Cargando…
Interleukin4Rα (IL4Rα) and IL13Rα1 Are Associated with the Progress of Renal Cell Carcinoma through Janus Kinase 2 (JAK2)/Forkhead Box O3 (FOXO3) Pathways
Specific kinds of interleukin (IL) receptors are known to mediate lymphocyte proliferation and survival. However, recent reports have suggested that the high expression of IL4Rα and IL13Rα1 in tumor tissue might be associated with tumorigenesis in several kinds of tumor. We found that a significant...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770213/ https://www.ncbi.nlm.nih.gov/pubmed/31540495 http://dx.doi.org/10.3390/cancers11091394 |
_version_ | 1783455419086143488 |
---|---|
author | Kang, Mi-Ae Lee, Jongsung Ha, Sang Hoon Lee, Chang Min Kim, Kyoung Min Jang, Kyu Yun Park, See-Hyoung |
author_facet | Kang, Mi-Ae Lee, Jongsung Ha, Sang Hoon Lee, Chang Min Kim, Kyoung Min Jang, Kyu Yun Park, See-Hyoung |
author_sort | Kang, Mi-Ae |
collection | PubMed |
description | Specific kinds of interleukin (IL) receptors are known to mediate lymphocyte proliferation and survival. However, recent reports have suggested that the high expression of IL4Rα and IL13Rα1 in tumor tissue might be associated with tumorigenesis in several kinds of tumor. We found that a significant association between mRNA level of IL4Rα or IL13Rα1 and the poor prognosis of renal cell carcinoma (RCC) from the public database (http://www.oncolnc.org/). Then, we evaluated the clinicopathological significance of the immunohistochemical expression of IL4Rα and IL13Rα1 in 199 clear cell RCC (CCRCC) patients. The individual and co-expression patterns of IL4Rα and IL13Rα1 were significantly associated with cancer-specific survival (CSS) and relapse-free survival (RFS) in univariate analysis. Multivariate analysis indicated IL4Rα-positivity and co-expression of IL4Rα and IL13Rα1 as the independent indicators of shorter CSS and RFS of CCRCC patients. For the in vitro evaluation of the oncogenic role of IL4Rα and IL13Rα1 in RCC, we knock-downed IL4Rα or IL13Rα1 and observed that the cell proliferation rate was decreased, and the apoptosis rate was increased in A498 and ACHN cells. Furthermore, we examined the possible role of Janus kinase 2 (JAK2), well-known down-stream tyrosine kinase under the heterodimeric receptor complex of IL4Rα and IL13Rα1. Interestingly, JAK2 interacted with Forkhead box O3 (FOXO3) to cause tyrosine-phosphorylation of FOXO3. Silencing IL4Rα or JAK2 in A498 and ACHN cells reduced the interaction between JAK2 and FOXO3. Moreover, pharmacological inhibition of JAK2 induced the nuclear localization of FOXO3, leading to increase apoptosis and decrease cell proliferation rate in A498 and ACHN cells. Taken together, these results suggest that IL4Rα and IL13Rα1 might be involved in the progression of RCC through JAK2/FOXO3 pathway, and their expression might be used as the novel prognostic factor and therapeutic target for RCC patients. |
format | Online Article Text |
id | pubmed-6770213 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-67702132019-10-30 Interleukin4Rα (IL4Rα) and IL13Rα1 Are Associated with the Progress of Renal Cell Carcinoma through Janus Kinase 2 (JAK2)/Forkhead Box O3 (FOXO3) Pathways Kang, Mi-Ae Lee, Jongsung Ha, Sang Hoon Lee, Chang Min Kim, Kyoung Min Jang, Kyu Yun Park, See-Hyoung Cancers (Basel) Article Specific kinds of interleukin (IL) receptors are known to mediate lymphocyte proliferation and survival. However, recent reports have suggested that the high expression of IL4Rα and IL13Rα1 in tumor tissue might be associated with tumorigenesis in several kinds of tumor. We found that a significant association between mRNA level of IL4Rα or IL13Rα1 and the poor prognosis of renal cell carcinoma (RCC) from the public database (http://www.oncolnc.org/). Then, we evaluated the clinicopathological significance of the immunohistochemical expression of IL4Rα and IL13Rα1 in 199 clear cell RCC (CCRCC) patients. The