MiR-26a and miR-138 block the G1/S transition by targeting the cell cycle regulating network in prostate cancer cells

Erdmann, Kati; Kaulke, Knut; Rieger, Christiane; Salomo, Karsten; Wirth, Manfred P.; Fuessel, Susanne

doi:10.1007/s00432-016-2222-4

Cited by 36 publications

(24 citation statements)

References 56 publications

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“…Interestingly, the present study showed that UC-MSCs decreased the mRNA level of CDK6 in both tumor cell lines, and also confirmed the expression at the protein level by reduction of CDK6 protein level in HL-60 cells. Furthermore, other studies also revealed that miR-34a, miR-26a, and miR-138 significantly diminished the expression of CCNE2 and CDK6 in tumor cells and arrested the cells at the G 1 /S transition 30,31 .…”

Section: Discussionmentioning

confidence: 87%

Human Mesenchymal Stem Cells-mediated Transcriptomic Regulation of Leukemic Cells in Delivering Anti-tumorigenic Effects

et al. 2020

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Treatment of leukemia has become much difficult because of resistance to the existing anticancer therapies. This has thus expedited the search for alternativ therapies, and one of these is the exploitation of mesenchymal stem cells (MSCs) towards control of tumor cells. The present study investigated the effect of human umbilical cord-derived MSCs (UC-MSCs) on the proliferation of leukemic cells and gauged the transcriptomic modulation and the signaling pathways potentially affected by UC-MSCs. The inhibition of growth of leukemic tumor cell lines was assessed by proliferation assays, apoptosis and cell cycle analysis. BV173 and HL-60 cells were further analyzed using microarray gene expression profiling. The microarray results were validated by RT-qPCR and western blot assay for the corresponding expression of genes and proteins. The UC-MSCs attenuated leukemic cell viability and proliferation in a dose-dependent manner without inducing apoptosis. Cell cycle analysis revealed that the growth of tumor cells was arrested at the G0/G1 phase. The microarray results identified that HL-60 and BV173 share 35 differentially expressed genes (DEGs) (same expression direction) in the presence of UC-MSCs. In silico analysis of these selected DEGs indicated a significant influence in the cell cycle and cell cycle-related biological processes and signaling pathways. Among these, the expression of DBF4, MDM2, CCNE2, CDK6, CDKN1A, and CDKN2A was implicated in six different signaling pathways that play a pivotal role in the anti-tumorigenic activity exerted by UC-MSCs. The UC-MSCs perturbate the cell cycle process of leukemic cells via dysregulation of tumor suppressor and oncogene expression.

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Section: Discussionmentioning

confidence: 87%

Human Mesenchymal Stem Cells-mediated Transcriptomic Regulation of Leukemic Cells in Delivering Anti-tumorigenic Effects

et al. 2020

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“…In concert with these ndings, our study demonstrates that lncRNA UPK1A-AS1 interacts with miR-138-5p that is reported to be a tumor suppressor in HCC. Of note, miR-138-5p was downregulated in HCC and acted as a tumor suppressor to inhibit several cell cycle-related genes like CDK6 [27][28][29]. Indeed, UPK1A-AS1-induced CDK6 overexpression is partially dependent on the activity of miR-138-5p, as overexpression of miR-138-5p can ablate UPK1A-AS1 activity in HCC.…”

Section: Discussionmentioning

confidence: 99%

Long noncoding RNA UPK1A-AS1 indicates poor prognosis of hepatocellular carcinoma and promotes cell proliferation through interacting with EZH2

Zhang

Sun

Zou

et al. 2020

Preprint

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Background: Dysregulations of lncRNA are responsible for cancer initiation and development, positioning lncRNAs as not only biomarkers but also promising therapeutic targets for cancer treatment. Growing number of lncRNAs have been reported in HCC but their functional and mechanistic roles remain unclear. Methods: Gene Set Enrichment Analysis was used to investigate the molecular mechanism of lncRNA UPK1A antisense RNA 1 (UPK1A-AS1). CCK-8 assay, EdU assay, flow cytometry, western blot, and xenograft assay were used to confirm the role of UPK1A-AS1 in the proliferation of HCC cells both in vitro and in vivo. Bioinformatics analysis and qRT-PCR were performed to explore the interplay between UPK1A-AS1 and Enhancer of Zeste Homologue 2 (EZH2). RNA immunoprecipitation (RIP), RNA-pull down assay, western blot, qRT-PCR, and were conducted to confirm the interaction between UPK1A-AS1 and EZH2. The interaction between UPK1A-AS1 and miR-138-5p was examined by luciferase reporter and RIP assays. Finally, the expression level and prognosis value of UPK1A-AS1 in HCC were analyzed using RNA-seq data from TCGA datasets.Results: We showed that UPK1A-AS1, a newly identified lncRNA, promoted cellular proliferation and tumor growth by accelerating cell cycle progression. Cell cycle related genes including CCND1, CDK2, CDK4, CCNB1 and CCNB2 were significantly upregulated in HCC cells with UPK1A-AS1 overexpression. Furthermore, overexpression of UPK1A-AS1 could protect HCC cells from cis-platinum toxicity. Mechanistically, UPK1A-AS1 interacted with EZH2 to mediate its nuclear translocation and reinforce its binding to SUZ12, leading to the increasing trimethylation of H27K3. Targeting EZH2 with specific siRNA impaired UPK1A-AS1-mediated upregulation of proliferation and cell cycle progression related genes. Moreover, miR-138-5p was identified as a direct target of UPK1A-AS1. Additionally, UPK1A-AS1 was significantly upregulated in HCC, and upregulation of UPK1A-AS1 predicted poor prognosis for patients with HCC. Conclusions: Our study reveals that UPK1A-AS1 promotes HCC development by accelerating cell cycle progression via interacting with EZH2 and sponging miR-138-5p, suggesting that UPK1A-AS1 possesses substantial potential as a novel biomarker for HCC prognosis and therapy.

