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Synaptotagmin 11 scaffolds MKK7–JNK signaling process to promote stem-like molecular subtype gastric cancer oncogenesis

BACKGROUND: Identifying biomarkers related to the diagnosis and treatment of gastric cancer (GC) has not made significant progress due to the heterogeneity of tumors. Genes involved in histological classification and genetic correlation studies are essential to develop an appropriate treatment for G...

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Autores principales: Kim, Bo-Kyung, Kim, Da-Mi, Park, Hyunkyung, Kim, Seon-Kyu, Hwang, Mi-Aie, Lee, Jungwoon, Kang, Mi-Jung, Byun, Jae-Eun, Im, Joo-Young, Kang, Minho, Park, Kyung Chan, Yeom, Young Il, Kim, Seon-Young, Jung, Haiyoung, Kweon, Dae-Hyuk, Cheong, Jae-Ho, Won, Misun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9241269/
https://www.ncbi.nlm.nih.gov/pubmed/35768842
http://dx.doi.org/10.1186/s13046-022-02420-3
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author Kim, Bo-Kyung
Kim, Da-Mi
Park, Hyunkyung
Kim, Seon-Kyu
Hwang, Mi-Aie
Lee, Jungwoon
Kang, Mi-Jung
Byun, Jae-Eun
Im, Joo-Young
Kang, Minho
Park, Kyung Chan
Yeom, Young Il
Kim, Seon-Young
Jung, Haiyoung
Kweon, Dae-Hyuk
Cheong, Jae-Ho
Won, Misun
author_facet Kim, Bo-Kyung
Kim, Da-Mi
Park, Hyunkyung
Kim, Seon-Kyu
Hwang, Mi-Aie
Lee, Jungwoon
Kang, Mi-Jung
Byun, Jae-Eun
Im, Joo-Young
Kang, Minho
Park, Kyung Chan
Yeom, Young Il
Kim, Seon-Young
Jung, Haiyoung
Kweon, Dae-Hyuk
Cheong, Jae-Ho
Won, Misun
author_sort Kim, Bo-Kyung
collection PubMed
description BACKGROUND: Identifying biomarkers related to the diagnosis and treatment of gastric cancer (GC) has not made significant progress due to the heterogeneity of tumors. Genes involved in histological classification and genetic correlation studies are essential to develop an appropriate treatment for GC. METHODS: In vitro and in vivo lentiviral shRNA library screening was performed. The expression of Synaptotagmin (SYT11) in the tumor tissues of patients with GC was confirmed by performing Immunohistochemistry, and the correlation between the expression level and the patient’s survival rate was analyzed. Phospho-kinase array was performed to detect Jun N-terminal kinase (JNK) phosphorylation. SYT11, JNK, and MKK7 complex formation was confirmed by western blot and immunoprecipitation assays. We studied the effects of SYT11 on GC proliferation and metastasis, real-time cell image analysis, adhesion assay, invasion assay, spheroid formation, mouse xenograft assay, and liver metastasis. RESULTS: SYT11 is highly expressed in the stem-like molecular subtype of GC in transcriptome analysis of 527 patients with GC. Moreover, SYT11 is a potential prognostic biomarker for histologically classified diffuse-type GC. SYT11 functions as a scaffold protein, binding both MKK7 and JNK1 signaling molecules that play a role in JNK1 phosphorylation. In turn, JNK activation leads to a signaling cascade resulting in cJun activation and expression of downstream genes angiopoietin-like 2 (ANGPTL2), thrombospondin 4 (THBS4), Vimentin, and junctional adhesion molecule 3 (JAM3), which play a role in epithelial-mesenchymal transition (EMT). SNU484 cells infected with SYT11 shRNA (shSYT11) exhibited reduced spheroid formation, mouse tumor formation, and liver metastasis, suggesting a pro-oncogenic role of SYT11. Furthermore, SYT11-antisense oligonucleotide (ASO) displayed antitumor activity in our mouse xenograft model and was conferred an anti-proliferative effect in SNU484 and MKN1 cells. CONCLUSION: SYT11 could be a potential therapeutic target as well as a prognostic biomarker in patients with diffuse-type GC, and SYT11-ASO could be used in therapeutic agent development for stem-like molecular subtype diffuse GC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-022-02420-3.
