scholarly journals The antihyperlipidemic drug Potassium Piperate impairs migration and tumorgenesis of breast cancer cells via upregulation of miR-31

2021 ◽  
Author(s):  
Junping Lu ◽  
Xiaoxia Tian ◽  
Mailisu Mailisu ◽  
Morigen Morigen ◽  
Lifei Fan
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cell Invasion ◽  
Combination Treatment ◽  
Breast Cancer Cells ◽  
Target Genes ◽  
Cancer Cell Invasion

Abstract Background Breast cancer is a leading malignant tumor which causes deaths among women, and metastasis is the primary cause for mortality in breast cancer. Due to the involvement of many regulatory molecules and signaling pathways, the occurrence and development process of metastasis needs to be further studied. MicroRNAs (miRNAs) are ubiquitously expressed small non-coding RNAs that have been shown to play an important role in the diagnosis and treatment of many diseases, as well as constituting an attractive candidate to control metastasis. In this study, we tried to uncover the mechanism of GBK in impairing breast cancer cell invasion and metastasis.Methods We treated cancer cells with GBK or not, found its target miRNA by analyzed miRNA transcriptional changes and the miRNA target genes by performed with the QT-PCR and Western Blot. The proliferation of breast cancer cells in vitro and in vivo under combination treatment with GBK and DDP was measured by CCK-8 kit and the nude mice tumor formation experiment.Results We found tumor suppressor miR-31 was a main target of GBK. GBK treatment affected the epigenetic modification at CpG sites by downregulating DNA methyltransferases, thus the methylation levels at CpG of lncRNA LOC554202 decreased significantly, and in turn upregulating of both miR-31 and its host gene LOC554202 in breast cancer cells. We also observed significant inhibition of miR-31 target genes under GBK stimulation, including RhoA, WAVE3 and SATB2, which all closely related to cancer cell invasion, migration and proliferation. Furthermore, we revealed that combination treatment with GBK and DDP had synergistic and dose reduction potential in inhibiting the proliferation of breast cancer cells in vitro and in vivo, especially in TNBC.Conclusion This study further analyzes the target and underlying mechanism of GBK in inhibiting breast cancer migration and invasion, and provides theoretical support for the development of GBK as an auxiliary drug for clinical treatment.

scholarly journals Integrin α3β1 Promotes Invasive and Metastatic Properties of Breast Cancer Cells through Induction of the Brn-2 Transcription Factor

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 480
Author(s):  
Rakshitha Pandulal Miskin ◽  
Janine S. A. Warren ◽  
Abibatou Ndoye ◽  
Lei Wu ◽  
John M. Lamar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Cancer Cells ◽  
Cell Invasion ◽  
Breast Cancer Cells ◽  
Gene Promoter ◽  
Akt Inhibitor ◽  
Integrin Α3β1

In the current study, we demonstrate that integrin α3β1 promotes invasive and metastatic traits of triple-negative breast cancer (TNBC) cells through induction of the transcription factor, Brain-2 (Brn-2). We show that RNAi-mediated suppression of α3β1 in MDA-MB-231 cells caused reduced expression of Brn-2 mRNA and protein and reduced activity of the BRN2 gene promoter. In addition, RNAi-targeting of Brn-2 in MDA-MB-231 cells decreased invasion in vitro and lung colonization in vivo, and exogenous Brn-2 expression partially restored invasion to cells in which α3β1 was suppressed. α3β1 promoted phosphorylation of Akt in MDA-MB-231 cells, and treatment of these cells with a pharmacological Akt inhibitor (MK-2206) reduced both Brn-2 expression and cell invasion, indicating that α3β1-Akt signaling contributes to Brn-2 induction. Analysis of RNAseq data from patients with invasive breast carcinoma revealed that high BRN2 expression correlates with poor survival. Moreover, high BRN2 expression positively correlates with high ITGA3 expression in basal-like breast cancer, which is consistent with our experimental findings that α3β1 induces Brn-2 in TNBC cells. Together, our study demonstrates a pro-invasive/pro-metastatic role for Brn-2 in breast cancer cells and identifies a role for integrin α3β1 in regulating Brn-2 expression, thereby revealing a novel mechanism of integrin-dependent breast cancer cell invasion.

