scholarly journals MiR-450a-5p strengthens the drug sensitivity of gefitinib in glioma chemotherapy via regulating autophagy by targeting EGFR

Oncogene ◽  
2020 ◽  
Vol 39 (39) ◽  
pp. 6190-6202 ◽  
Author(s):  
Yu Liu ◽  
Liang Yang ◽  
Fan Liao ◽  
Wei Wang ◽  
Zhi-Fei Wang
Keyword(s):  
Signaling Pathway ◽  
Drug Sensitivity ◽  
Kinase Inhibitor ◽  
Glioma Cells ◽  
Mtor Signaling ◽  
Migration And Invasion ◽  
Mtor Signaling Pathway ◽  
Glioma Growth

Abstract Glioma reported to be refractory to EGFR tyrosine kinase inhibitor is the most common malignant tumor in central nervous system. Our research showed the low expression of miR-450a-5p and high expression of EGFR in glioma tissues. MiR-450a-5p was also observed to synergize with gefitinib to inhibit the proliferation, migration and invasion and induce the apoptosis and autophagy of glioma cells. Furthermore, miR-450a-5p was demonstrated to target 3′UTR of EGFR, and regulated EGFR-induced PI3K/AKT/mTOR signaling pathway. Moreover, the above effects induced by miR-450a-5p in glioma cells were reversed by WIPI1 silencing. The inhibition role of miR-450a-5p on glioma growth was also confirmed in vivo by subcutaneous and intracranial tumor xenografts. Therefore, we conclude that miR-450a-5p synergizes with gefitinib to inhibit the glioma tumorigenesis through inducing autophagy by regulating the EGFR-induced PI3K/AKT/mTOR signaling pathway, thereby enhancing the drug sensitivity of gefitinib.

scholarly journals M2 macrophage-derived exosomal microRNAs inhibit cell migration and invasion in gliomas through PI3K/AKT/mTOR signaling pathway

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jie Yao ◽  
Zefen Wang ◽  
Yong Cheng ◽  
Chao Ma ◽  
Yahua Zhong ◽  
...  
Keyword(s):  
Cell Migration ◽  
Western Blot ◽  
Signaling Pathway ◽  
Target Gene ◽  
Glioma Cells ◽  
Mtor Signaling ◽  
Migration And Invasion ◽  
M2 Macrophage ◽  
Mtor Signaling Pathway ◽  
Cell Migration And Invasion

Abstract Background Glioma, the most common primary brain tumor, account Preparing figures for 30 to 40% of all intracranial tumors. Herein, we aimed to study the effects of M2 macrophage-derived exosomal microRNAs (miRNAs) on glioma cells. Methods First, we identified seven differentially expressed miRNAs in infiltrating macrophages and detected the expression of these seven miRNAs in M2 macrophages. We then selected hsa-miR-15a-5p (miR-15a) and hsa-miR-92a-3p (miR-92a) for follow-up studies, and confirmed that miR-15a and miR-92a were under-expressed in M2 macrophage exosomes. Subsequently, we demonstrated that M2 macrophage-derived exosomes promoted migration and invasion of glioma cells, while exosomal miR-15a and miR-92a had the opposite effects on glioma cells. Next, we performed the target gene prediction in four databases and conducted target gene validation by qRT-PCR, western blot and dual luciferase reporter gene assays. Results The results revealed that miR-15a and miR-92a were bound to CCND1 and RAP1B, respectively. Western blot assays demonstrated that interference with the expression of CCND1 or RAP1B reduced the phosphorylation level of AKT and mTOR, indicating that both CCND1 and RAP1B can activate the PI3K/AKT/mTOR signaling pathway. Conclusion Collectively, these findings indicate that M2 macrophage-derived exosomal miR-15a and miR-92a inhibit cell migration and invasion of glioma cells through PI3K/AKT/mTOR signaling pathway.

scholarly journals Inhibition of Prostate Cancer DU-145 Cells Proliferation by Anthopleura anjunae Oligopeptide (YVPGP) via PI3K/AKT/mTOR Signaling Pathway