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spelling pubmed-92412692022-06-30 Synaptotagmin 11 scaffolds MKK7–JNK signaling process to promote stem-like molecular subtype gastric cancer oncogenesis Kim, Bo-Kyung Kim, Da-Mi Park, Hyunkyung Kim, Seon-Kyu Hwang, Mi-Aie Lee, Jungwoon Kang, Mi-Jung Byun, Jae-Eun Im, Joo-Young Kang, Minho Park, Kyung Chan Yeom, Young Il Kim, Seon-Young Jung, Haiyoung Kweon, Dae-Hyuk Cheong, Jae-Ho Won, Misun J Exp Clin Cancer Res Research BACKGROUND: Identifying biomarkers related to the diagnosis and treatment of gastric cancer (GC) has not made significant progress due to the heterogeneity of tumors. Genes involved in histological classification and genetic correlation studies are essential to develop an appropriate treatment for GC. METHODS: In vitro and in vivo lentiviral shRNA library screening was performed. The expression of Synaptotagmin (SYT11) in the tumor tissues of patients with GC was confirmed by performing Immunohistochemistry, and the correlation between the expression level and the patient’s survival rate was analyzed. Phospho-kinase array was performed to detect Jun N-terminal kinase (JNK) phosphorylation. SYT11, JNK, and MKK7 complex formation was confirmed by western blot and immunoprecipitation assays. We studied the effects of SYT11 on GC proliferation and metastasis, real-time cell image analysis, adhesion assay, invasion assay, spheroid formation, mouse xenograft assay, and liver metastasis. RESULTS: SYT11 is highly expressed in the stem-like molecular subtype of GC in transcriptome analysis of 527 patients with GC. Moreover, SYT11 is a potential prognostic biomarker for histologically classified diffuse-type GC. SYT11 functions as a scaffold protein, binding both MKK7 and JNK1 signaling molecules that play a role in JNK1 phosphorylation. In turn, JNK activation leads to a signaling cascade resulting in cJun activation and expression of downstream genes angiopoietin-like 2 (ANGPTL2), thrombospondin 4 (THBS4), Vimentin, and junctional adhesion molecule 3 (JAM3), which play a role in epithelial-mesenchymal transition (EMT). SNU484 cells infected with SYT11 shRNA (shSYT11) exhibited reduced spheroid formation, mouse tumor formation, and liver metastasis, suggesting a pro-oncogenic role of SYT11. Furthermore, SYT11-antisense oligonucleotide (ASO) displayed antitumor activity in our mouse xenograft model and was conferred an anti-proliferative effect in SNU484 and MKN1 cells. CONCLUSION: SYT11 could be a potential therapeutic target as well as a prognostic biomarker in patients with diffuse-type GC, and SYT11-ASO could be used in therapeutic agent development for stem-like molecular subtype diffuse GC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-022-02420-3. BioMed Central 2022-06-29 /pmc/articles/PMC9241269/ /pubmed/35768842 http://dx.doi.org/10.1186/s13046-022-02420-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Kim, Bo-Kyung
Kim, Da-Mi
Park, Hyunkyung
Kim, Seon-Kyu
Hwang, Mi-Aie
Lee, Jungwoon
Kang, Mi-Jung
Byun, Jae-Eun
Im, Joo-Young
Kang, Minho
Park, Kyung Chan
Yeom, Young Il
Kim, Seon-Young
Jung, Haiyoung
Kweon, Dae-Hyuk
Cheong, Jae-Ho
Won, Misun
Synaptotagmin 11 scaffolds MKK7–JNK signaling process to promote stem-like molecular subtype gastric cancer oncogenesis
title Synaptotagmin 11 scaffolds MKK7–JNK signaling process to promote stem-like molecular subtype gastric cancer oncogenesis
title_full Synaptotagmin 11 scaffolds MKK7–JNK signaling process to promote stem-like molecular subtype gastric cancer oncogenesis
title_fullStr Synaptotagmin 11 scaffolds MKK7–JNK signaling process to promote stem-like molecular subtype gastric cancer oncogenesis
title_full_unstemmed Synaptotagmin 11 scaffolds MKK7–JNK signaling process to promote stem-like molecular subtype gastric cancer oncogenesis
title_short Synaptotagmin 11 scaffolds MKK7–JNK signaling process to promote stem-like molecular subtype gastric cancer oncogenesis
title_sort synaptotagmin 11 scaffolds mkk7–jnk signaling process to promote stem-like molecular subtype gastric cancer oncogenesis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9241269/
https://www.ncbi.nlm.nih.gov/pubmed/35768842
http://dx.doi.org/10.1186/s13046-022-02420-3
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