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SDC2 Stabilization by USP14 Promotes Gastric Cancer Progression through Co-option of PDK1

Gastric cancer (GC) is a common malignancy and remains the fourth-leading cause of cancer-related deaths worldwide. Oncogenic potential of SDC2 has been implicated in multiple types of cancers, yet its role and underlying molecular mechanisms in GC remain unknown. Here, we found that SDC2 was highly...

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Autores principales: You, Li, Dou, Yi, Zhang, Yu, Xiao, Hongwei, Lv, Hong, Wei, Gong-Hong, Xu, Dazhi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10367555/
https://www.ncbi.nlm.nih.gov/pubmed/37496999
http://dx.doi.org/10.7150/ijbs.84331
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author You, Li
Dou, Yi
Zhang, Yu
Xiao, Hongwei
Lv, Hong
Wei, Gong-Hong
Xu, Dazhi
author_facet You, Li
Dou, Yi
Zhang, Yu
Xiao, Hongwei
Lv, Hong
Wei, Gong-Hong
Xu, Dazhi
author_sort You, Li
collection PubMed
description Gastric cancer (GC) is a common malignancy and remains the fourth-leading cause of cancer-related deaths worldwide. Oncogenic potential of SDC2 has been implicated in multiple types of cancers, yet its role and underlying molecular mechanisms in GC remain unknown. Here, we found that SDC2 was highly expressed in GC and its upregulation correlated with poor prognosis in GC patients. Depletion of SDC2 significantly suppressed the growth and invasive capability of GC cells, while overexpressing SDC2 exerts opposite effects. Combined bioinformatics and experimental analyses substantiated that overexpression of SDC2 activated the AKT signaling pathway in GC, mechanistically through the interaction between SDC2 and PDK1-PH domain, thereby facilitating PDK1 membrane translocation to promote AKT activation. Moreover, SDC2 could also function as a co-receptor for FGF2 and was profoundly involved in the FGF2-AKT signaling axis in GC. Lastly, we revealed a mechanism on the USP14-mediated stabilization of SDC2 that is likely to contribute to SDC2 upregulation in GC tissues. Furthermore, we showed that IU1, a potent USP14 inhibitor, decreased the abundance of SDC2 in GC cells. Our findings indicate that SDC2 functions as a novel GC oncogene and has potential utility as a diagnostic marker and therapeutic target for GC.
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spelling pubmed-103675552023-07-26 SDC2 Stabilization by USP14 Promotes Gastric Cancer Progression through Co-option of PDK1 You, Li Dou, Yi Zhang, Yu Xiao, Hongwei Lv, Hong Wei, Gong-Hong Xu, Dazhi Int J Biol Sci Research Paper Gastric cancer (GC) is a common malignancy and remains the fourth-leading cause of cancer-related deaths worldwide. Oncogenic potential of SDC2 has been implicated in multiple types of cancers, yet its role and underlying molecular mechanisms in GC remain unknown. Here, we found that SDC2 was highly expressed in GC and its upregulation correlated with poor prognosis in GC patients. Depletion of SDC2 significantly suppressed the growth and invasive capability of GC cells, while overexpressing SDC2 exerts opposite effects. Combined bioinformatics and experimental analyses substantiated that overexpression of SDC2 activated the AKT signaling pathway in GC, mechanistically through the interaction between SDC2 and PDK1-PH domain, thereby facilitating PDK1 membrane translocation to promote AKT activation. Moreover, SDC2 could also function as a co-receptor for FGF2 and was profoundly involved in the FGF2-AKT signaling axis in GC. Lastly, we revealed a mechanism on the USP14-mediated stabilization of SDC2 that is likely to contribute to SDC2 upregulation in GC tissues. Furthermore, we showed that IU1, a potent USP14 inhibitor, decreased the abundance of SDC2 in GC cells. Our findings indicate that SDC2 functions as a novel GC oncogene and has potential utility as a diagnostic marker and therapeutic target for GC. Ivyspring International Publisher 2023-07-09 /pmc/articles/PMC10367555/ /pubmed/37496999 http://dx.doi.org/10.7150/ijbs.84331 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
You, Li
Dou, Yi
Zhang, Yu
Xiao, Hongwei
Lv, Hong
Wei, Gong-Hong
Xu, Dazhi
SDC2 Stabilization by USP14 Promotes Gastric Cancer Progression through Co-option of PDK1
title SDC2 Stabilization by USP14 Promotes Gastric Cancer Progression through Co-option of PDK1
title_full SDC2 Stabilization by USP14 Promotes Gastric Cancer Progression through Co-option of PDK1
title_fullStr SDC2 Stabilization by USP14 Promotes Gastric Cancer Progression through Co-option of PDK1
title_full_unstemmed SDC2 Stabilization by USP14 Promotes Gastric Cancer Progression through Co-option of PDK1
title_short SDC2 Stabilization by USP14 Promotes Gastric Cancer Progression through Co-option of PDK1
title_sort sdc2 stabilization by usp14 promotes gastric cancer progression through co-option of pdk1
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10367555/
https://www.ncbi.nlm.nih.gov/pubmed/37496999
http://dx.doi.org/10.7150/ijbs.84331
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