Marine Drugs ◽  
2018 ◽  
Vol 16 (9) ◽  
pp. 325 ◽  
Author(s):  
Xiaojuan Li ◽  
Yunping Tang ◽  
Fangmiao Yu ◽  
Yu Sun ◽  
Fangfang Huang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Signaling Pathway ◽  
Caspase 3 ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Nude Mouse Model ◽  
Dose Dependent

We investigated the antitumor mechanism of Anthopleura anjunae oligopeptide (AAP-H, YVPGP) in prostate cancer DU-145 cells in vitro and in vivo. Results indicated that AAP-H was nontoxic and exhibited antitumor activities. Cell cycle analysis indicated that AAP-H may arrest DU-145 cells in the S phase. The role of the phosphatidylinositol 3-kinase/protein kinase B/mammalian rapamycin target protein (PI3K/AKT/mTOR) signaling pathway in the antitumor mechanism of APP-H was investigated. Results showed that AAP-H treatment led to dose-dependent reduction in the levels of p-AKT (Ser473), p-PI3K (p85), and p-mTOR (Ser2448), whereas t-AKT and t-PI3K levels remained unaltered compared to the untreated DU-145 cells. Inhibition of PI3K/AKT/mTOR signaling pathway in the DU-145 cells by employing inhibitor LY294002 (10 μM) or rapamycin (20 nM) effectively attenuated AAP-H-induced phosphorylation of AKT and mTOR. At the same time, inhibitor addition further elevated AAP-H-induced cleaved-caspase-3 levels. Furthermore, the effect of AAP-H on tumor growth and the role of the PI3K/AKT/mTOR signaling pathway in nude mouse model were also investigated. Immunohistochemical analysis showed that activated AKT, PI3K, and mTOR levels were reduced in DU-145 xenografts. Western blotting showed that AAP-H treatment resulted in dose-dependent reduction in p-AKT (Ser473), p-PI3K (p85), and p-mTOR (Ser2448) levels, whereas t-AKT and t-PI3K levels remained unaltered. Similarly, Bcl-xL levels decreased, whereas that of Bax increased after AAP-H treatment. AAP-H also increased initiator (caspase 8 and 9) and executor caspase (caspase 3 and 7) levels. Therefore, the antitumor mechanism of APP-H on DU-145 cells may involve regulation of the PI3K/AKT/mTOR signaling pathway, which eventually promotes apoptosis via mitochondrial and death receptor pathways. Thus, the hydrophobic oligopeptide (YVPGP) can be developed as an adjuvant for the prevention or treatment of prostate cancer in the future.

scholarly journals MicroRNA-1271-5p inhibits the tumorigenesis of ovarian cancer through targeting E2F5 and negatively regulates the mTOR signaling pathway

2020 ◽  
Author(s):  
Qin Li ◽  
Junyu Shi ◽  
Xiaoli Xu
Keyword(s):  
Ovarian Cancer ◽  
Signaling Pathway ◽  
Poor Prognosis ◽  
Mtor Signaling ◽  
Luciferase Assay ◽  
Migration And Invasion ◽  
Mtor Signaling Pathway ◽  
Direct Target ◽  
The Relationship

Abstract Background: MicroRNA-1271-5p (miR-1271-5p) has been reported to participate in the progression of many human cancers. However, the role of miR-1271-5p still remains unclear in ovarian cancer (OC). Therefore, we explored the effect of miR-1271-5p on the development of OC in present study. Methods: We measured the miR-1271-5p expression via the qRT-PCR assay. Then the function of miR-1271-5p was analyzed through MTT and Transwell assays. The relationship among miR-1271-5p and E2F5 was verified by dual luciferase assay. The protein expression levels were examined through western blot.Results: MiR-1271-5p was downregulated in OC tissues which predicted poor prognosis of OC patients. Moreover, E2F5 was a direct target of miR-1271-5p in OC. And miR-1271-5p suppressed cell proliferation, migration and invasion in OC through targeting E2F5. Furthermore, E2F5 was upregulated in OC tissues which predicted poor prognosis of OC patients. Besides that, miR-1271-5p suppressed EMT and mTOR pathway in OC. Conclusion: MiR-1271-5p inhibited the tumorigenesis of OC through targeting E2F5 and negatively regulated the mTOR signaling pathway.