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“…Notably, miR-138-5p was downregulated in HCC and acted as a tumor suppressor to inhibit several cell cycle-related genes such as CDK6 [27][28][29]. Indeed, UPK1A-AS1-induced CDK6 overexpression was partially dependent on the activity of miR-138-5p, as overexpression of miR-138-5p ablated UPK1A-AS1 activity in HCC.…”

Section: Discussionmentioning

confidence: 99%

Long noncoding RNA UPK1A-AS1 indicates poor prognosis of hepatocellular carcinoma and promotes cell proliferation through interaction with EZH2

Zhang

Sun

Zou

et al. 2020

Preprint

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Background: Dysregulation of long non-coding RNAs (lncRNAs) is responsible for cancer initiation and development, positioning lncRNAs as not only biomarkers but also promising therapeutic targets for cancer treatment. A growing number of lncRNAs have been reported in hepatocellular carcinoma (HCC), but their functional and mechanistic roles remain unclear. Methods: Gene Set Enrichment Analysis was used to investigate the molecular mechanism of UPK1A antisense RNA 1 (UPK1A-AS1). Cell Counting Kit-8 assays, EdU assays, flow cytometry, western blotting, and xenograft assays were used to confirm the role of UPK1A-AS1 in the proliferation of HCC cells in vitro and in vivo . Bioinformatics analyses and quantitative polymerase chain reaction (qRT-PCR) were performed to explore the interplay between UPK1A-AS1 and enhancer of zeste homologue 2 (EZH2). RNA immunoprecipitation (RIP), RNA pull-down assays, western blotting, and qRT-PCR were conducted to confirm the interaction between UPK1A-AS1 and EZH2. The interaction between UPK1A-AS1 and miR-138-5p was examined by luciferase reporter and RIP assays. Finally, the expression level and prognosis value of UPK1A-AS1 in HCC were analyzed using RNA sequencing data from The Cancer Genome Atlas datasets. Results: We showed that UPK1A-AS1, a newly identified lncRNA, promoted cellular proliferation and tumor growth by accelerating cell cycle progression. Cell cycle-related genes, including CCND1, CDK2, CDK4, CCNB1, and CCNB2, were significantly upregulated in HCC cells overexpressing UPK1A-AS1. Furthermore, overexpression of UPK1A-AS1 could protect HCC cells from cis-platinum toxicity. Mechanistically, UPK1A-AS1 interacted with EZH2 to mediate its nuclear translocation and reinforce its binding to SUZ12, leading to increased H27K3 trimethylation. Targeting EZH2 with specific small interfering RNA impaired the UPK1A-AS1-mediated upregulation of proliferation and cell cycle progression-related genes. Moreover, miR-138-5p was identified as a direct target of UPK1A-AS1. Additionally, UPK1A-AS1 was significantly upregulated in HCC, and the upregulation of UPK1A-AS1 predicted poor prognosis for patients with HCC. Conclusions: Our study revealed that UPK1A-AS1 promotes HCC development by accelerating cell cycle progression through interaction with EZH2 and sponging of miR-138-5p, suggesting that UPK1A-AS1 possesses substantial potential as a novel biomarker for HCC prognosis and therapy.

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MiR-26a and miR-138 block the G1/S transition by targeting the cell cycle regulating network in prostate cancer cells

Abstract: The present findings suggest an anti-proliferative role for miR-26a and miR-138 in PCa by blocking the G1/S-phase transition independent of EZH2 but via a concerted inhibition of crucial cell cycle regulators.

Cited by 36 publications

References 56 publications

Human Mesenchymal Stem Cells-mediated Transcriptomic Regulation of Leukemic Cells in Delivering Anti-tumorigenic Effects

Human Mesenchymal Stem Cells-mediated Transcriptomic Regulation of Leukemic Cells in Delivering Anti-tumorigenic Effects

Long noncoding RNA UPK1A-AS1 indicates poor prognosis of hepatocellular carcinoma and promotes cell proliferation through interacting with EZH2

Long noncoding RNA UPK1A-AS1 indicates poor prognosis of hepatocellular carcinoma and promotes cell proliferation through interaction with EZH2

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