Nanoliposomal Delivery of MicroRNA-203 Suppresses Migration of Triple-Negative Breast Cancer through Distinct Target Suppression.
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ABSTRACT:
SUBMITTER: Song S
PROVIDER: S-EPMC8395754 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundTriple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancer in women globally. This subtype often has early and high recurrence rates, resulting in poor survival, partially due to lack of targeted therapies. To date, the detailed molecular mechanisms underlying TNBC progression are unclear. Given the crucial role of microRNAs (miRNAs) in cancer metastasis, we aimed to analyse the expression and function of a metastasis-associated miRNA named miR-211-5p in TNBC.MethodsMiRNA array analysis was performed to search for metastasis-associated miRNAs in TNBC. The miR-211-5p expression in tumour tissues, adjacent non-tumourous breast tissues of TNBC patients and cell lines were evaluated by real-time PCR. The protein expression levels were analysed by western blot, immunohistochemistry and in situ hybridisation. Luciferase reporter assays were employed to validate the target of miR-211-5p. The effect of miR-211-5p on TNBC progression was investigated in vitro and in vivo.ResultsMiR-211-5p was significantly downregulated in TNBC, and its expression level was associated with overall survival in TNBC. The expression of miR-211-5p suppressed TNBC cell proliferation, invasion, migration and metastasis in vitro and in vivo. Furthermore, SETBP1 was identified as a target of miR-211-5p. Through gain-of-function and loss-of-function studies, SETBP1 was shown to significantly affect colony and cell number in vitro. Enforced expression of miR-211-5p inhibited the expression of SETBP1 significantly and the restoration of SETBP1 expression reversed the inhibitory effects of miR-211-5p on TNBC cell proliferation and metastasis.ConclusionsThese findings collectively demonstrate a tumour suppressor role of miR-211-5p in TNBC progression by targeting SETBP1, suggesting that miR-211-5p could serve as a potential prognostic biomarker and therapeutic target for TNBC.
| S-EPMC5520212 | biostudies-literature
Project description:Cutaneous squamous cell carcinoma (CSCC) is a malignant proliferation of cutaneous epithelium that has been observed to have an alarming rise in incidence. Numerous studies have demonstrated microRNAs (miRNAs or miRs) as important biomarkers in the diagnosis, prognosis, and treatment of CSCC. This study aims to investigate the effects of miR-203 on the behaviors of CSCC cells and possible mechanisms associated with protein regulator of cytokinesis-1 (PRC1) and Wnt/β-catenin signaling pathway. PRC1 was suggested as a target of miR-203 in squamous cell carcinoma cell line 1 (SCL-1) cells by dual-luciferase reporter gene assay. Based on the immunohistochemical staining and qRT-PCR, PRC1 was abundantly expressed while miR-203 was poorly expressed in CSCC tissues. miR-203 mimic or inhibitor was transfected into SCL-1 cells to upregulate or downregulate its expression. Upregulation of miR-203 downregulated PRC1 expression to block the Wnt/β-catenin signaling pathway. By conducting 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), scratch test, and Transwell and flow cytometric analyses, miR-203 was witnessed to restrain SCL-1 cell proliferation, migration, and invasion while accelerating their apoptosis. The rescue experiments addressed that inhibition of the Wnt/β-catenin signaling pathway conferred the anti-tumor effect of miR-203. These results establish a tumor-suppressive role for miR-203 in CSCC cell line SCL-1. Hence, miR-203 has promising potential as a therapeutic target for CSCC.
| S-EPMC7358222 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis and lacks effective targeted therapies. The microRNA-200 (miR-200) family is found to inhibit or promote breast cancer metastasis; however, the underlying mechanism is not well understood. This study was performed to investigate the effect and mechanism of miR-200b on TNBC metastasis and identify targets for developing more efficient treatment for TNBC. We found that miR-200 family expression levels are significantly lower in highly migratory TNBC cells and metastatic TNBC tumors than other types of breast cancer cells and tumors. Ectopically expressing a single member (miR-200b) of the miR-200 family drastically reduces TNBC cell migration and inhibits tumor metastasis in an orthotopic mouse mammary xenograft tumor model. We identified protein kinase C? (PKC?) as a new direct target of miR-200b and found that PKC? protein levels are inversely correlated with miR-200b levels in 12 kinds of breast cancer cells. Inhibiting PKC? activity or knocking down PKC? levels significantly reduces TNBC cell migration. In contrast, forced expression of PKC? impairs the inhibitory effect of miR-200b on cell migration and tumor metastasis. Further mechanistic studies revealed that PKC? downregulation by miR-200b results in a significant decrease of Rac1 activation in TNBC cells. These results show that loss of miR-200b expression plays a crucial role in TNBC aggressiveness and that miR-200b suppresses TNBC cell migration and tumor metastasis by targeting PKC?. Our findings suggest that miR-200b and PKC? may serve as promising therapeutic targets for metastatic TNBC.
