scholarly journals MicroRNA-15a-5p acts as a tumor suppressor in histiocytosis by mediating CXCL10-ERK-LIN28a-let-7 axis

Leukemia ◽  
2021 ◽  
Author(s):  
Ran Weissman ◽  
Eli L. Diamond ◽  
Julien Haroche ◽  
Benjamin H. Durham ◽  
Fleur Cohen ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Erk Signaling ◽  
Luciferase Assay ◽  
Recurrent Mutations ◽  
Potential Therapeutic Role ◽  
Chemokine Ligand ◽  
Sequential Samples ◽  
Mapk Inhibitors ◽  
Induced Apoptosis ◽  
Post Transcriptional Regulation

AbstractErdheim–Chester disease (ECD) is characterized by excessive production and accumulation of histiocytes within multiple tissues and organs. ECD patients harbor recurrent mutations of genes associated with the RAS/RAF/MEK/ERK signaling pathway, particularly, the BRAFV600E mutation. Following our previous finding that miR-15a-5p is the most prominently downregulated microRNA in ECD patients compared to healthy individuals, we elucidated its role in ECD pathogenesis. Bioinformatics analysis followed by a luciferase assay showed that chemokine ligand 10 (CXCL10) is a target gene regulated by miRNA-15a-5p. This was confirmed in 24/34 ECD patients that had low expression of miR-15a-5p concurrent with upregulated CXCL10. Overexpression of miR-15a-5p in cell lines harboring BRAF or RAS mutations (Ba/F3, KG-1a and OCI-AML3) resulted in CXCL10 downregulation, followed by LIN28a and p-ERK signaling downregulation and let-7 family upregulation. Overexpression of miR-15a-5p inhibited cell growth and induced apoptosis by decreasing Bcl-2 and Bcl-xl levels. Analysis of sequential samples from 7 ECD patients treated with MAPK inhibitors (vemurafenib/cobimetinib) for 4 months showed miR-15a-5p upregulation and CXCL10 downregulation. Our findings suggest that miR-15a-5p is a tumor suppressor in ECD through the CXCL10-ERK-LIN28a-let7 axis, highlighting another layer of post-transcriptional regulation in this disease. Upregulation of miR-15a-5p in ECD patients may have a potential therapeutic role.

Isoliquiritigenin Inhibits Proliferation and Induces Apoptosis in Tongue Squamous Cell Carcinoma by Modulating miR-21/FOXG1 Pathway

2019 ◽  
Vol 17 (4) ◽  
pp. 463-469
Author(s):  
Hou Deqiang ◽  
Gao Yufeng ◽  
Bai Ning ◽  
Dong Yu
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Carcinoma Cells ◽  
Tongue Squamous Cell Carcinoma ◽  
Luciferase Assay ◽  
Forkhead Box ◽  
Proliferation And Apoptosis ◽  
Mrna And Protein Expression ◽  
Induced Apoptosis

Isoliquiritigenin is a flavonoid commonly found in liquorice and has been identified as a potent anti-tumor agent. The aim of this study was to investigate whether isoliquiritigenin regulates the proliferation and apoptosis of tongue squamous cell carcinoma cells by regulating forkhead box G1 expression via miR-21. MTT assay and flow cytometry were used to analyze cell proliferation and apoptosis, respectively. Quantitative real time polymerase chain reaction and western blotting were used to detect mRNA and protein expression levels, respectively. The relationship between miR-21 and forkhead box G1 was detected by dual luciferase assay. Isoliquiritigenin inhibited proliferation and induced apoptosis of tongue squamous cell carcinoma cells, and decreased miR-21 levels and promoted forkhead box G1 expression. Forkhead box G1 was then identified as a target of miR-21 and ISL could promote forkhead box G1 expression by inhibiting miR-21. Further analysis suggested that upregulation of miR-21 improved proliferation and suppressed apoptosis of tongue squamous cell carcinoma cells by inhibiting forkhead box G1 expression. Finally, our results revealed that isoliquiritigenin inhibited proliferation and induced apoptosis of tongue squamous cell carcinoma cells by regulating miR-21. Isoliquiritigenin might act as a novel therapeutic treatment for tongue squamous cell carcinoma cells through up-regulation of forkhead box G1 expression via inhibiting miR-21expression.