scholarly journals Long non-coding RNA LINC00473 acts as a microRNA-29a-3p sponge to promote hepatocellular carcinoma development by activating Robo1-dependent PI3K/AKT/mTOR signaling pathway

2020 ◽  
Vol 12 ◽  
pp. 175883592093789
Author(s):  
Qiqin Song ◽  
Hongyue Zhang ◽  
Jinan He ◽  
Hongyan Kong ◽  
Ran Tao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Tumor Progression ◽  
Signaling Pathway ◽  
Underlying Mechanism ◽  
Mtor Signaling ◽  
Migration And Invasion ◽  
Mtor Signaling Pathway ◽  
Regulatory Effects

Background: Long non-coding RNAs have suppressive or oncogenic effects in various types of cancers by serving as competing endogenous RNAs for specific microRNAs. In the present study, we aim to delineate the underlying mechanism by which the LINC00473/miR-29a-3p/Robo1 axis affects cell proliferation, migration, invasion, and metastasis in hepatocellular carcinoma (HCC). Methods: The level of Robo1 was examined in HCC tissues and cells, along with its regulatory effects on proliferation, migration, and invasion of HCC cells. Afterwards, the possible involvement of the PI3K/AKT/mTOR signaling pathway was determined. Next, miR-29a-3p expression was overexpressed or inhibited to investigate its regulatory role on HCC cell activities. The interaction among miR-29a-3p, Robo1, and LINC00473 was further characterized. Finally, a xenograft tumor in nude mice was conducted to measure tumorigenesis and metastasis in vivo. Results: miR-29a-3p was downregulated while Robo1 was upregulated in HCC tissues and cells. miR-29a-3p targeted Robo1 and negatively regulated its expression. In response to miR-29a-3p overexpression, Robo1 silencing or LINC00473 silencing, HCC cell proliferation, migration, invasion, tumor progression, and metastasis were impeded, which was involved with the inactivation of the PI3K/AKT/mTOR signaling pathway. Notably, LINC00473 could competitively bind to miR-29a-3p to upregulate Robo1 expression. Conclusion: LINC00473 might be involved in HCC progression by acting as a miR-29a-3p sponge to upregulate the expression of Robo1 that activates the PI3K/AKT/mTOR signaling pathway, which leads to enhanced cell proliferation, migration, invasion, tumor progression, and metastasis in HCC.

scholarly journals Down-regulated microRNA-30b-3p inhibits proliferation, invasion and migration of glioma cells via inactivation of the AKT signaling pathway by up-regulating RECK

2019 ◽  
Vol 39 (8) ◽  
Author(s):  
Yan Jian ◽  
Chun-Hua Xu ◽  
You-Ping Li ◽  
Bin Tang ◽  
She-Hao Xie ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Glioma Cells ◽  
Akt Signaling ◽  
Migration And Invasion ◽  
Akt Signaling Pathway ◽  
Related Factors ◽  
Invasion And Migration ◽  
And Migration