scholarly journals Osteoblast-Derived Paracrine and Juxtacrine Signals Protect Disseminated Breast Cancer Cells from Stress

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1366
Author(s):  
Russell Hughes ◽  
Xinyue Chen ◽  
Natasha Cowley ◽  
Penelope D. Ottewell ◽  
Rhoda J. Hawkins ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Survival ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Metastatic Breast ◽  
Accessory Cell ◽  
Cancer Cell Survival

Metastatic breast cancer in bone is incurable and there is an urgent need to develop new therapeutic approaches to improve survival. Key to this is understanding the mechanisms governing cancer cell survival and growth in bone, which involves interplay between malignant and accessory cell types. Here, we performed a cellular and molecular comparison of the bone microenvironment in mouse models representing either metastatic indolence or growth, to identify mechanisms regulating cancer cell survival and fate. In vivo, we show that regardless of their fate, breast cancer cells in bone occupy niches rich in osteoblastic cells. As the number of osteoblasts in bone declines, so does the ability to sustain large numbers of breast cancer cells and support metastatic outgrowth. In vitro, osteoblasts protected breast cancer cells from death induced by cell stress and signaling via gap junctions was found to provide important juxtacrine protective mechanisms between osteoblasts and both MDA-MB-231 (TNBC) and MCF7 (ER+) breast cancer cells. Combined with mathematical modelling, these findings indicate that the fate of DTCs is not controlled through the association with specific vessel subtypes. Instead, numbers of osteoblasts dictate availability of protective niches which breast cancer cells can colonize prior to stimulation of metastatic outgrowth.

scholarly journals PFKFB4 Promotes Breast Cancer Metastasis via Induction of Hyaluronan Production in a p38-Dependent Manner

2018 ◽  
Vol 50 (6) ◽  
pp. 2108-2123 ◽  
Author(s):  
Ruifang Gao ◽  
Yanhua Liu ◽  
Dan Li ◽  
Jing Xun ◽  
Wei Zhou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Tumor Metastasis ◽  
Dependent Manner ◽  
Fructose 2

Background/Aims: The bi-functional enzyme 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase-4 (PFKFB4) is highly expressed in many types of cancer and its requirement for tumor survival has been demonstrated in glioma, lung, and prostate cancers. However, whether PFKFB4 plays a role in the tumor metastasis remains uncertain. This study explores the role of PFKFB4 in tumor metastasis and its underlying mechanisms in breast cancer cells. Methods: The expression of PFKFB4 was first analyzed using the Cancer Genome Atlas (TCGA) dataset, and confirmed by immunohistochemical staining of tissue microarray and breast cancer tissues from patient samples. Gain- and loss-of- function approaches were used to investigate the effects of PFKFB4 on breast cancer cell migration in vitro. Orthotopic xenograft model and experimental metastasis model were used to assess the effects of PFKFB4 on breast cancer cell metastasis in vivo. ELISA and immunofluorescence staining were used to examine HA production. Quantitative RT-PCR and western blotting were used to explore the mRNA and protein levels of HAS2, respectively. Results: We found that PFKFB4 enhances the migration/invasiveness of breast cancer cells in vitro as well as in vivo. Notably, the effects of PFKFB4 on migration are mediated by induction of HAS2 expression and HA production. Moreover, PFKFB4-induced HAS2 up-regulation depends upon the activation of p38 signaling. Conclusion: PFKFB4 promotes the metastasis of breast cancer cells via induction of HAS2 expression and HA production in a p38-dependent manner. Therefore, the PFKFB4/p38/HAS2 signaling pathway may serve as a potential therapeutic target for metastatic breast cancer.

scholarly journals Breast cancer cell-derived extracellular vesicles transfer miR-182-5p and promote breast carcinogenesis via the CMTM7/EGFR/AKT axis

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Chong Lu ◽  
Yu Zhao ◽  
Jing Wang ◽  
Wei Shi ◽  
Fang Dong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Extracellular Vesicles ◽  
Breast Cancer Cells ◽  
Akt Signaling ◽  
Cancer Tissues

Abstract Background Extracellular 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. Methods Differentially 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. Results miR-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. Conclusions Taken 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.

