STAT3/miR-135b/NF-κB axis confers aggressiveness and unfavorable prognosis in non-small-cell lung cancer
Abstract Non-small-cell lung cancer (NSCLC) is one of the most commonly diagnosed cancers worldwide but has limited effective therapies. Uncovering the underlying pathological and molecular changes, as well as mechanisms, will improve the treatment. Dysregulated microRNAs (miRNAs) have been proven t...
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Format: | Article |
Language: | English |
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Nature Publishing Group
2021-05-01
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Series: | Cell Death and Disease |
Online Access: | https://doi.org/10.1038/s41419-021-03773-x |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jinlin Zhao Xin Wang Zeyun Mi Xiangli Jiang Lin Sun Boyu Zheng Jing Wang Maobin Meng Lu Zhang Zhongqiu Wang Junwei Song Zhiyong Yuan Zhiqiang Wu |
spellingShingle |
Jinlin Zhao Xin Wang Zeyun Mi Xiangli Jiang Lin Sun Boyu Zheng Jing Wang Maobin Meng Lu Zhang Zhongqiu Wang Junwei Song Zhiyong Yuan Zhiqiang Wu STAT3/miR-135b/NF-κB axis confers aggressiveness and unfavorable prognosis in non-small-cell lung cancer Cell Death and Disease |
author_facet |
Jinlin Zhao Xin Wang Zeyun Mi Xiangli Jiang Lin Sun Boyu Zheng Jing Wang Maobin Meng Lu Zhang Zhongqiu Wang Junwei Song Zhiyong Yuan Zhiqiang Wu |
author_sort |
Jinlin Zhao |
title |
STAT3/miR-135b/NF-κB axis confers aggressiveness and unfavorable prognosis in non-small-cell lung cancer |
title_short |
STAT3/miR-135b/NF-κB axis confers aggressiveness and unfavorable prognosis in non-small-cell lung cancer |
title_full |
STAT3/miR-135b/NF-κB axis confers aggressiveness and unfavorable prognosis in non-small-cell lung cancer |
title_fullStr |
STAT3/miR-135b/NF-κB axis confers aggressiveness and unfavorable prognosis in non-small-cell lung cancer |
title_full_unstemmed |
STAT3/miR-135b/NF-κB axis confers aggressiveness and unfavorable prognosis in non-small-cell lung cancer |
title_sort |
stat3/mir-135b/nf-κb axis confers aggressiveness and unfavorable prognosis in non-small-cell lung cancer |
publisher |
Nature Publishing Group |
series |
Cell Death and Disease |
issn |
2041-4889 |
publishDate |
2021-05-01 |
description |
Abstract Non-small-cell lung cancer (NSCLC) is one of the most commonly diagnosed cancers worldwide but has limited effective therapies. Uncovering the underlying pathological and molecular changes, as well as mechanisms, will improve the treatment. Dysregulated microRNAs (miRNAs) have been proven to play important roles in the initiation and progression of various cancers, including NSCLC. In this manuscript, we identified microRNA-135b (miR-135b) as a tumor-promoting miRNA in NSCLC. We found that miR-135b was significantly upregulated and that its upregulation was associated with poor prognosis in NSCLC patients. miR-135b was an independent prognostic factor in NSCLC. Overexpressing miR-135b significantly promoted the aggressiveness of NSCLC, as evidenced by enhanced cell proliferation, migration, invasion, anti-apoptosis, and angiogenesis in vitro and in vivo, and knockdown of miR-135b had the opposite effects. Mechanistically, our results reveal that miR-135b directly targets the 3′-untranslated region (UTR) of the deubiquitinase CYLD, thereby modulating ubiquitination and activation of NF-κB signaling. Moreover, we found that interleukin-6 (IL-6)/STAT3 could elevate miR-135b levels and that STAT3 directly bound the promoter of miR-135b; thus, these findings highlight a new positive feedback loop of the IL-6/STAT3/miR-135b/NF-κB signaling in NSCLC and suggest that miR-135b could be a potential therapeutic target for NSCLC. |
url |
https://doi.org/10.1038/s41419-021-03773-x |
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doaj-7ac5d38eeb4c4870831306edda0f79be2021-05-16T11:04:50ZengNature Publishing GroupCell Death and Disease2041-48892021-05-0112511610.1038/s41419-021-03773-xSTAT3/miR-135b/NF-κB axis confers aggressiveness and unfavorable prognosis in non-small-cell lung cancerJinlin Zhao0Xin Wang1Zeyun Mi2Xiangli Jiang3Lin Sun4Boyu Zheng5Jing Wang6Maobin Meng7Lu Zhang8Zhongqiu Wang9Junwei Song10Zhiyong Yuan11Zhiqiang Wu12Department of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for CancerDepartment of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for CancerDepartment of Biochemistry and Molecular Biology, College of Basic Medical Science, Tianjin Medical UniversityDepartment of Thoracic Medical Oncology, Tianjin Medical University Cancer Institute & HospitalDepartment of Pathology, Tianjin Medical University Cancer Institute & HospitalDepartment of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for CancerDepartment of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for CancerDepartment of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for CancerDepartment of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for CancerDepartment of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for CancerGuangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Department of Pathogen Biology, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University School of MedicineDepartment of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for CancerDepartment of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for CancerAbstract Non-small-cell lung cancer (NSCLC) is one of the most commonly diagnosed cancers worldwide but has limited effective therapies. Uncovering the underlying pathological and molecular changes, as well as mechanisms, will improve the treatment. Dysregulated microRNAs (miRNAs) have been proven to play important roles in the initiation and progression of various cancers, including NSCLC. In this manuscript, we identified microRNA-135b (miR-135b) as a tumor-promoting miRNA in NSCLC. We found that miR-135b was significantly upregulated and that its upregulation was associated with poor prognosis in NSCLC patients. miR-135b was an independent prognostic factor in NSCLC. Overexpressing miR-135b significantly promoted the aggressiveness of NSCLC, as evidenced by enhanced cell proliferation, migration, invasion, anti-apoptosis, and angiogenesis in vitro and in vivo, and knockdown of miR-135b had the opposite effects. Mechanistically, our results reveal that miR-135b directly targets the 3′-untranslated region (UTR) of the deubiquitinase CYLD, thereby modulating ubiquitination and activation of NF-κB signaling. Moreover, we found that interleukin-6 (IL-6)/STAT3 could elevate miR-135b levels and that STAT3 directly bound the promoter of miR-135b; thus, these findings highlight a new positive feedback loop of the IL-6/STAT3/miR-135b/NF-κB signaling in NSCLC and suggest that miR-135b could be a potential therapeutic target for NSCLC.https://doi.org/10.1038/s41419-021-03773-x |