COX-2/PGE2 upregulation contributes to the chromosome 17p-deleted lymphoma
Abstract Deletions of chromosome 17p, where TP53 gene locates, are the most frequent chromosome alterations in human cancers and associated with poor outcomes in patients. Our previous work suggested that there were p53–independent mechanisms involved in chromosome 17p deletions-driven cancers. Here...
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Nature Publishing Group
2023-02-01
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Series: | Oncogenesis |
Online Access: | https://doi.org/10.1038/s41389-023-00451-9 |
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author | Lu Qi Xiangyu Pan Xuelan Chen Pengpeng Liu Mei Chen Qi Zhang Xiaohang Hang Minghai Tang Dan Wen Lunzhi Dai Chong Chen Yu Liu Zhengmin Xu |
author_facet | Lu Qi Xiangyu Pan Xuelan Chen Pengpeng Liu Mei Chen Qi Zhang Xiaohang Hang Minghai Tang Dan Wen Lunzhi Dai Chong Chen Yu Liu Zhengmin Xu |
author_sort | Lu Qi |
collection | DOAJ |
description | Abstract Deletions of chromosome 17p, where TP53 gene locates, are the most frequent chromosome alterations in human cancers and associated with poor outcomes in patients. Our previous work suggested that there were p53–independent mechanisms involved in chromosome 17p deletions-driven cancers. Here, we report that altered arachidonate metabolism, due to the deficiency of mouse Alox8 on chromosome 11B3 (homologous to human ALOX15B on chromosome 17p), contributes to the B cell malignancy. While the metabolites produced from lipoxygenase pathway reduced, chromosome 11B3 deletions or Alox8 loss, lead to upregulating its paralleling cyclooxygenase pathway, indicated by the increased levels of oncometabolite prostaglandin E2. Ectopic PGE2 prevented the apoptosis and differentiation of pre-B cells. Further studies revealed that Alox8 deficiency dramatically and specifically induced Cox-2(Ptgs2) gene expression. Repressing Cox-2 by its shRNAs impaired the tumorigenesis driven by Alox8 loss. And, in turn, tumor cells with Alox8 or 11B3 loss were sensitive to the COX-2 inhibitor celecoxib. This correlation between COX-2 upregulation and chromosome 17p deletions was consistent in human B-cell lymphomas. Hence, our studies reveal that the arachidonate metabolism abnormality with unbalanced ALOX and COX pathways underlies human cancers with 17p deletions and suggest new susceptibility for this disease. |
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issn | 2157-9024 |
language | English |
last_indexed | 2024-04-10T15:41:09Z |
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spelling | doaj.art-975f3c683e924fb88770790ccca7a1902023-02-12T12:23:04ZengNature Publishing GroupOncogenesis2157-90242023-02-011211810.1038/s41389-023-00451-9COX-2/PGE2 upregulation contributes to the chromosome 17p-deleted lymphomaLu Qi0Xiangyu Pan1Xuelan Chen2Pengpeng Liu3Mei Chen4Qi Zhang5Xiaohang Hang6Minghai Tang7Dan Wen8Lunzhi Dai9Chong Chen10Yu Liu11Zhengmin Xu12Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan UniversityDepartment of Rheumatology, North Sichuan Medical College First Affiliated Hospital, Institute of Material Medicine, North Sichuan Medical CollegeDepartment of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityAbstract Deletions of chromosome 17p, where TP53 gene locates, are the most frequent chromosome alterations in human cancers and associated with poor outcomes in patients. Our previous work suggested that there were p53–independent mechanisms involved in chromosome 17p deletions-driven cancers. Here, we report that altered arachidonate metabolism, due to the deficiency of mouse Alox8 on chromosome 11B3 (homologous to human ALOX15B on chromosome 17p), contributes to the B cell malignancy. While the metabolites produced from lipoxygenase pathway reduced, chromosome 11B3 deletions or Alox8 loss, lead to upregulating its paralleling cyclooxygenase pathway, indicated by the increased levels of oncometabolite prostaglandin E2. Ectopic PGE2 prevented the apoptosis and differentiation of pre-B cells. Further studies revealed that Alox8 deficiency dramatically and specifically induced Cox-2(Ptgs2) gene expression. Repressing Cox-2 by its shRNAs impaired the tumorigenesis driven by Alox8 loss. And, in turn, tumor cells with Alox8 or 11B3 loss were sensitive to the COX-2 inhibitor celecoxib. This correlation between COX-2 upregulation and chromosome 17p deletions was consistent in human B-cell lymphomas. Hence, our studies reveal that the arachidonate metabolism abnormality with unbalanced ALOX and COX pathways underlies human cancers with 17p deletions and suggest new susceptibility for this disease.https://doi.org/10.1038/s41389-023-00451-9 |
spellingShingle | Lu Qi Xiangyu Pan Xuelan Chen Pengpeng Liu Mei Chen Qi Zhang Xiaohang Hang Minghai Tang Dan Wen Lunzhi Dai Chong Chen Yu Liu Zhengmin Xu COX-2/PGE2 upregulation contributes to the chromosome 17p-deleted lymphoma Oncogenesis |
title | COX-2/PGE2 upregulation contributes to the chromosome 17p-deleted lymphoma |
title_full | COX-2/PGE2 upregulation contributes to the chromosome 17p-deleted lymphoma |
title_fullStr | COX-2/PGE2 upregulation contributes to the chromosome 17p-deleted lymphoma |
title_full_unstemmed | COX-2/PGE2 upregulation contributes to the chromosome 17p-deleted lymphoma |
title_short | COX-2/PGE2 upregulation contributes to the chromosome 17p-deleted lymphoma |
title_sort | cox 2 pge2 upregulation contributes to the chromosome 17p deleted lymphoma |
url | https://doi.org/10.1038/s41389-023-00451-9 |
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