scholarly journals Tumoral Neuroligin 1 Promotes Cancer–Nerve Interactions and Synergizes with the Glial Cell Line-Derived Neurotrophic Factor

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 280
Author(s):  
Laura Bizzozero ◽  
Margherita Pergolizzi ◽  
Davide Pascal ◽  
Elena Maldi ◽  
Giulia Villari ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Line ◽  
Glial Cell ◽  
Cancer Cell ◽  
Cell Invasion ◽  
Neurotrophic Factor ◽  
Regulatory Protein ◽  
Cancer Cell Invasion

Many nervous proteins are expressed in cancer cells. In this report, we asked whether the synaptic protein neuroligin 1 (NLGN1) was expressed by prostatic and pancreatic carcinomas; in addition, given the tendency of these tumors to interact with nerves, we asked whether NLGN1 played a role in this process. Through immunohistochemistry on human tissue microarrays, we showed that NLGN1 is expressed by prostatic and pancreatic cancer tissues in discrete stages and tumor districts. Next, we performed in vitro and in vivo assays, demonstrating that NLGN1 promotes cancer cell invasion and migration along nerves. Because of the established role of the neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) in tumor–nerve interactions, we assessed a potential NLGN1–GDNF cooperation. We found that blocking GDNF activity with a specific antibody completely inhibited NLGN1-induced in vitro cancer cell invasion of nerves. Finally, we demonstrated that, in the presence of NLGN1, GDNF markedly activates cofilin, a cytoskeletal regulatory protein, altering filopodia dynamics. In conclusion, our data further prove the existence of a molecular and functional cross-talk between the nervous system and cancer cells. NLGN1 was shown here to function along one of the most represented neurotrophic factors in the nerve microenvironment, possibly opening new therapeutic avenues.

Abstract 246: Translocation Of Myomirs Via Gap Junction Channels Prevents Cancer Cell Growth

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Laura Graciotti ◽  
Toru Hosoda ◽  
Marcello Rota ◽  
Giulia Borghetti ◽  
Sergio Signore ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gap Junctions ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Connexin 43 ◽  
Breast Cancer Cells ◽  
Fold Increase ◽  
Tumor Formation

The adult heart is resistant to cancer formation and the metastatic invasion of distant neoplasms. This biological advantage may be dictated by the molecular properties of myocytes that constitutes 90% of the myocardium. We raised the possibility that microRNAs (miRs) highly expressed in myocytes (myomirs) may translocate via gap junctions to neighboring cancer cells, preventing their growth or inhibiting their survival. First, we established whether overexpression of myomirs interferes with the proliferation and death of MCF7 human breast cancer cells. Infection of MCF7 with lentiviruses carrying miR-1, miR-133a and miR-499 (miR-MCF7) resulted in a 5-fold decrease in Ki67 labeling and a 20% increase in the fraction of cells arrested at G0/G1. In contrast, TdT-positive apoptotic cells averaged 0.5% and did not differ in miR-MCF7 and control cells. To mimic the in vivo condition, EGFP-labeled MCF7 were co-cultured with myocytes and, 4 days later, the expression of myomirs was measured in FACS-sorted MCF7. With respect to baseline, co-cultured MCF7 showed 100-fold, 16-fold, and 27-fold increase in the expression of miR-1, miR-133a and miR-499, respectively. Co-culture of myocytes and MCF7 led to the formation of gap junctions made of connexin 43 (Cx43) and connexin 45 (Cx45). Silencing of Cx43 and Cx45 decreased significantly the expression of myomirs in co-cultured MCF7. Importantly, proximity of MCF7 to myocytes reduced markedly the growth rate of the cancer cells. Subsequently, 1 x 106 MCF7 or miR-MCF7 were injected subcutaneously in NOD-scid mice. At 5 weeks, the tumors developed from miR-MCF7 were 70% smaller than those originated from control MCF7. Two doses of breast cancer cells were injected intramyocardially to establish their in situ tumorigenic effects. Tumor formation was found in all hearts that received 1 x 106 MCF7. Conversely, mice injected with 1 x 105 cells did not show macroscopic evidence of neoplastic lesions. The lack of tumor development in the latter case is consistent with the ability of the heart to prevent neoplasm development when cancer cell colonization is not massive. Our findings document that miR-1, miR-133a and miR-499 translocate from myocytes to cancer cells via gap junctions, inhibiting tumor growth in vitro and in vivo.

