Dataset Information

Investigation of BRCAness associated miRNA-gene axes in breast cancer: cell-free miR-182-5p as a potential expression signature of BRCAness.

ABSTRACT: The concept of the 'BRCAness' phenotype implies the properties that some sporadic breast cancers (BC) share with BRCA1/2-mutation carriers with hereditary BC. Breast tumors with BRCAness have deficiencies in homologous recombination repair (HRR), like BRCA1/2-mutation carriers, and consequently could benefit from poly-(ADP)-ribose polymerase (PARP) inhibitors and DNA-damaging chemotherapy. Triple-negative breast cancers (TNBC) show a higher frequency of BRCAness than the other BC subtypes. Therefore, looking for BRCAness-related biomarkers could improve personalized management of TNBC patients. microRNAs (miRNAs) play a pivotal role in onco-transcriptomic profiles of tumor cells besides their suitable features as molecular biomarkers. The current study aims to evaluate the expression level of some critical miRNAs-mRNA axes in HRR pathway in tumors and plasma samples from BC patients. The expression levels of three multi-target miRNAs, including miR-182-5p, miR-146a-5p, and miR-498, as well as six downstream HRR-related protein-coding genes, have been investigated in the breast tumors and paired adjacent normal tissues by Real-time PCR. In the next step, based on the results derived from the previous step, we examined the level of cell-free miR-182-5p in the blood plasma samples from the patients. Our results highlight the difference between TNBC and non-TNBC tumor subgroups regarding the dysregulation of the key miRNA/mRNA axes involved in the HRR pathway. Also, for the first time, we show that the level of cell-free miR-182-5p in plasma samples from BC patients could be a clue for screening BC patients eligible for receiving PARP inhibitors through a personalized manner. Altogether, some sporadic BC patients, especially sporadic TNBC, have epigenetically dysregulated HRR pathway that could be identified and benefit from BRCAness-specific therapeutic agents.

SUBMITTER: Darbeheshti F

PROVIDER: S-EPMC9206264 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Investigation of BRCAness associated miRNA-gene axes in breast cancer: cell-free miR-182-5p as a potential expression signature of BRCAness.

Darbeheshti Farzaneh F Kadkhoda Sepideh S Keshavarz-Fathi Mahsa M Razi Sepideh S Bahramy Afshin A Mansoori Yaser Y Rezaei Nima N

BMC cancer 20220617 1

The concept of the 'BRCAness' phenotype implies the properties that some sporadic breast cancers (BC) share with BRCA1/2-mutation carriers with hereditary BC. Breast tumors with BRCAness have deficiencies in homologous recombination repair (HRR), like BRCA1/2-mutation carriers, and consequently could benefit from poly-(ADP)-ribose polymerase (PARP) inhibitors and DNA-damaging chemotherapy. Triple-negative breast cancers (TNBC) show a higher frequency of BRCAness than the other BC subtypes. There ...[more]

PMID: 35715772

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Project description:BackgroundDNA damage and DNA damage repair (DDR) are important therapeutic targets for triple-negative breast cancer (TNBC), a subtype with limited chemotherapy efficiency and poor outcome. However, the role of microRNAs in the therapy is emerging. In this study, we explored whether miR-26a-5p could act as BRCAness and enhance chemotherapy sensitivity in TNBC.MethodsQuantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to detect the expression of miR-26a-5p in breast cancer tissues and cell lines. CCK-8 was used to measure drug sensitivity in concentration gradient and time gradient. Comet assay was used to detect DNA damage. Flow cytometry was performed to examine apoptosis. Moreover, we used western blot and immunofluorescence to detect biomarkers. Luciferase reporter assay was performed to verify the combination of miR-26a-5p and 3'UTR of target gene. Hormone deprivation and stimulation assay were used to validate the effect of hormone receptors on the expression of miR-26a-5p. Chromatin immunoprecipitation (ChIP) assays were used to verify the binding sites of ER-a or PR with the promoter of miR-26a-5p. Animal experiments were performed to the effect of miR-26a-5p on Cisplatin treatment.ResultsThe expression of miR-26a-5p was significantly downregulated in TNBC. Overexpressing miR-26a-5p enhanced the Cisplatin-induced DNA damage and following apoptosis. Interestingly, miR-26a-5p promoted the expression of Fas without Cisplatin stimulating. It suggested that miR-26a-5p provided a hypersensitivity state of death receptor apoptosis and promoted the Cisplatin sensitivity of TNBC cells in vitro and in vivo. Besides, miR-26a-5p negatively regulated the expression of BARD1 and NABP1 and resulted in homologous recombination repair defect (HRD). Notably, overexpressing miR-26a-5p not only facilitated the Olaparib sensitivity of TNBC cells but also the combination of Cisplatin and Olaparib. Furthermore, hormone receptors functioned as transcription factors in the expression of miR-26a-5p, which explained the reasons that miR-26a-5p expressed lowest in TNBC.ConclusionsTaken together, we reveal the important role of miR-26a-5p in Cisplatin sensitivity and highlight its new mechanism in DNA damage and synthetic lethal.

