Inhibitory effect of microRNA-608 on lung cancer cell proliferation, migration, and invasion by targeting BRD4 through the JAK2/STAT3 pathway

Xu, Weigang; Sun, Dapeng; Wang, Yanqin; Zheng, Xinlin; Li, Yan; Yu, Xinbing; Teng, Ya'nan

doi:10.17305/bjbms.2019.4216

Cited by 16 publications

(16 citation statements)

References 44 publications

(44 reference statements)

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“…MiRNAs are small non-coding regulatory RNAs that bind to the 3′ untranslated region (3′ UTR) of mRNA and regulate its function and that of endogenous genes by influencing the translation process [22,23]. Dysregulation of miRNA expression is associated with abnormal gene expression and is involved in the development of lung adenocarcinoma, such as cell proliferation, apoptosis, migration, invasion, and differentiation [24,25]. In this study, we selected miR-1307-5p from among 40 different miRNA expression profiles that we had screened by second-generation high-throughput sequencing after p65 transfection of A549 cells to investigate the mechanism of miR-1307-5p regulation in lung adenocarcinoma [26].…”

Section: Introductionmentioning

confidence: 99%

MiR-1307-5p targeting TRAF3 upregulates the MAPK/NF-κB pathway and promotes lung adenocarcinoma proliferation

Wang

Liu

et al. 2020

Cancer Cell Int

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Background Non-small cell lung cancer (NSCLC) includes lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). MicroRNA (miRNA) plays an important role in the regulation of post-transcriptional gene expression in animals and plants, especially in lung adenocarcinoma. Methods MiR-1307-5p is an miRNA with significant differences screened by the second generation of high-throughput sequencing in the early stage of our research group. In the current study, a series of in vitro and in vivo experiments were carried out. MiR-1307-5p mimic, miR-1307-5p inhibitor, and NC were transfected into A549 and H1299 lung adenocarcinoma cells. The correlation between miR-1307-5p and clinicopathological features in pathological samples was analyzed using a lung adenocarcinoma tissue microarray, and miR-1307-5p expression was detected by qPCR. CCK-8, EdU, colony formation, scratch test, and Transwell assays were used to observe cell proliferation and migration. Double luciferase assay, western blot, qPCR, and immunohistochemistry were employed in confirming the target relationship between miR-1307-5p and TRAF3. Western blotting was used to analyze the relationship between miR-1307-5p and the NF-κB/MAPK pathway. Finally, the effect of miR-1307-5p on tumor growth was studied using a subcutaneous tumorigenesis model in nude mice. Results Increased miR-1307-5p expression was significantly related to decreased overall survival rate of lung adenocarcinoma patients, revealing miR-1307-5p as a potential oncogene in lung adenocarcinoma. MiR-1307-5p mimic significantly promoted while miR-1307-5p inhibitor reduced the growth and proliferation of A549 and H1299 cells. MiR-1307-5p overexpression significantly enhanced the migration ability while miR-1307-5p inhibition reduced the migration ability of A549 and H1299 cells. Target binding of miR-1307-5p to TRAF3 was confirmed by double luciferase assay, western blot, qPCR, and immunohistochemistry. miR-1307-5p caused degradation of TRAF3 mRNA and protein. MiR-1307-5p targeted TRAF3 and activated the NF-κB/MAPK pathway. TRAF3 colocalized with p65 and the localization of TRAF3 and p65 changed in each treatment group. Tumor volume of the lv-miR-1307-5p group was significantly larger than that of the lv-NC group, and that of the lv-miR-1307-5p-inhibitor group was significantly smaller than that of the lv-NC group. Conclusion In conclusion, miR-1307-5p targets TRAF3 and activates the NF-κB/MAPK pathway to promote proliferation in lung adenocarcinoma.

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Section: Introductionmentioning

confidence: 99%

MiR-1307-5p targeting TRAF3 upregulates the MAPK/NF-κB pathway and promotes lung adenocarcinoma proliferation

Wang

Liu

et al. 2020

Cancer Cell Int

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“…Interestingly, we found that the level of BRD4 protein increased after CAV-2 overexpression. Xu et al [37] found that targeting BRD4 through the JAK2/STAT3 pathway could inhibit tumor cell proliferation, migration, and invasion. Kwon et al [38] revealed that phosphotyrosine-caveolin-2 was a novel regulator for transcriptional activation of STAT3.…”