AbstractmicroRNAs (miRNAs) have been found to affect various cancers, and expression of numerous miRNAs is revealed in glioma. However, the role of microRNA-30b-3p (miR-30b-3p) in glioma remains elusive. Therefore, the present study aims to explore the specific mechanism by which miR-30b-3p influence the development of glioma in relation to the AKT signaling pathway. First, glioma cell lines were collected with miR-30b-3p and reversion-inducing cysteine-rich protein with kazal motifs (RECK) expression measured. The functional role of miR-30b-3p and RECK in glioma was determined via gain- and loss-of-function approaches. Subsequently, the expression of invasion- and migration-related factors (MMP-2 and MMP-9) and the AKT signaling pathway-related factors (AKT, p-AKT and PI3K-p85) was detected. Moreover, in vivo experiments were also conducted to investigate how miR-30b-3p influences in vivo tumorigenesis. The results showed that miR-30b-3p was up-regulated and RECK was down-regulated in glioma. RECK was a target gene of miR-30b-3p. Decreased miR-30b-3p and overexpressed RECK led to decreased expression of MMP-2, MMP-9 and p-AKT. Overexpressed RECK and LY294002 could decrease p-AKT and PI3K-p85 expression accompanied with unchanged expression of total protein of AKT. Additionally, proliferation, migration and invasion of glioma cells and tumor formation in nude mice were repressed owing to reduced expression of miR-30b-3p or elevated expression of RECK. In summary, miR-30b-3p inhibition suppresses metastasis of glioma cells by inactivating the AKT signaling pathway via RECK up-regulation, providing a new target for glioma treatment.

scholarly journals CircHIPK3/miR-381-3p axis modulates proliferation, migration, and glycolysis of lung cancer cells by regulating the AKT/mTOR signaling pathway

2020 ◽  
Vol 15 (1) ◽  
pp. 683-695
Author(s):  
Feng Gu ◽  
Junhan Zhang ◽  
Lin Yan ◽  
Dong Li
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Mtor Signaling ◽  
Lung Cancer Cells ◽  
Luciferase Reporter ◽  
Mtor Signaling Pathway

AbstractLung cancer is a lethal malignancy. Plenty of circular RNAs (circRNAs) have been identified to be the vital regulators in lung cancer development. Here, we intended to clarify the functional role of circRNA HIPK3 (circHIPK3, also called hsa_circ_0021593) and its underlying mechanism of action. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was employed to evaluate the levels of circHIPK3 and miR-381-3p. Cell viability and apoptosis rate were monitored by Cell Counting Kit-8 assay and flow cytometry, respectively. Cell migration was estimated through the Transwell assay. To assess glycolysis, commercial kits were utilized to measure the levels of glucose and lactate and the enzyme activity of hexokinase-2 (HK2). Expression of related proteins was detected via western blot analysis. The target connection between circHIPK3 and miR-381-3p was validated by dual-luciferase reporter, RIP, and pull-down assays. The role of circHIPK3 in vivo was determined via the xenograft assay. CircHIPK3 was upregulated, while miR-381-3p was downregulated in lung cancer tissues and cells. And circHIPK3 deficiency inhibited lung cancer progression by lowering cell proliferation, migration, glycolysis, and promoting apoptosis of lung cancer cells in vitro. MiR-381-3p was a target of circHIPK3, and miR-381-3p interference alleviated circHIPK3 knockdown-induced lung cancer progression inhibition. CircHIPK3 could activate the protein kinase B/mammalian target of rapamycin (AKT/mTOR) signaling pathway. Moreover, circHIPK3 knockdown suppressed tumor growth in vivo by inactivating the AKT/mTOR signaling pathway. In conclusion, the silencing of circHIPK3 inhibited lung cancer progression, at least in part, by sponging miR-381-3p and inactivating the AKT/mTOR signaling pathway.

scholarly journals Mir-20a-5p Induced WTX Deficiency Promotes Gastric Cancer Progressions Through Regulating PI3K/AKT Signaling Pathway

2020 ◽  
Author(s):  
Jian Li ◽  
Danli Ye ◽  
Peng Shen ◽  
Xiaorong Liu ◽  
Peirong Zhou ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Signaling Pathway ◽  
Wilms Tumor ◽  
Mtor Signaling ◽  
Luciferase Assay ◽  
Mtor Signaling Pathway ◽  
Pathway Analyses

