Loss of miR-101-3p Promotes Transmigration of Metastatic Breast Cancer Cells through the Brain Endothelium by Inducing COX-2/MMP1 Signaling

Harati, Rania; Mohammad, Mohammad G.; Tlili, Abdelaziz; El‐Awady, Raafat; Hamoudi, Rifat

doi:10.3390/ph13070144

Cited by 32 publications

(33 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In another study, brain metastatic cancer cells were shown to release microRNA-181c-containing extracellular vesicles capable of destructing the BBB [63]. In addition, we recently demonstrated that loss of miR-101-3p promote transmigration of BC cells by inducing COX-2/MMP1 signaling [64]. These observations point to miRNA as promising therapeutic targets, however, more research is still needed to unravel the panel of specific micro-RNA profiles that regulate the different steps of breast cancer brain metastatic cascade and that are suitable as therapeutic agents to suppress or prevent BM.…”

Section: Discussionmentioning

confidence: 92%

Silencing miR-202-3p increases MMP-1 and promotes a brain invasive phenotype in metastatic breast cancer cells

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background Brain metastasis (BM) is a major cause of morbidity and mortality in breast cancer (BC) and its molecular mechanism remains poorly understood. Transmigration of metastatic cells through the brain endothelium is an essential step in BM. Metalloproteinase-1 (MMP-1) overexpression plays a key role in promoting trans-endothelial migration by degrading the inter-endothelial junctions and disrupting the endothelial integrity. However, little is known about the molecular mechanisms that induce MMP-1 in metastatic cells granting them a brain invasive phenotype. MiR-202-3p is downregulated in brain metastases compared to primary breast tumors and directly targets MMP-1. Here, we unraveled a critical role of miR-202-3p loss in MMP-1 upregulation promoting transmigration of metastatic cells through the brain endothelium. Methods A variant of the MDA-MB-231 human BC cell line (MDA-MB-231-BrM2) selected for its propensity to form brain metastases was found to express high levels of MMP-1 and low levels of miR-202-3p compared to the parental cells. Using a gain-and-loss of function approach, we modulated levels of miR-202-3p and examined the resultant effect on MMP-1 expression. Effect of miR-202-3p modulation on integrity of the brain endothelium and the transmigrative ability of BC cells were also examined. Results Loss of miR-202-3p in breast cancer cells enhanced their transmigration through the brain endothelium by upregulating MMP-1 and disrupting the inter-endothelial junctions (claudin-5, ZO-1 and ß-catenin). Restoring miR-202-3p exerted a metastasis-suppressive effect and preserved the endothelial barrier integrity.

show abstract

Section: Discussionmentioning

confidence: 92%

Silencing miR-202-3p increases MMP-1 and promotes a brain invasive phenotype in metastatic breast cancer cells

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…In our study, we found high expression in the cavernous and differentiated histological subtypes. Claudin-5 could be used as a marker with greater sensitivity and could also be of diagnostic value in the differential diagnosis of canine HSAs from other sarcomas with hemorrhage or increased vascularization [16,17,[32][33][34]. Claudin-5 might also represent an interesting prognostic marker for canine HSA metastasis.…”

Section: Discussionmentioning

confidence: 99%

Investigation of Prognostic Value of Claudin-5, PSMA, and Ki67 Expression in Canine Splenic Hemangiosarcoma