scholarly journals HBP1-mediated transcriptional repression of AFP inhibits hepatoma progression

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Zhengyi Cao ◽  
Yuning Cheng ◽  
Jiyin Wang ◽  
Yujuan Liu ◽  
Ruixiang Yang ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Transcriptional Repression ◽  
Chinese Herb ◽  
Gene Promoter ◽  
Hepatoma Cells ◽  
Luciferase Assay ◽  
B Virus ◽  
And Migration ◽  
Induced Apoptosis ◽  
Common Malignancy

Abstract Background Hepatoma is a common malignancy of the liver. The abnormal high expression of alpha-fetoprotein (AFP) is intimately associated with hepatoma progress, but the mechanism of transcriptional regulation and singularly activation of AFP gene in hepatoma is not clear. Methods The expression of transcription factor HBP1 and AFP and clinical significance were further analyzed in hepatoma tissues from the patients who received surgery or TACE and then monitored for relapse for up 10 years. HBP1-mediated transcriptional regulation of AFP was analyzed by Western blotting, Luciferase assay, Realtime-PCR, ChIP and EMSA. After verified the axis of HBP-AFP, its impact on hepatoma was measured by MTT, Transwell and FACS in hepatoma cells and by tumorigenesis in HBP1−/− mice. Results The relative expressions of HBP1 and AFP correlated with survival and prognosis in hepatoma patients. HBP1 repressed the expression of AFP gene by directly binding to the AFP gene promoter. Hepatitis B Virus (HBV)-encoded protein HBx promoted malignancy in hepatoma cells through binding to HBP1 directly. Icaritin, an active ingredient of Chinese herb epimedium, inhibited malignancy in hepatoma cells through enhancing HBP1 transrepression of AFP. The repression of AFP by HBP1 attenuated AFP effect on PTEN, MMP9 and caspase-3, thus inhibited proliferation and migration, and induced apoptosis in hepatoma cells. The deregulation of AFP by HBP1 contributed to hepatoma progression in mice. Conclusions Our data clarify the mechanism of HBP1 in inhibiting the expression of AFP and its suppression in malignancy of hepatoma cells, providing a more comprehensive theoretical basis and potential solutions for the diagnosis and treatment of hepatoma.

Bone Marrow-Derived Mesenchymal Stem Cells (BMSCs)-Exosome Carrying MiRNA-312 Inhibits Sevoflurane-Induced Cardiomyocyte Apoptosis Through Activation of Phosphatidylinositol 3-Kinase/Protein Kinase B (PI3K/AKT) Pathway

2022 ◽  
Vol 12 (5) ◽  
pp. 947-952
Author(s):  
Jun Zhang ◽  
Yuying Gao ◽  
Peng Chen ◽  
Yu Zhou ◽  
Sheng Guo ◽  
...  
Keyword(s):  
Protein Kinase B ◽  
Cardiomyocyte Apoptosis ◽  
Erk Signaling ◽  
Akt Pathway ◽  
Cardiomyocyte Proliferation ◽  
Akt Signaling Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Dmso Treatment ◽  
Induced Apoptosis ◽  
Related Proteins

This study was to explore the mechanism by how exosomes (exo) derived from BMSCs affects cardiomyocyte apoptosis. BMSCs were isolated and incubated with cardiomyocytes while the cardiomyocytes were exposed to sevoflurane or DMSO treatment. Apoptotic cells were calculated and level of apoptosis related proteins was detected by Western blot. Through transfection with microRNA-(miRNA)-312 inhibitor, we evaluated the effect of BMSC-exo on the sevoflurane-induced apoptosis. Sevoflurane significantly inhibited the viability of cardiomyocytes and induced cardiomyocyte apoptosis. Besides, sevoflurane decreased the expression of miR-312 and enhanced Bax expression in cardiomyocytes through restraining the phosphorylation of MAPK/ERK. Treatment with BMSC-exo, however, activated MAPK/ERK signaling by up-regulating miR-312, thereby inhibiting cardiomyocyte apoptosis, promoting cardiomyocyte proliferation, and elevating the level of Bcl-2. In conclusion, BMSC-exo-derived miR-312 inhibits sevoflurane-induced cardiomyocyte apoptosis by activating PI3K/AKT signaling pathway.