scholarly journals Osterix Decreases the Chemosensitivity of Breast Cancer Cells by Upregulating GALNT14

2017 ◽  
Vol 44 (3) ◽  
pp. 998-1010 ◽  
Author(s):  
Jiahui Wu ◽  
Xiang Chen ◽  
Qianyi Bao ◽  
Rui Duan ◽  
Yucui Jin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Target Genes ◽  
Disease Free Survival ◽  
Breast Cancer Patients ◽  
Elevated Expression ◽  
Hoechst Staining

Background/Aims: Osterix (Osx), a key regulator of osteoblast differentiation and bone formation, has been recently reported to be associated with the progression of breast cancer. However, the precise roles of Osx in breast cancer remain unclear. Methods: Drug sensitivity of the cancer cells was assessed using an 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Target genes were obtained by high-throughput Illumina sequencing and were confirmed in vitro and in vivo. Apoptosis was analysed by Hoechst staining and western blotting. A tissue microarray including 129 samples from breast cancer patients was used for immunohistochemistry (IHC) assays. Results: Overexpression of Osx decreased the chemosensitivity of breast cancer cells, while knockdown of Osx increased the chemosensitivity of breast cancer cells. In particular, we found that the decreased chemosensitivity effect was significantly associated with elevated expression of the polypeptide N-acetylgalactosaminyltransferase 14 (GALNT14). Silencing of GALNT14 in Osx-overexpressed cells restored the decreased chemosensitivity. Conversely, overexpression of GALNT14 in Osx-knockdown cells abrogated the increased chemosensitivity in breast cancer cells. In addition, we revealed that Osx decreased GALNT14-dependent chemosensitivity by enhancing anti-apoptosis. GALNT14 expression exhibited a significant association with breast cancer stages as well as the disease-free survival (DFS) rate. Conclusion: Osx plays an important role in the chemosensitivity and inhibition of Osx expression may represent a therapeutic strategy to enhance the chemosensitivity of breast cancer.

scholarly journals Extracellular Matrix-Mediated Breast Cancer Cells Morphological Alterations, Invasiveness, and Microvesicles/Exosomes Release

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2031
Author(s):  
Marco Franchi ◽  
Zoi Piperigkou ◽  
Konstantinos-Athanasios Karamanos ◽  
Leonardo Franchi ◽  
Valentina Masola
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cell Invasion ◽  
Breast Cancer Cells ◽  
Morphological Changes ◽  
Metastatic Potential ◽  
Cancer Cell Invasion ◽  
Collagen Network ◽  
Morphological Alterations

Breast cancer is a leading disease in women. Several studies are focused to evaluate the critical role of extracellular matrix (ECM) in various biochemical and molecular aspects but also in terms of its effect on cancer cell morphology and therefore on cancer cell invasion and metastatic potential. ECM fibrillar components, such as collagen and fibronectin, affect cell behavior and properties of mammary cancer cells. The aim of this study was to investigate using the scanning electron microscopy (SEM) how the highly invasive MDA-MB-231 breast cancer cells, interplaying with ECM substrates during cell migration/invasion, modify their morphological characteristics and cytoplasmic processes in relation to their invasive potential. In particular we reproduced and analyzed how natural structural barriers to cancer cell invasion, such as the basement membrane (Matrigel) and fibrillar components of dermis (fibronectin as well as the different concentrations/array of type I collagen), could induce morphological changes in 3D cultures. Interestingly, we demonstrate that, even with different effects, all collagen concentrations/arrays lead to morphological alterations of breast cancer cells. Intriguingly, the elongated mesenchymal shaped cells were more prominent in 3D cultures with a dense and thick substrate (thick Matrigel, high concentrated collagen network, and densely packed collagen fibers), even though cells with different shape produced and released microvesicles and exosomes as well. It is therefore evident that the peri-tumoral collagen network may act not only as a barrier but also as a dynamic scaffold which stimulates the morphological changes of cancer cells, and modulates tumor development and metastatic potential in breast cancer.

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