Rozolen

Teodoro

Sobral³

et al. 2021

Animals

View full text Add to dashboard Cite

Splenic hemangiosarcoma (HSA) is a malignant tumor of endothelial cells that affects middle-aged and elderly dogs and is characterized by the formation of new blood vessels, commonly associated with necrotic and hemorrhagic areas. Despite its importance in veterinary medicine, few studies have identified markers with prognostic value for canine HSA. Thus, this study aimed to associate the clinicopathological findings (prostate-specific membrane antigen [PSMA], Claudin-5, and Ki67 gene and protein expression) with overall survival in HSA-affected patients. Fifty-three formalin-fixed and paraffin-embedded canine splenic HSA samples, previously diagnosed by histopathological examination, were used in this study. Claudin-5, PSMA, and Ki67 protein expression levels were evaluated by immunohistochemistry, and gene expression was evaluated by quantitative polymerase chain reaction. Claudin-5 protein overexpression was observed in patients with metastasis (p = 0.0078) and with stage III tumors compared to those with stage I and II tumors (p = 0.0451). In patients treated with surgery alone, low PSMA gene and protein expression (p = 0.05 and p = 0.0355, respectively) were associated with longer survival time. Longer survival time was observed in patients with a low Ki67 index (p = 0.0488). Our results indicate that Claudin-5 protein expression is associated with metastatic status, and PSMA gene and protein expression, and Ki67 index are associated with survival time.

show abstract

“…MMPs not only promote tumour cell invasion and proliferation by destroying the ECM barrier but also act on cell signalling in a variety of ways 46 . One study reported a link between MMP1 and brain metastasis in breast cancer, 47 and several studies have examined the influence of MMP11 expression on the prognosis of patients with breast cancer 48,49 . The relationship between MMP13 and metastatic breast cancer has not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

Identification of genes and pathways related to breast cancer metastasis in an integrated cohort

Wang

et al. 2021

Eur J Clin Investigation

View full text Add to dashboard Cite

Background Breast cancer is the most common malignant disease in women. Metastasis is the most common cause of death from this cancer. Screening genes related to breast cancer metastasis may help elucidate the mechanisms governing metastasis and identify molecular targets for antimetastatic therapy. The development of advanced algorithms enables us to perform cross‐study analysis to improve the robustness of the results. Materials and methods Ten data sets meeting our criteria for differential expression analyses were obtained from the Gene Expression Omnibus (GEO) database. Among these data sets, five based on the same platform were formed into a large cohort using the XPN algorithm. Differentially expressed genes (DEGs) associated with breast cancer metastasis were identified using the differential expression via distance synthesis (DEDS) algorithm. A cross‐platform method was employed to verify these DEGs in all ten selected data sets. The top 50 validated DEGs are represented with heat maps. Based on the validated DEGs, Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Protein interaction (PPI) networks were constructed to further illustrate the direct and indirect associations among the DEGs. Survival analysis was performed to explore whether these genes can affect breast cancer patient prognosis. Results A total of 817 DEGs were identified using the DEDS algorithm. Of these DEGs, 450 genes were validated by the second algorithm. Enriched KEGG pathway terms demonstrated that these 450 DEGs may be involved in the cell cycle and oocyte meiosis in addition to their functions in ECM‐receptor interaction and protein digestion and absorption. PPI network analysis for the proteins encoded by the DEGs indicated that these genes may be primarily involved in the cell cycle and extracellular matrix. In particular, several genes played roles in multiple signalling pathways and were related to patient survival. These genes were also observed to be targetable in the CTD2 database. Conclusions Our study analysed multiple cross‐platform data sets using two different algorithms, helping elucidate the molecular mechanisms and identify several potential therapeutic targets of metastatic breast cancer. In addition, several genes exhibited promise for applications in targeted therapy against metastasis in future research.

show abstract

Loss of miR-101-3p Promotes Transmigration of Metastatic Breast Cancer Cells through the Brain Endothelium by Inducing COX-2/MMP1 Signaling

Cited by 32 publications

References 54 publications

Silencing miR-202-3p increases MMP-1 and promotes a brain invasive phenotype in metastatic breast cancer cells

Silencing miR-202-3p increases MMP-1 and promotes a brain invasive phenotype in metastatic breast cancer cells

Investigation of Prognostic Value of Claudin-5, PSMA, and Ki67 Expression in Canine Splenic Hemangiosarcoma

Identification of genes and pathways related to breast cancer metastasis in an integrated cohort

Contact Info

Product

Resources

About