Abstract 265: Uroetensin II Protects Cardiomyocytes from Apoptosis Induced by Oxidative Stress through Cystathionine-γ-Lyase (CSE)/Hydrogen Sulfide Pathway

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Hui Gong ◽  
Zhidan Chen ◽  
Xiaoyi Zhang ◽  
Jie Zhang ◽  
Yang Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Erk Signaling ◽  
Cardiac Protection ◽  
Health Control ◽  
Cardiology Department ◽  
Apoptotic Protein ◽  
Induced Apoptosis ◽  
H2s Production

Plasma UII has been observed to be raised in patients with acute myocardial infarction, a lower UII response is associated with more severe injury of myocardium, suggesting a possible cardioprotective role for this peptide. In the present study, we studied plasma UII concentration of thirty patients admitted to the Cardiology Department with acute myocardial infartion.The results showed that plasma UII was sharply increased in patients compared to that in health control within one week after admission. We then explore whether UII could protect cardiomyocytes from injury induced by oxidative stress. Cultured cardiomyocyte were treated with H2O2 to induce oxidative stress, and the influence of UII on H2O2-induced apoptosis was observed. The results showed that UII pretreatment significantly reduced the number of TUNEL-positive cardiomyocytes induced by H2O2, and it partly abolished the upregulation of pro-apoptotic protein Bax and the down-regulation of anti-apoptotic protein Bcl-2. siRNA targeted to urotensin receptor (UT) greatly inhibited these effects. H2S has been reported to exert protective effect on cardiomyocytes, we detected the effect of UII on H2S production and CSE (Major H2S-producing enzyme) expressions in cardiomyocytes exposed to H2O2.The present data revealed that UII increased the H2S production by enhancing the expression of CSE by activating the ERK signaling in cardiomyocytes exposed to H2O2. Si-CSE or ERK inhibitor not only greatly inhibited the upregulation of CSE or the phosphorylation of ERK induced by UII but also reversed UII-induced-upregulation of H2S production and anti-apoptosis in cadiomyocytes exposed to H2O2. In conclusion, UII rapidly promoted the phosphorylation of ERK, increased CSE exression and induced H2S production, which in turn enhanced the p-ERK level to protect cardiomyocytes from apoptosis under ischemic or oxidative stress. The increased plasma UII level in patients may be critical for cardiac protection in patients at early-phase of acute myocardial infarction.

scholarly journals Differential Expression of MicroRNA-19b Promotes Proliferation of Cancer Stem Cells by Regulating the TSC1/mTOR Signaling Pathway in Multiple Myeloma

2018 ◽  
Vol 50 (5) ◽  
pp. 1804-1814 ◽  
Author(s):  
Ni Wang ◽  
Xiaohua Liang ◽  
Weijian Yu ◽  
Shihang Zhou ◽  
Meiyun  Fang
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Cancer Stem Cells ◽  
Real Time ◽  
Caspase 3 ◽  
In Silico Analysis ◽  
Luciferase Assay ◽  
Downstream Target ◽  
Induced Apoptosis

Background/Aims: MiR-19b has been reported to be involved in several malignancies, but its role in multiple myeloma (MM) is still unknown. The objective of this study was to explore the biological mechanism of miR-19b in the progression of MM. Methods: First, we performed real-time polymerase chain reaction (PCR) and Western blot to study the expression of miR-19b, tuberous sclerosis 1 (TSC1), and caspase-3 in different groups. MTT assay was performed to explore the effect of miR-19b on survival and apoptosis of cancer stem cells (CSCs). Computation analysis and luciferase assay were utilized to confirm the interaction between miR-19b and TSC1. Results: A total of 38 participants comprising 20 subjects with MM and 18 healthy subjects as normal controls were enrolled in our study. Real-time PCR showed dramatic upregulation of miR-19b, but TSC1 was evidently suppressed in the MM group. MiR-19b overexpression substantially promoted clonogenicity and cell viability, and further inhibited apoptosis of CSCs in vitro. Furthermore, miR-19b overexpression downregulated the expression of caspase-3, which induced apoptosis. Using in silico analysis, we identified that TSC1 might be a direct downstream target of miR-19b, and this was further confirmed by luciferase assay showing that miR-19b apparently reduced the luciferase activity of wild-type TSC1 3´-UTR, but not that of mutant TSC1 3´-UTR. There was also evident decrease in TSC1 mRNA and protein in CSCs following introduction of miR-19b. Interestingly, reintroduction of TSC1 abolished the miR-19b-induced proliferation promotion and apoptosis inhibition in CSCs. Conclusion: These findings collectively suggest that miR-19b promotes cell survival and suppresses apoptosis of MM CSCs via targeting TSC1 directly, indicating that miR-19b may serve as a potential and novel therapeutic target of MM based on miRNA expression.