Abstract Background: The X-linked gene WTX (also called AMER1), has been reported to act as a tumor suppress gene in Wilms tumor. Our previous study reported that WTX expression was significantly reduced in gastric cancer (GC), but the function and mechanism of WTX loss had not been fully elucidated yet. Methods: WTX/miR-20a-5p expression was analyzed in paraffin-embedded archived GC tissues and validated in public databases. KEGG pathway analyses were performed to explore the mechanism of WTX in GC progression. The role of WTX/miR-20a-5p in cell growth, migration, invasion and angiogenesis was investigated in vitro and in vivo. Western blot, immunohistochemistry, RT-PCR, luciferase assay, and Co-immunoprecipitation (Co-IP) were used to detect the regulation of WTX and PI3K/AKT/mTOR signaling by miR-20a-5p.Results: We revealed that WTX served as a tumor suppressor whose loss associated with the aggressive feature of GC by showing hyperproliferation in vitro and high metastasis phenotype in vivo. And WTX expression level was positively correlated with the overall survival of GC patients. Microarray, bioinformatics analysis, and verification experiments showed that WTX loss activated PI3K/AKT/mTOR pathway, and promoted the proliferation and invasion of GC cells. We also discovered that the miR-20a-5P aberrant upregulation was one of the reasons inducing WTX loss in GC which stimulated PI3K phosphorylation to activate PI3K/AKT/mTOR signaling pathway, thus promoted GC progression.Conclusions: This study unveiled the mechanism of GC progression which was, at least partially, caused by miR-20a-5p aberrant upregulation which inhibited WTX expression and thus activate PI3K/AKT/mTOR signaling pathway. It provided a comprehensive understanding of the action of miR-20a-5p/WTX/PI3K/AKT/mTOR signaling pathway in the progression and metastasis of GC.

scholarly journals Histone demethylase KDM4A plays an oncogenic role in nasopharyngeal carcinoma by promoting cell migration and invasion

2021 ◽  
Author(s):  
Jingyi Zhao ◽  
Bingyan Li ◽  
Yongxia Ren ◽  
Tiansong Liang ◽  
Juan Wang ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Signaling Pathway ◽  
Tumor Formation ◽  
Mtor Signaling ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Mtor Signaling Pathway ◽  
Tissue Samples

AbstractCompelling evidence has indicated the vital role of lysine-specific demethylase 4 A (KDM4A), hypoxia-inducible factor-1α (HIF1α) and the mechanistic target of rapamycin (mTOR) signaling pathway in nasopharyngeal carcinoma (NPC). Therefore, we aimed to investigate whether KDM4A affects NPC progression by regulating the HIF1α/DDIT4/mTOR signaling pathway. First, NPC and adjacent tissue samples were collected, and KDM4A protein expression was examined by immunohistochemistry. Then, the interactions among KDM4A, HIF1α and DDIT4 were assessed. Gain- and loss-of-function approaches were used to alter KDM4A, HIF1α and DDIT4 expression in NPC cells. The mechanism of KDM4A in NPC was evaluated both in vivo and in vitro via RT-qPCR, Western blot analysis, MTT assay, Transwell assay, flow cytometry and tumor formation experiments. KDM4A, HIF1α, and DDIT4 were highly expressed in NPC tissues and cells. Mechanistically, KDM4A inhibited the enrichment of histone H3 lysine 9 trimethylation (H3K9me3) in the HIF1α promoter region and thus inhibited the methylation of HIF1α to promote HIF1α expression, thus upregulating DDIT4 and activating the mTOR signaling pathway. Overexpression of KDM4A, HIF1α, or DDIT4 or activation of the mTOR signaling pathway promoted SUNE1 cell proliferation, migration, and invasion but inhibited apoptosis. KDM4A silencing blocked the mTOR signaling pathway by inhibiting the HIF1α/DDIT4 axis to inhibit the growth of SUNE1 cells in vivo. Collectively, KDM4A silencing could inhibit NPC progression by blocking the activation of the HIF1α/DDIT4/mTOR signaling pathway by increasing H3K9me3, highlighting a promising therapeutic target for NPC.

