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Anti-Tumor Role of CAMK2B in Remodeling the Stromal Microenvironment and Inhibiting Proliferation in Papillary Renal Cell Carcinoma

The tumor microenvironment (TME) is variable across tumor types and has diverse effects on malignant progression, based on the type and number of infiltrating stromal cells. In particular, TME effector genes and their competitive endogenous RNA (ceRNA) networks play a critical role in regulating mal...

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Autores principales: Jia, Qingan, Liao, Xia, Zhang, Yaoyao, Xu, Binghui, Song, Yuna, Bian, Ganlan, Fu, Xiaoliang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8815460/
https://www.ncbi.nlm.nih.gov/pubmed/35127542
http://dx.doi.org/10.3389/fonc.2022.740051
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author Jia, Qingan
Liao, Xia
Zhang, Yaoyao
Xu, Binghui
Song, Yuna
Bian, Ganlan
Fu, Xiaoliang
author_facet Jia, Qingan
Liao, Xia
Zhang, Yaoyao
Xu, Binghui
Song, Yuna
Bian, Ganlan
Fu, Xiaoliang
author_sort Jia, Qingan
collection PubMed
description The tumor microenvironment (TME) is variable across tumor types and has diverse effects on malignant progression, based on the type and number of infiltrating stromal cells. In particular, TME effector genes and their competitive endogenous RNA (ceRNA) networks play a critical role in regulating malignant tumor progression. However, the core effector molecules involved in TME modulation of kidney renal papillary cell carcinoma (KIRP) are poorly understood. To address this question, a cohort containing 233 KIRP patients was derived from The Cancer Genome Atlas (TCGA) database, and the data were processed using the ESTIMATE algorithm. We further evaluated the relationship between immune scores (ISs) and stromal scores (SSs) and disease progression and found that high SSs were associated with a poor prognosis in KIRP. Differentially expressed genes (DEGs) were therefore screened based on SS scores, resulting in 2509 DEGs, including 1668 mRNAs, 783 long noncoding (lnc)RNAs, and 58 micro (mi)RNAs. DEGs were then filtered using the random variance and subjected to hierarchical clustering using EPCLUST. Weighted gene co-expression network analysis (WGCNA) was used to assess the prognostic capacity of these DEGs and identify target ceRNA networks, and lncRNA GUSBP11/miR-432-5p/CAMK2B in the turquoise module was selected as a promising ceRNA network. From this analysis CAMK2B was selected as the core gene predicted to be involved in stromal TMA regulation. We therefore explored the expression and function of CAMK2B in vitro and in vivo and provide evidence that this protein promotes stromal TME remodulation and inhibits proliferation in KIRP. Lastly, we show that vascular endothelial growth factor (VEGF), transforming growth factor (TGF)β, and close homolog of L1 (CHL1) act as downstream effectors of CAMK2B in KIRP. Thus, in this study, we show that the TME determines prognosis of KIRP patients via the core effector molecule CAMK2B, which mediates both microenvironmental remodeling and tumor progression. Based on these findings, we propose that remodeling of the stromal microenvironment could represent an improved therapeutic approach relative to immunotherapy for KIRP.
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spelling pubmed-88154602022-02-05 Anti-Tumor Role of CAMK2B in Remodeling the Stromal Microenvironment and Inhibiting Proliferation in Papillary Renal Cell Carcinoma Jia, Qingan Liao, Xia Zhang, Yaoyao Xu, Binghui Song, Yuna Bian, Ganlan Fu, Xiaoliang Front Oncol Oncology The tumor microenvironment (TME) is variable across tumor types and has diverse effects on malignant progression, based on the type and number of infiltrating stromal cells. In particular, TME effector genes and their competitive endogenous RNA (ceRNA) networks play a critical role in regulating malignant tumor progression. However, the core effector molecules involved in TME modulation of kidney renal papillary cell carcinoma (KIRP) are poorly understood. To address this question, a cohort containing 233 KIRP patients was derived from The Cancer Genome Atlas (TCGA) database, and the data were processed using the ESTIMATE algorithm. We further evaluated the relationship between immune scores (ISs) and stromal scores (SSs) and disease progression and found that high SSs were associated with a poor prognosis in KIRP. Differentially expressed genes (DEGs) were therefore screened based on SS scores, resulting in 2509 DEGs, including 1668 mRNAs, 783 long noncoding (lnc)RNAs, and 58 micro (mi)RNAs. DEGs were then filtered using the random variance and subjected to hierarchical clustering using EPCLUST. Weighted gene co-expression network analysis (WGCNA) was used to assess the prognostic capacity of these DEGs and identify target ceRNA networks, and lncRNA GUSBP11/miR-432-5p/CAMK2B in the turquoise module was selected as a promising ceRNA network. From this analysis CAMK2B was selected as the core gene predicted to be involved in stromal TMA regulation. We therefore explored the expression and function of CAMK2B in vitro and in vivo and provide evidence that this protein promotes stromal TME remodulation and inhibits proliferation in KIRP. Lastly, we show that vascular endothelial growth factor (VEGF), transforming growth factor (TGF)β, and close homolog of L1 (CHL1) act as downstream effectors of CAMK2B in KIRP. Thus, in this study, we show that the TME determines prognosis of KIRP patients via the core effector molecule CAMK2B, which mediates both microenvironmental remodeling and tumor progression. Based on these findings, we propose that remodeling of the stromal microenvironment could represent an improved therapeutic approach relative to immunotherapy for KIRP. Frontiers Media S.A. 2022-01-21 /pmc/articles/PMC8815460/ /pubmed/35127542 http://dx.doi.org/10.3389/fonc.2022.740051 Text en Copyright © 2022 Jia, Liao, Zhang, Xu, Song, Bian and Fu https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Jia, Qingan
Liao, Xia
Zhang, Yaoyao
Xu, Binghui
Song, Yuna
Bian, Ganlan
Fu, Xiaoliang
Anti-Tumor Role of CAMK2B in Remodeling the Stromal Microenvironment and Inhibiting Proliferation in Papillary Renal Cell Carcinoma
title Anti-Tumor Role of CAMK2B in Remodeling the Stromal Microenvironment and Inhibiting Proliferation in Papillary Renal Cell Carcinoma
title_full Anti-Tumor Role of CAMK2B in Remodeling the Stromal Microenvironment and Inhibiting Proliferation in Papillary Renal Cell Carcinoma
title_fullStr Anti-Tumor Role of CAMK2B in Remodeling the Stromal Microenvironment and Inhibiting Proliferation in Papillary Renal Cell Carcinoma
title_full_unstemmed Anti-Tumor Role of CAMK2B in Remodeling the Stromal Microenvironment and Inhibiting Proliferation in Papillary Renal Cell Carcinoma
title_short Anti-Tumor Role of CAMK2B in Remodeling the Stromal Microenvironment and Inhibiting Proliferation in Papillary Renal Cell Carcinoma
title_sort anti-tumor role of camk2b in remodeling the stromal microenvironment and inhibiting proliferation in papillary renal cell carcinoma
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8815460/
https://www.ncbi.nlm.nih.gov/pubmed/35127542
http://dx.doi.org/10.3389/fonc.2022.740051
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