scholarly journals The MEK/ERK/miR-21 Signaling Is Critical in Osimertinib Resistance in EGFR-Mutant Non-Small Cell Lung Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6005
Author(s):  
Wen-Chien Huang ◽  
Vijesh Kumar Yadav ◽  
Wei-Hong Cheng ◽  
Chun-Hua Wang ◽  
Ming-Shou Hsieh ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Tumor Suppressor ◽  
Growth Inhibition ◽  
Xenograft Model ◽  
Growth Factor Receptor ◽  
Mek Inhibitor ◽  
Small Cell ◽  
Erk Signaling ◽  
Small Cell Lung

Background: The third-generation epidermal growth factor receptor (EGFR) inhibitor, Osimertinib, is used to treat non-small cell lung cancer (NSCLC) patients with tyrosine kinase inhibitor (TKI) resistance caused by acquired EGFR T790M mutation. However, patients eventually develop resistance against Osimertinib with mechanisms not yet fully clarified. Activated alternative survival pathways within the tumor cells and cancer-associated fibroblasts (CAFs) have been proposed to contribute to Osimertinib resistance. MET and MEK inhibitors may overcome EGFR-independent resistance. Another acquired resistance mechanism of EGFR-TKI is the up-regulation of the RAS/RAF/MEK/ERK signaling pathway, which is the key to cell survival and proliferation; this may occur downstream of various other signaling pathways. In this report, we reveal the possible regulatory mechanism and inhibitory effect of the MEK inhibitor trametinib applied to MEK/ERK/miR-21 axis and PDCD4 in Osimertinib resistance. We found a possible regulatory role of PDCD4 in ERK signaling. PDCD4 is a new type of tumor suppressor that has multiple functions of inhibiting cell growth, tumor invasion, metastasis, and inducing apoptosis. Previous bioinformatics analysis has confirmed that PDCD4 contains the binding site of miR-21 and acts as a tumor suppressor in the regulation of various processes associated with the development of cancer, including cell proliferation, invasion, metastasis, and neoplastic transformation. Based on the above analysis, we hypothesized that the tumor suppressor PDCD4 is one of the effective inhibitory targets of miR-21-5p. Methods: The expression between EGFR and ERK2 in lung adenocarcinoma was evaluated from the TCGA database. Osimertinib-sensitive and resistant NSCLC cells obtained from patients were used to co-culture with human lung fibroblasts (HLFs) to generate CAF cells (termed CAF_R1 and CAF_S1), and the functional roles of these CAF cells plus the regulatory mechanisms were further explored. Then, MEK inhibitor Trametinib with or without Osimertinib was applied in xenograft model derived from patients to validate the effects on growth inhibition of Osimertinib-resistant NSCLC tumors. Result: ERK2 expression correlated with EGFR expression and higher ERK2 level was associated with worse prognosis of patients and Osimertinib resistance. CAFs derived from Osimertinib-resistant cells secreted more IL-6, IL-8, and hepatocyte growth factor (HGF), expressed stronger CAF markers including α-smooth muscle actin (α-SMA), fibroblast activation protein (FAP) plus platelet-derived growth factor receptor (PDGFR), and enhanced stemness and Osimertinib resistance in NSCLC cells. Meanwhile, increased MEK/ERK/miR-21 expressions were found in both CAFs and NSCLC cells. MEK inhibitor Trametinib significantly abrogated the abovementioned effects by modulating β-catenin, STAT3, and ERK. The xenograft model showed combining Osimertinib and Trametinib resulted in the most prominent growth inhibition of Osimertinib-resistant NSCLC tumors. Conclusions: Our results suggested that MEK/ERK/miR-21 signaling is critical in Osimertinib resistance and CAF transformation of NSCLC cells, and MEK inhibitor Trametinib significantly suppressed Osimertinib-resistant NSCLC tumor growth by abolishing both processes.

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