Up-regulation of exosomal miR-125a in pneumoconiosis inhibits lung cancer development by suppressing expressions of EZH2 and hnRNPK

Zhang, Lin; Li, Jiangfeng; Hao, Changfu; Guo, Weijian; Wang, Di; Zhang, Jianhui; Zhao, Yong; Duan, Shuyin; Yao, Wu

doi:10.1039/c8ra03081b

Cited by 10 publications

(18 citation statements)

References 38 publications

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“…The dominant role of autophagy in the proliferation, migration, and invasion of lung cancer cells has been well-established throughout previous studies (3–5). However, the mechanism underlying the initiation of autophagy is still unclear.…”

Section: Introductionmentioning

confidence: 77%

Exogenous Let-7a-5p Induces A549 Lung Cancer Cell Death Through BCL2L1-Mediated PI3Kγ Signaling Pathway

Duan

Yuan

et al. 2019

Front. Oncol.

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Elevated expression of let-7a-5p contributes to suppression of lung cancer, in which let-7a-5p, as exosome cargo, can be transported from macrophages to lung cancer cells, yet the role of let-7a-5p remains unclear. Utilizing bioinformatics methods and cellular experiments, this study was designed and conducted to identify let-7a-5p regulatory network in lung cancer. Bioinformatics analysis and Kaplan-Meier survival analysis revealed that let-7a-5p could directly target BCL2L1, and aberrant expression of let-7a-5p affects the survival of lung cancer patients, which was confirmed in A549 lung cancer cells using luciferase reporter assay. Moreover, let-7a-5p inhibited BCL2L1 expression and suppressed lung cancer cell proliferation, migration, and invasion. Functionally, overexpression of let-7a-5p promoted both autophagy and cell death in A549 lung cancer cells through PI3Kγ signaling pathway, whereas the apoptosis and pyroptosis of A549 lung cancer cells were unaffected. Furthermore, aberrant expression of BCL2L1 significantly altered the expression of lung cancer biomarkers such as MYC, EGFR, and Vimentin. To sum up, these data demonstrate that exogenous let-7a-5p induces A549 lung cancer cell death through BCL2L1-mediated PI3Kγ signaling pathway, which may be a useful target for lung cancer treatment.

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Section: Introductionmentioning

confidence: 77%

Exogenous Let-7a-5p Induces A549 Lung Cancer Cell Death Through BCL2L1-Mediated PI3Kγ Signaling Pathway

Duan

Yuan

et al. 2019

Front. Oncol.

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“…Both of these factors simultaneously target WASL and VASP inducing inflammatory responses in lung tissue [ 8 ]. Moreover, let-7a was shown to be differentially expressed in different subtypes of non-small cell lung cancer [ 9 – 11 ]. Therefore, let-7 families may be useful as specific biomarkers for distinguishing different subtypes of lung cancer.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of exosomal let-7a-5p in dust exposed- workers contributes to lung cancer development

et al. 2018

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BackgroundEither chronic or acute exposure to dust particles may lead to pneumoconiosis and lung cancer, and lung cancer mortality among patients diagnosed with pneumoconiosis is increasing. Utilizing genome-wide sequencing technology, this study aimed to identify methods to decrease the number of patients with pneumoconiosis who die from lung cancer.MethodsOne hundred fifty-four subjects were recruited, including 54 pneumoconiosis patients and 100 healthy controls. Exosomes were isolated from the venous blood of every subject. Distinctive miRNAs were identified using high throughput sequencing technology, and bioinformatics analysis predicted target genes involved in lung cancer as well as their corresponding biological functions. Moreover, cross-cancer alterations of genes related to lung cancer were investigated, and survival analysis was performed using 2437 samples with an average follow-up period of 49 months.ResultsLet-7a-5p was revealed to be downregulated by 21.67% in pneumoconiosis. Out of the 683 let-7a-5p target genes identified from bioinformatics analysis, four genes related to five signaling pathways were confirmed to be involved in lung cancer development. Alterations in these four target genes were then explored in 4105 lung cancer patients, and BCL2L1 and IGF1R were demonstrated to be aberrantly expressed. Survival analysis further revealed that high expression of BCL2L1 corresponded to reduced survival of lung cancer patients (HR (95%CI) = 1.75(1.33~2.30)), while patient survival time was unaffected by expression of IGF1R (HR (95%CI) = 1.15 (0.98~1.36)).ConclusionsIn patients with lung adenocarcinoma, simultaneous downregulation of exosomal let-7a-5p and elevated expression of BCL2L1 are useful as predictive biomarkers for poor survival.

