Introduction of hsa-miR-512-3p as a new regulator of HER2 signaling pathway in breast cancer

Mohamadzade, Zahra; Mahjoubi, Frouzande; Soltani, Bahram Mohammad

doi:10.1007/s10549-020-05937-3

Cited by 9 publications

(6 citation statements)

References 29 publications

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“…For instance, the combined decitabine/PBA treatment caused 47- and 35-fold induced expression of miRNA 517a-3p and miRNA512-3p (Fig. 4 A), and both tumor suppressors promote apoptosis [ 85 , 86 ]. Likewise, the combined decitabine/PBA treatment of Caco-2 cells caused 29-, 22-, 14- and 12-fold induced expression of miRNA516b-5p, miRNA519c-5p, miRNA526a and miRNA498, and these tumor suppressors inhibit cell proliferation [ 87 – 90 ].…”

Section: Resultsmentioning

confidence: 99%

Combined inhibition of histone deacetylase and cytidine deaminase improves epigenetic potency of decitabine in colorectal adenocarcinomas

2023

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Background Targeting the epigenome of cancerous diseases represents an innovative approach, and the DNA methylation inhibitor decitabine is recommended for the treatment of hematological malignancies. Although epigenetic alterations are also common to solid tumors, the therapeutic efficacy of decitabine in colorectal adenocarcinomas (COAD) is unfavorable. Current research focuses on an identification of combination therapies either with chemotherapeutics or checkpoint inhibitors in modulating the tumor microenvironment. Here we report a series of molecular investigations to evaluate potency of decitabine, the histone deacetylase inhibitor PBA and the cytidine deaminase (CDA) inhibitor tetrahydrouridine (THU) in patient derived functional and p53 null colon cancer cell lines (CCCL). We focused on the inhibition of cell proliferation, the recovery of tumor suppressors and programmed cell death, and established clinical relevance by evaluating drug responsive genes among 270 COAD patients. Furthermore, we evaluated treatment responses based on CpG island density. Results Decitabine caused marked repression of the DNMT1 protein. Conversely, PBA treatment of CCCL recovered acetylation of histone 3 lysine residues, and this enabled an open chromatin state. Unlike single decitabine treatment, the combined decitabine/PBA treatment caused > 95% inhibition of cell proliferation, prevented cell cycle progression especially in the S and G2-phase and induced programmed cell death. Decitabine and PBA differed in their ability to facilitate re-expression of genes localized on different chromosomes, and the combined decitabine/PBA treatment was most effective in the re-expression of 40 tumor suppressors and 13 genes typically silenced in cancer-associated genomic regions of COAD patients. Furthermore, this treatment repressed expression of 11 survival (anti-apoptotic) genes and augmented expression of X-chromosome inactivated genes, especially the lncRNA Xist to facilitate p53-mediated apoptosis. Pharmacological inhibition of CDA by THU or its gene knockdown prevented decitabine inactivation. Strikingly, PBA treatment recovered the expression of the decitabine drug-uptake transporter SLC15A1, thus enabling high tumor drug-loads. Finally, for 26 drug responsive genes we demonstrated improved survival in COAD patients. Conclusion The combined decitabine/PBA/THU drug treatment improved drug potency considerably, and given their existing regulatory approval, our findings merit prospective clinical trials for the triple combination in COAD patients.

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Section: Resultsmentioning

confidence: 99%

Combined inhibition of histone deacetylase and cytidine deaminase improves epigenetic potency of decitabine in colorectal adenocarcinomas

2023

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“…Here, we suggested that LINC01405 sponges miR‐29b and miR‐497 through which, it upregulated common target genes of these miRNAs, resulting in the upregulating of Wnt, PI3K, and TGFB signaling. Here, we took the first step to investigate the effect of LINC01405 on breast cancer, but it is necessary to conduct comprehensive study programs to find its role in different cancers and more breast cancer samples 35–38 …”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Here, we took the first step to investigate the effect of LINC01405 on breast cancer, but it is necessary to conduct comprehensive study programs to find its role in different cancers and more breast cancer samples. [35][36][37][38] Details associated with the LINC01405 (Loc100131138) function in the cell are represented by a schematic (Figure 8).…”

Section: Acknowledgmentsmentioning

confidence: 99%

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In‐silico and in‐vitro evidence suggest LINC01405 as a sponge for miR‐29b and miR‐497‐5p, and a potential regulator of Wnt, PI3K, and TGFB signaling pathways in breast carcinoma