individual and co-expression patterns of IL4Rα and IL13Rα1 were significantly associated with cancer-specific survival (CSS) and relapse-free survival (RFS) in univariate analysis. Multivariate analysis indicated IL4Rα-positivity and co-expression of IL4Rα and IL13Rα1 as the independent indicators of shorter CSS and RFS of CCRCC patients. For the in vitro evaluation of the oncogenic role of IL4Rα and IL13Rα1 in RCC, we knock-downed IL4Rα or IL13Rα1 and observed that the cell proliferation rate was decreased, and the apoptosis rate was increased in A498 and ACHN cells. Furthermore, we examined the possible role of Janus kinase 2 (JAK2), well-known down-stream tyrosine kinase under the heterodimeric receptor complex of IL4Rα and IL13Rα1. Interestingly, JAK2 interacted with Forkhead box O3 (FOXO3) to cause tyrosine-phosphorylation of FOXO3. Silencing IL4Rα or JAK2 in A498 and ACHN cells reduced the interaction between JAK2 and FOXO3. Moreover, pharmacological inhibition of JAK2 induced the nuclear localization of FOXO3, leading to increase apoptosis and decrease cell proliferation rate in A498 and ACHN cells. Taken together, these results suggest that IL4Rα and IL13Rα1 might be involved in the progression of RCC through JAK2/FOXO3 pathway, and their expression might be used as the novel prognostic factor and therapeutic target for RCC patients. MDPI 2019-09-18 /pmc/articles/PMC6770213/ /pubmed/31540495 http://dx.doi.org/10.3390/cancers11091394 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Kang, Mi-Ae Lee, Jongsung Ha, Sang Hoon Lee, Chang Min Kim, Kyoung Min Jang, Kyu Yun Park, See-Hyoung Interleukin4Rα (IL4Rα) and IL13Rα1 Are Associated with the Progress of Renal Cell Carcinoma through Janus Kinase 2 (JAK2)/Forkhead Box O3 (FOXO3) Pathways |
title | Interleukin4Rα (IL4Rα) and IL13Rα1 Are Associated with the Progress of Renal Cell Carcinoma through Janus Kinase 2 (JAK2)/Forkhead Box O3 (FOXO3) Pathways |
title_full | Interleukin4Rα (IL4Rα) and IL13Rα1 Are Associated with the Progress of Renal Cell Carcinoma through Janus Kinase 2 (JAK2)/Forkhead Box O3 (FOXO3) Pathways |
title_fullStr | Interleukin4Rα (IL4Rα) and IL13Rα1 Are Associated with the Progress of Renal Cell Carcinoma through Janus Kinase 2 (JAK2)/Forkhead Box O3 (FOXO3) Pathways |
title_full_unstemmed | Interleukin4Rα (IL4Rα) and IL13Rα1 Are Associated with the Progress of Renal Cell Carcinoma through Janus Kinase 2 (JAK2)/Forkhead Box O3 (FOXO3) Pathways |
title_short | Interleukin4Rα (IL4Rα) and IL13Rα1 Are Associated with the Progress of Renal Cell Carcinoma through Janus Kinase 2 (JAK2)/Forkhead Box O3 (FOXO3) Pathways |
title_sort | interleukin4rα (il4rα) and il13rα1 are associated with the progress of renal cell carcinoma through janus kinase 2 (jak2)/forkhead box o3 (foxo3) pathways |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770213/ https://www.ncbi.nlm.nih.gov/pubmed/31540495 http://dx.doi.org/10.3390/cancers11091394 |
work_keys_str_mv | AT kangmiae interleukin4rail4raandil13ra1areassociatedwiththeprogressofrenalcellcarcinomathroughjanuskinase2jak2forkheadboxo3foxo3pathways AT leejongsung interleukin4rail4raandil13ra1areassociatedwiththeprogressofrenalcellcarcinomathroughjanuskinase2jak2forkheadboxo3foxo3pathways AT hasanghoon interleukin4rail4raandil13ra1areassociatedwiththeprogressofrenalcellcarcinomathroughjanuskinase2jak2forkheadboxo3foxo3pathways AT leechangmin interleukin4rail4raandil13ra1areassociatedwiththeprogressofrenalcellcarcinomathroughjanuskinase2jak2forkheadboxo3foxo3pathways AT kimkyoungmin interleukin4rail4raandil13ra1areassociatedwiththeprogressofrenalcellcarcinomathroughjanuskinase2jak2forkheadboxo3foxo3pathways AT jangkyuyun interleukin4rail4raandil13ra1areassociatedwiththeprogressofrenalcellcarcinomathroughjanuskinase2jak2forkheadboxo3foxo3pathways AT parkseehyoung interleukin4rail4raandil13ra1areassociatedwiththeprogressofrenalcellcarcinomathroughjanuskinase2jak2forkheadboxo3foxo3pathways |