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“…6 Currently, multiple miRNAs are known to participate in regulating the proliferation, differentiation, metabolism, and apoptosis of tumor cells. [14][15][16] The study has revealed that miR-125b controls proliferation and apoptosis by downregulating P53 and the genes involved in the P53 pathway including BAK1 and PUMA, which provides for the first time a potential mechanism for the development of secondary hematologic malignancies in patients treated with IMiD compounds. 9,10 Studies have shown that miR-125b acts as a tumor-suppressor gene in chronic lymphocytic leukemia (CLL) and MM, 11,12 whereas miR-125a is a newly discovered member of miR-125, whose precursor can produce two kinds of mature miR-125a-3p and miR-125a-5p, 13 which have also been reported to be tumorsuppressor genes in various malignant tumors, such as prostate tumor, lung tumor, and ovarian tumor.…”

mentioning

confidence: 99%

“…9,10 Studies have shown that miR-125b acts as a tumor-suppressor gene in chronic lymphocytic leukemia (CLL) and MM, 11,12 whereas miR-125a is a newly discovered member of miR-125, whose precursor can produce two kinds of mature miR-125a-3p and miR-125a-5p, 13 which have also been reported to be tumorsuppressor genes in various malignant tumors, such as prostate tumor, lung tumor, and ovarian tumor. [14][15][16] The study has revealed that miR-125b controls proliferation and apoptosis by downregulating P53 and the genes involved in the P53 pathway including BAK1 and PUMA, which provides for the first time a potential mechanism for the development of secondary hematologic malignancies in patients treated with IMiD compounds. 17 However, there are relatively few studies on the effect of miR-125a on hematological diseases.…”

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confidence: 99%

RETRACTED: miR‐125a suppresses malignancy of multiple myeloma by reducing the deubiquitinase USP5

Wu¹,

Zhang²,

Chen³

et al. 2019

J of Cellular Biochemistry

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miR‐125a is a microRNA that is frequently diminished in various human malignancies. However, the mechanism by which impaired miR‐125a promotes cancer growth remains undefined. In this study, we investigated the role of miR‐125a in the proliferation and apoptosis of multiple myeloma (MM). To do this, we used MM tissue samples (from 40 anonymous patients), normal matched control samples, and five MM‐derived cell lines. We also established a mouse model of MM xenograft to explore the effect of overexpression of miR‐125a on the MM growth in vivo. Quantitative real‐time polymerase chain reaction revealed that the miR‐125a expression was broadly reduced in MM tissues and cell lines. The impairment of miR‐125a in MM tissues was functionally relevant because the overexpression of miR‐125a remarkably decreased the cell viability and colony‐forming activity, at least in part, by promoting apoptosis in two miR‐125a‐deficient MM cell lines: NCI‐H929 and U266. Interestingly, we also discovered that the human gene encoding the ubiquitin‐specific peptidase 5 (USP5), which is known to promote cellular deubiquitination and ubiquitin/proteasome‐dependent proteolysis, was a direct transcriptional target for miR‐125a to repress. More importantly, the heterologous expression of USP5 significantly reversed the growth‐inhibitory effects of miR‐125a on MM cells in vitro. In the mouse xenograft model, overexpressed miR‐125a prominently inhibited the growth of MM tumors and concomitantly reduced the expression of USP5 in tumor tissues. These results suggest that miR‐125a inhibits the expression of USP5, thereby mitigating the proliferation and survival of malignant MM cells. We propose that USP5 acts as an oncoprotein in miR‐125a‐missing cancers.

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Up-regulation of exosomal miR-125a in pneumoconiosis inhibits lung cancer development by suppressing expressions of EZH2 and hnRNPK

Abstract: Exosomal miR-125a may act as a bridge between pneumoconiosis and lung cancer.

Cited by 10 publications

References 38 publications

Exogenous Let-7a-5p Induces A549 Lung Cancer Cell Death Through BCL2L1-Mediated PI3Kγ Signaling Pathway

Exogenous Let-7a-5p Induces A549 Lung Cancer Cell Death Through BCL2L1-Mediated PI3Kγ Signaling Pathway

Downregulation of exosomal let-7a-5p in dust exposed- workers contributes to lung cancer development

RETRACTED: miR‐125a suppresses malignancy of multiple myeloma by reducing the deubiquitinase USP5

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