scholarly journals Sempervirine Mediates Autophagy and Apoptosis via the Akt/mTOR Signaling Pathways in Glioma Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Gaopan Li ◽  
Yuhuan Zhong ◽  
Wenyi Wang ◽  
Xiaokang Jia ◽  
Huaichang Zhu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Signaling Pathway ◽  
Glioma Cells ◽  
Mtor Signaling ◽  
Autophagic Flux ◽  
Mtor Signaling Pathway ◽  
Phase Arrest ◽  
M Phase

The potential antitumor effects of sempervirine (SPV), an alkaloid compound derived from the traditional Chinese medicine Gelsemium elegans Benth., on different malignant tumors were described in detail. The impact of SPV on glioma cells and the basic atomic components remain uncertain. This study aimed to investigate the activity of SPV in vitro and in vivo. The effect of SPV on the growth of human glioma cells was determined to explore three aspects, namely, cell cycle, cell apoptosis, and autophagy. In this study, glioma cells, U251 and U87 cells, and one animal model were used. Cells were treated with SPV (0, 1, 4, and 8 μM) for 48 h. The cell viability, cell cycle, apoptosis rate and autophagic flux were examined. Cell cycle, apoptotic, autophagy, and Akt/mTOR signal pathway-related proteins, such as CDK1, Cyclin B1, Beclin-1, p62, LC3, AKT, and mTOR were investigated by Western blot approach. As a result, cells induced by SPV led to G2/M phase arrest and apoptosis. SPV also promoted the effect of autophagic flux and accumulation of LC3B. SPV reduced the expression of p62 protein and induced the autophagic death of glioma cells. Furthermore, SPV downregulated the expressions of AKT and mTOR phosphorylated proteins in the mTOR signaling pathway, thereby affecting the onset of apoptosis and autophagy in U251 cells. In conclusion, SPV induced cellular G2/M phase arrest and blockade of the Akt/mTOR signaling pathway, thereby triggering apoptosis and cellular autophagy. The in vivo and in vitro studies confirmed that SPV inhibits the growth of glioma cancer.

scholarly journals Deubiquitinase OTUD5 Modulates mTOR Signaling Pathways to Promote Bladder Cancer Progression

2021 ◽  
Author(s):  
Tao Hou ◽  
Weichao Dan ◽  
Tianjie Liu ◽  
Bo Liu ◽  
Yi Wei ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Mtor Signaling ◽  
Cancer Tissue ◽  
Mtor Signaling Pathway ◽  
Western Blot Assay

Abstract BackgroundThe mammalian target of Rapamycin (mTOR) pathway serves as a crucial regulator of various biological processes such as cell growth and cancer progression. In bladder cancer, recent discoveries showing the cancer-promoting role of mTOR complex 1 have attracted wide attention. However, the regulation of mTOR signaling in bladder cancer is complicated and the underlying mechanism remains elusive. Here, we report that the deubiquitinating enzyme, ovarian tumor domain-containing protein 5 (OTUD5), can activate the mTOR signaling pathway, promote cancer progression, and show its oncogenic potential in bladder cancer.MethodsThe expression of OTUD5 in bladder cancer was analyzed using bladder cancer tissue microarrays and Western blotting analysis. Meanwhile, to demonstrate the role of OTUD5-RNF186-Sestrin2-mTOR axis in bladder cancer, we have adopted a series of biochemical and molecular biological methods to verify in vivo and in vitro. The methods used included quantitative real time PCR assay; western blot assay; Immunofluorescence staining assay; MTT assay; colony formation assay; Co-immunoprecipitation assay; In vivo ubiquitination assay; Immunohistochemical assay and Bladder Cancer xenograft animal model.ResultsIn our study, we found that OTUD5 deubiquitinated a RING-type E3 ligase, RNF186, and stabilized its function. In addition, the stabilization of RNF186 further led to the degradation of Sestrin2, which is an inhibitor of mTOR signaling pathway. ConclusionTogether, we first proved that OTUD5 can promote bladder cancer progression through the OTUD5-RNF186-Sestrin2-mTOR axis and provided novel insights into the diagnosis and treatment of bladder cancer.

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