Norouzi,

Mohamadzade,

Norouzi

et al. 2024

Cancer Reports

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BackgroundCarcinoma of the breast, a prevailing factor in female mortality worldwide, involves dysregulation of lncRNAs and microRNAs.AimThe main goal of this research was to predict and experimentally examine the LINC01405 expression status in breast cancer subtypes, along with investigation of its interaction with miR‐29b and miR‐497‐5p that results in regulating PI3‐Kinase, WNT, and TGF‐beta signaling pathways.Methods and ResultsWe performed a meta‐analysis of five GEO datasets, encompassing microarray and RNA‐seq data, to identify differentially expressed genes. The Cancer Genome Atlas transcriptome dataset was also analyzed to determine essential gene modules, associated with different stages of breast cancer by weighted gene co‐expression networks. In addition, networks of drug‐gene interactions were constructed to explore potential treatment options. LINC01405 as a microRNA sponge was chosen and examined. furthermore, downstream target genes were discovered.Experimental validation consisted of plasmid constructs used in cell culture experiments, RT‐qPCR for expression analysis, and cell cycle assays. Our bioinformatics findings showed higher LINC01405 expression in Basal‐like triple‐negative breast carcinoma. In contrast, lower expression in Luminal samples was observed compared with normal samples, which was consistently observed in both breast cancer tissues and cell lines. LINC01405 expression level was correlated with miR‐29b and miR‐497 levels. The MDA‐MB‐231 cell line demonstrated higher LINC01405 expression and lower miR‐29b and miR‐497 expression levels. However, SKBR3 and MCF7 cells had lower LINC01405 expression and higher miR‐29b and miR‐497 levels, suggesting a regulatory role for LINC01405 as a competing endogenous RNA. This was experimentally confirmed when LINC01405 was overexpressed in SKBR3 cells, and the common target genes of miR‐29b and miR‐497 were upregulated. Additionally, LINC01405 upregulation led to the increased cell populations, proliferation, and upregulation of critical cancer‐related genes, including AKT1, AKT3, mTOR, WNT3A, SMAD3, CYCLIN D1, CYCLIN D2, BCL2, and GSK3B.ConclusionWe revealed the differential expression of LINC01405 in several types of breast cancer and its role in regulating signaling pathways, potentially via scavenging miRNAs. These findings clarified the role of LINC01405 in breast cancer development and identified potential therapeutic targets.

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“…After intersecting with 289 DEmiRNAs, 25 miRNAs were obtained. Among them, 7 miRNAs (miR-671-5p, miR-940, miR-124-3p, miR-944, miR-93-5p, miR-512-3p and miR-142-5p) have been reported in breast cancer ( Flores-Pérez et al, 2016 ; Tan et al, 2016 ; Wang et al, 2016 ; Zhang et al, 2020a ; Elango et al, 2020 ; Mohamadzade et al, 2021 ; Pan et al, 2021 ). For instance, overexpression of miR-671-5p suppressed FOXM1 expression, thereby reducing breast cancer cells growth and invasion ( Tan et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Upregulation of circ_0008812 and circ_0001583 predicts poor prognosis and promotes breast cancer proliferation

Lin

Long

Zhang³

et al. 2022

Front. Mol. Biosci.

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Background: Accumulating evidence suggests that circular RNAs (circRNAs) are highly correlated with tumor progression and pathogenesis in breast cancer. Whereas, their regulatory roles and corresponding mechanisms in breast cancer are still not exhaustive. Thus, we intended to establish circRNA-mediated competive endogenous RNA (ceRNA) network to uncover the possible roles and clinical implications of circRNAs in breast cancer.Methods: Microarray and RNA-sequencing (RNA-seq) data were download from GEO and TCGA database to screen for differentially expressed RNAs (DEcircRNAs, DEmiRNAs, DEmRNAs) in breast cancer. By implementing online databases, we established ceRNA networks, performed gene set enrichment analysis, constructed protein-protein interaction (PPI) networks, and assessed the expression levels and prognostic significance of hub genes. Subsequently, we explored the functions of prognosis-related genes and constructed gene-drug interaction networks. Finally, the functional roles of DEcircRNAs in breast cancer were revealed via MTT and colony formation assay.Results: Based on the identified 8 DEcircRNAs, 25 miRNAs and 216 mRNAs, a ceRNA regulatory network was established. Further analysis revealed that prominent enrichments were transcription factor binding, transforming growth factor-beta (TGF-β) and Apelin signaling pathway etc. PPI network and survival curves analysis showed that elevated levels of hub genes (RACGAP1 and KPNA2) were associated with poorer prognosis. They were found to be positively relevant to cell cycle and proliferation. Then a prognostic sub-network of ceRNA was constructed, consisting of 2 circRNAs, 4 miRNAs and 2 mRNAs. The gene-drug interaction network showed that numerous drugs could regulate the expression of these two prognosis-related genes. Functional experiments showed that depletion of circ_0008812 and circ_0001583 could significantly inhibit the proliferation of MCF-7 cells.Conclusion: Our study constructed 4 prognostic regulatory axes that are significantly correlated with tumor prognosis in breast cancer patients, and uncover the roles of circ_0008812 and circ_0001583 in breast cancer, providing a new perspective into the molecular mechanisms of breast cancer pathogenesis.

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Introduction of hsa-miR-512-3p as a new regulator of HER2 signaling pathway in breast cancer

Cited by 9 publications

References 29 publications

Combined inhibition of histone deacetylase and cytidine deaminase improves epigenetic potency of decitabine in colorectal adenocarcinomas

Combined inhibition of histone deacetylase and cytidine deaminase improves epigenetic potency of decitabine in colorectal adenocarcinomas

In‐silico and in‐vitro evidence suggest LINC01405 as a sponge for miR‐29b and miR‐497‐5p, and a potential regulator of Wnt, PI3K, and TGFB signaling pathways in breast carcinoma

Upregulation of circ_0008812 and circ_0001583 predicts poor prognosis and promotes breast cancer proliferation

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