequencing. In addition to the identification of six well-known CRC driver genes (APC, TP53, KRAS, FBXW7, PIK3CA, and PABPC), two tumor-related genes (MTCH2 and HSPA6) were detected, along with RRP7A and GXYLT1, which have not been previously linked to cancer. GXYLT1 was mutated in 40% (18/45) of the samples in our cohort. Functionally, GXYLT1 promoted migration and invasion in vitro and metastasis in vivo, while the GXYLT1(S212*) mutant induced significantly greater effect. Furthermore, both GXYLT1 and GXYLT1(S212*) interacted with ERK2. GXYLT1 induced metastasis via a mechanism involving the Notch and MAPK pathways, whereas the GXYLT1(S212*) mutant mainly promoted metastasis by activating the MAPK pathway. We propose that GXYLT1 acts as a novel metastasis-associated driver gene and GXYLT1(S212*) might serve as a potential indicator for therapies targeting the MAPK pathway in CRC.
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spelling pubmed-90338062022-04-28 A stop-gain mutation in GXYLT1 promotes metastasis of colorectal cancer via the MAPK pathway Peng, Lin Zhao, Min Liu, Tianqi Chen, Jiangbo Gao, Pin Chen, Lei Xing, Pu Wang, Zaozao Di, Jiabo Xu, Qiang Qu, Hong Jiang, Beihai Su, Xiangqian Cell Death Dis Article Genomic instability plays a key role in the initiation and progression of colorectal cancer (CRC). Although cancer driver genes in CRC have been well characterized, identifying novel genes associated with carcinogenesis and treatment remains challenging because of tumor heterogeneity. Here, we analyzed the genomic alterations of 45 samples from CRC patients in northern China by whole-exome sequencing. In addition to the identification of six well-known CRC driver genes (APC, TP53, KRAS, FBXW7, PIK3CA, and PABPC), two tumor-related genes (MTCH2 and HSPA6) were detected, along with RRP7A and GXYLT1, which have not been previously linked to cancer. GXYLT1 was mutated in 40% (18/45) of the samples in our cohort. Functionally, GXYLT1 promoted migration and invasion in vitro and metastasis in vivo, while the GXYLT1(S212*) mutant induced significantly greater effect. Furthermore, both GXYLT1 and GXYLT1(S212*) interacted with ERK2. GXYLT1 induced metastasis via a mechanism involving the Notch and MAPK pathways, whereas the GXYLT1(S212*) mutant mainly promoted metastasis by activating the MAPK pathway. We propose that GXYLT1 acts as a novel metastasis-associated driver gene and GXYLT1(S212*) might serve as a potential indicator for therapies targeting the MAPK pathway in CRC. Nature Publishing Group UK 2022-04-22 /pmc/articles/PMC9033806/ /pubmed/35459861 http://dx.doi.org/10.1038/s41419-022-04844-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Peng, Lin
Zhao, Min
Liu, Tianqi
Chen, Jiangbo
Gao, Pin
Chen, Lei
Xing, Pu
Wang, Zaozao
Di, Jiabo
Xu, Qiang
Qu, Hong
Jiang, Beihai
Su, Xiangqian
A stop-gain mutation in GXYLT1 promotes metastasis of colorectal cancer via the MAPK pathway
title A stop-gain mutation in GXYLT1 promotes metastasis of colorectal cancer via the MAPK pathway
title_full A stop-gain mutation in GXYLT1 promotes metastasis of colorectal cancer via the MAPK pathway
title_fullStr A stop-gain mutation in GXYLT1 promotes metastasis of colorectal cancer via the MAPK pathway
title_full_unstemmed A stop-gain mutation in GXYLT1 promotes metastasis of colorectal cancer via the MAPK pathway
title_short A stop-gain mutation in GXYLT1 promotes metastasis of colorectal cancer via the MAPK pathway
title_sort stop-gain mutation in gxylt1 promotes metastasis of colorectal cancer via the mapk pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9033806/
https://www.ncbi.nlm.nih.gov/pubmed/35459861
http://dx.doi.org/10.1038/s41419-022-04844-3
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