Section: Discussionmentioning

confidence: 99%

Caveolin-2 is regulated by BRD4 and contributes to cell growth in pancreatic cancer

et al. 2020

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Background: The bromodomain and extra-terminal domain (BET) family of proteins, especially BRD4 play an important role in epigenetic regulation, and are essential for cell survival and also are promising anticancer targets. This study aims to analyze the effect of BRD4 on the cell growth and progression of pancreatic cancer and novel mechanisms involved.Methods: Expression of BRD4 in pancreatic cancer and paired adjacent noncancerous tissues from 76 patients was analyzed by western blotting, immunohistochemistry, and real time PCR. Its correlation with the clinicopathological characteristics and prognosis of pancreatic cancer patients was analyzed. The effects of BRD4 on the cell proliferation were detected by colony formation assay and sulforhodamine B assay. Migration and invasion were determined by Transwell assays, and the effect of BRD4 on subcutaneous tumor formation was verified in nude mice. Cell cycle analysis was detected by flow cytometry. The potential downstream targets of BRD4 and related molecular mechanisms were clarified by RNA sequencing, chromatin immunoprecipitation and dual luciferase reporter assay.Results: BRD4 was overexpressed in pancreatic cancer. Biological results showed that BRD4 functioned as tumor promoter, facilitated cell proliferation, migration and invasion in vitro and in vivo. Further, caveolin-2 was selected as the downstream gene of BRD4 by RNA sequencing. Caveolin-2 overexpression can partially reverse the decreased cell growth ability caused by BRD4 knockdown, but did not affect cell migration and invasion. Chromatin immunoprecipitation assay and dual luciferase reporter assay revealed BRD4 could bind to the promoter region of caveolin-2 and upregulate caveolin-2 expression. Clinical data further indicated a positive correlation between BRD4 and caveolin-2 expression. BRD4 (high)/caveolin-2 (high) correlated with shorter overall survival of patients with pancreatic cancer. Multivariate analysis revealed that both BRD4 and caveolin-2 were independent factors. Conclusions:Our findings reveal the oncogenic effects of BRD4 in pancreatic cancer and elucidate a possible mechanism by which BRD4 and caveolin-2 act to enhance cell growth. Targeting the BRD4-caveolin-2 interaction by development of BET inhibitors will be a therapeutic strategy for pancreatic cancer.

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“…Studies have suggested that expression of BRD4-targeting miRNAs could be a novel and efficient strategy to inhibit human cancer cells with BRD4 overexpression [23][24][25]. The results of this study indentified microRNA-4651 (miR-4651) as a novel BRD4-targeting miRNA, suppressing NSCLC cell progression in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 89%

MicroRNA-4651 targets bromodomain-containing protein 4 to inhibit non-small cell lung cancer cell growth

Zheng

Dong

Zhang

et al. 2019

Preprint

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Background: Bromodomain-containing protein 4 (BRD4) overexpression in non-small cell lung cancer (NSCLC) is important for cancer cell progression. The aim of the present study is to silence BRD4 through expression of its targeted microRNAs in NSCLC cells. Methods: Expression of BRD4 and its targeting miRNA, microRNA-4651 (miR-4651), was tested by qPCR and Western blotting assays. Genetic strategies were utilized to exogenously alter miR-4651 expression. NSCLC cell growth, proliferation and migration were tested. Results: miR-4651 selectively targets and negatively regulates BRD4 in A549 and primary human NSCLC cells. The Ago-2 immunoprecipitation experiments further confirmed that miR-4651 directly binds to BRD4 mRNA. Significantly, in A549 cells and primary NSCLC cells ectopic overexpression of miR-4651 downregulated BRD4’s 3-UTR activity and its expression, both were however elevated with miR-4651 inhibition. Functional studies demonstrated that NSCLC cell growth, proliferation and migration were significantly inhibited with miR-4651 overexpression, but enhanced with miR-4651 inhibition. BRD4 re-expression, by an 3’-UTR mutant BRD4, reversed miR-4651 overexpression-induced inhibitions on A549 cells. Additionally, miR-4651 overexpression or inhibition failed to affect the functions of BRD4-KO A549 cells. In vivo, miR-4651-overexpressed A549 xenografts grew significantly slower than control A549 xenografts in severe combined immunodeficient mice. At last we show that miR-4651 is downregulated in human NSCLC tissues, correlating with BRD4 elevation. Conclusions: miR-4651 targets BRD4 to inhibit NSCLC cell growth in vitro and in vivo.

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Inhibitory effect of microRNA-608 on lung cancer cell proliferation, migration, and invasion by targeting BRD4 through the JAK2/STAT3 pathway

Cited by 16 publications

References 44 publications

MiR-1307-5p targeting TRAF3 upregulates the MAPK/NF-κB pathway and promotes lung adenocarcinoma proliferation

MiR-1307-5p targeting TRAF3 upregulates the MAPK/NF-κB pathway and promotes lung adenocarcinoma proliferation

Caveolin-2 is regulated by BRD4 and contributes to cell growth in pancreatic cancer

MicroRNA-4651 targets bromodomain-containing protein 4 to inhibit non-small cell lung cancer cell growth

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