Project description:ObjectiveThis study aimed to delineate the diagnostic significance of miR-182-5p by investigating its influence on myocardial apoptosis and function, employing both in vivo and in vitro myocardial infarction models.MethodsA rat myocardial infarction model was established. Myocardial infarction area was detected using the 2,3,5-chlorotriphenyltetrazolium (TTC) method, myocardial enzyme spectrums were measured using enzyme-linked immunosorbent assay (ELISA), myocardial structure was detected by hematoxylin and eosin (HE) staining, myocardial apoptosis was detected using the TUNEL method, and expression levels of miR-182-5p and apoptosis-related molecules were detected using real-time fluorescence quantitative PCR (qPCR) and Western blot. miR-182-5p mimics and inhibitor were transfected into rat H9C2 cardiomyocytes and mouse HL-1 cardiomyocytes to establish a hypoxia model. Cardiomyocyte viability was detected using the CCK-8 method, expression levels of apoptosis-related indicators were detected using Western blot, and caspase-3/7 activity was detected using a caspase-3/7 activity detection kit. AAV9 adeno-associated virus was used to construct an miR-182-5p overexpression virus, which was injected into mice through the tail vein to create a mouse myocardial infarction model. TTC, ELISA, HE staining, echocardiography, real-time fluorescence qPCR, and Western blot methods were used to detect the effects of AAV9-miR-182-5p on myocardial injury, myocardial function, and myocardial apoptosis levels in myocardial infarction.ResultsThe rat model displayed reduced miR-182-5p expression concurrent with an increase in apoptosis. The in vitro H9C2 and HL-1 hypoxia models revealed that miR-182-5p augmented the hypoxia-induced decrease in myocardial cell viability, suppressed Bcl-2 expression, and increased Bax, Bnip3, and caspase-3/7 activity levels. The injection of AAV9-miR-182-5p significantly exacerbated myocardial tissue damage, impaired myocardial function, and enhanced apoptosis.ConclusionmiR-182-5p escalates myocardial injury during myocardial infarction by fostering apoptosis. Interventions that aim to reduce miR-182-5p levels might be crucial in halting the progression of myocardial infarction.

Project description:Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset disease marked by a progressive degeneration of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. Death in most patients usually occurs within 2-4 years after symptoms onset. Despite promising progress in delineating underlying mechanisms, such as disturbed proteostasis, DNA/RNA metabolism, splicing or proper nucleocytoplasmic shuttling, there are no effective therapies for the vast majority of cases. A reason for this might be the disease heterogeneity and lack of substantial clinical and molecular biomarkers. The identification and validation of such pathophysiology driven biomarkers could be useful for early diagnosis and treatment stratification. Recent advances in next generation RNA-sequencing approaches have provided important insights to identify key changes of non-coding RNAs (ncRNAs) implicated with ALS disease. Especially, microRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression to target several genes/pathways by degrading messenger RNAs (mRNAs) or repressing levels of gene expression. In this study, we expand our previous work to identify top-regulated differentially expressed (DE)-miRNAs by combining different normalizations to search for important and generalisable pathomechanistic dysregulations in ALS as putative novel biomarkers of the disease. For this we performed a consensus pipeline of existing datasets to investigate the transcriptomic profile (mRNAs and miRNAs) of MN cell lines from iPSC-derived SOD1- and TARDBP (TDP-43 protein)-mutant-ALS patients and healthy controls to identify potential signatures and their related pathways associated with neurodegeneration. Transcriptional profiling of miRNA-mRNA interactions from MN cell lines in ALS patients revealed differential expression of genes showed greater vulnerability to KEAP1-NRF2 stress response pathway, sharing a common molecular denominator linked to both disease conditions. We also reported that mutations in above genes led to significant upregulation of the top candidate miR-10b-5p, which we could validate in immortalized lymphoblast cell lines (LCLs) derived from sporadic and familial ALS patients and postmortem tissues of familial ALS patients. Collectively, our findings suggest that miRNA analysis simultaneously performed in various human biological samples may reveal shared miRNA profiles potentially useful as a biomarker of the disease.

Project description:BackgroundExtracellular vesicles (EVs) derived from tumor cells are implicated in the progression of malignancies through the transfer of molecular cargo microRNAs (miRNAs or miRs). We aimed to explore the role of EVs derived from breast cancer cells carrying miR-182-5p in the occurrence and development of breast cancer.MethodsDifferentially expressed miRNAs and their downstream target genes related to breast cancer were screened through GEO and TCGA databases. miR-182-5p expression was examined in cancer tissues and adjacent normal tissues from patients with breast cancer. EVs were isolated from breast cancer cell line MDA-MB-231 cells and identified. The gain- and loss-of function approaches of miR-182-5p and CKLF-like MARVEL transmembrane domain-containing 7 (CMTM7) were performed in MDA-MB-231 cells and the isolated EVs. Human umbilical vein endothelial cells (HUVECs) were subjected to co-culture with MDA-MB-231 cell-derived EVs and biological behaviors were detected by CCK-8 assay, flow cytometry, immunohistochemical staining, Transwell assay and vessel-like tube formation in vitro. A xenograft mouse model in nude mice was established to observe the tumorigenesis and metastasis of breast cancer cells in vivo.ResultsmiR-182-5p was highly expressed in breast cancer tissues and cells, and this high expression was associated with poor prognosis of breast cancer patients. miR-182-5p overexpression was shown to promote tumor angiogenesis in breast cancer. Moreover, our data indicated that miR-182-5p was highly enriched in EVs from MDA-MD-231 cells and then ultimately enhanced the proliferation, migration, and angiogenesis of HUVECs in vitro and in vivo. Moreover, we found that CMTM7 is a target of miR-182-5p. EVs-miR-182-5p promotes tumorigenesis and metastasis of breast cancer cells by regulating the CMTM7/EGFR/AKT signaling axis.ConclusionsTaken altogether, our findings demonstrates that EVs secreted by breast cancer cells could carry miR-182-5p to aggravate breast cancer through downregulating CMTM7 expression and activating the EGFR/AKT signaling pathway.

Dataset Information

Investigation of BRCAness associated miRNA-gene axes in breast cancer: cell-free miR-182-5p as a potential expression signature of BRCAness.

Publications

Investigation of BRCAness associated miRNA-gene axes in breast cancer: cell-free miR-182-5p as a potential expression signature of BRCAness.

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