| S-EPMC4178468 | biostudies-literature
Project description:MicroRNAs (miRNAs) are emerging as critical mediators in tumors, including triple-negative breast cancer (TNBC). The role of miR-518a-3p in TNBC was investigated to identify potential therapeutic target. Data from KM Plotter database (www.kmplot.com) showed that high miR-518a-3p expression was significantly associated with overall survival of patients with TNBC (p = 0.04). The expression of miR-518a-3p was dysregulated in TNBC cells. Functional assays revealed that over-expression of miR-518a-3p inhibited cell invasion and migration of TNBC. Additionally, miR-518a-3p could target TMEM2 (transmembrane protein 2), and decreased protein and mRNA expression of TMEM2 in TNBC cells. Knockdown of TMEM2 suppressed cell invasion and migration through inhibiting phospho (p)-JAK1 (Janus kinase 1) and p-STAT (signal transducer and activator of transcription protein) 1/2. Moreover, over-expression of TMEM2 counteracted the suppressive effect of miR-518a-3p on TNBC invasion and migration through promoting the levels of p-JAK1 and p-STAT1/2. In conclusion, miR-518a-3p negatively regulates the JAK/STAT pathway via targeting TMEM2 and suppresses invasion and migration in TNBC, suggesting that miR-518a-3p may be a potential therapeutic target in TNBC.
| S-EPMC7705184 | biostudies-literature
Project description:MicroRNAs play important roles in regulating the gene expression and life cycle of cancer cells. In particular, miR-21, an oncogenic miRNA is a major player involved in tumor initiation, progression, invasion and metastasis in several cancers, including triple negative breast cancer (TNBC). However, delivery of therapeutic miRNA or anti-miRNA specifically into cancer cells in vivo without collateral damage to healthy cells remains challenging. We report here the application of RNA nanotechnology for specific and efficient delivery of anti-miR-21 to block the growth of TNBC in orthotopic mouse models. The 15 nm therapeutic RNA nanoparticles contains the 58-nucleotide (nt) phi29 pRNA-3WJ as a core, a 8-nt sequence complementary to the seed region of miR-21, and a 39-nt epidermal growth factor receptor (EGFR) targeting aptamer for internalizing RNA nanoparticles into cancer cells via receptor mediated endocytosis. The RNase resistant and thermodynamically stable RNA nanoparticles remained intact after systemic injection into mice and strongly bound to tumors with little or no accumulation in healthy organs 8 h postinjection, and subsequently repressed tumor growth at low doses. The observed specific cancer targeting and tumor regression is a result of several key attributes of RNA nanoparticles: anionic charge which disallows nonspecific passage across negatively charged cell membrane; "active" targeting using RNA aptamers which increases the homing of RNA nanoparticles to cancer cells; nanoscale size and shape which avoids rapid renal clearance and engulfment by lung macrophages and liver Kupffer cells; favorable biodistribution profiles with little accumulation in healthy organs, which minimizes nonspecific side effects; and favorable pharmacokinetic profiles with extended in vivo half-life. The results demonstrate the clinical potentials of RNA nanotechnology based platform to deliver miRNA based therapeutics for cancer treatment.
| S-EPMC4723066 | biostudies-other
Project description:MicroRNAs (miRNAs) play important roles in differentiation of stem cells. However, the precise dynamics of miRNA induction during stem cell differentiation have not been visualized and molecular mechanisms through which miRNAs execute their function remain unclear. Using high-resolution in situ hybridization together with cell lineage and proliferation markers in mouse skin, we show that miR-203 is transcriptionally activated in the differentiating daughter cells upon the asymmetric cell division of interfollicular progenitor cells. Once induced, miR-203 rapidly promotes the cell cycle exit within 6 hours and abolishes self-renewal of the progenitor cells. With an inducible mouse model, we identify numerous miR-203 in vivo targets that are highly enriched in regulation of cell cycle and cell division, as well as in response to DNA damage. Importantly, co-suppression of individual targets, including p63, Skp2 and Msi2 by miR-203 is required for its function of promoting the cell cycle exit and inhibiting the long-term proliferation. Together, our findings reveal the rapid and widespread impact of miR-203 on the self-renewal program and provide mechanistic insights into the potent role of miR-203 during the epidermal differentiation. These results should also contribute to understanding the role of miR-203 in the development of skin cancer.
| S-EPMC3631964 | biostudies-literature
Project description:Nowadays, microRNA is considered an attractive strategy for the effective treatment of cancer. A significant delivery of microRNA for cancer therapy remains a significant obstacle to target cancer cells. The restoring microRNA-1296 (miR-1296) has immense therapeutic efficacy in triple-negative breast cancer (TNBC). TNBC is an aggressive subtype of breast tumors with the progression of malignant transformation. This study aimed to develop a cationic nanoliposome that can serve as a miR-1296 carrier and studied its efficiency in TNBC. The efficacy of miR-1296 liposomes was evaluated on its apoptotic effect, cellular uptake, and potential chemotherapy sensitization in the TNBC cell line (MDA-MB-231). For in vitro viability study, the apoptotic effect was performed to validate protein expression using Alamar blue kit and western blot. The transfection of miR-1296 into TNBC cells was also investigated using cisplatin as a TNBC resistance drug. The fluorescent miR-1296-cy3 liposome was used for cellular uptake study. The miR-liposome was successfully prepared with a particle size of 123.6 ± 1.3 nm and encapsulation efficiency of 94.33%. A dose of 0.5 uM has significantly reduced the viability of MDA-MB-231 to be 33.45%±5.29 (P < 0.001). This result was validated by down-expression of CCND1, and PARP1, the miR-1296 receptor, and apoptosis marker. The image of the miR-1296-cy3 liposome showed cytoplasmic intracellular localization. It was found high sensitization of TNBC cell line for miR-1296 liposome compared to cisplatin (P < 0.001). Future in vivo research may answer questions concerning safety and stability. This study demonstrates that miR-191 liposomes may have promising clinical applications for TNBC therapy.
| S-EPMC8180610 | biostudies-literature
Project description:Long noncoding RNAs (lncRNAs) are implicated in various cancers, including colon cancer. Liver metastasis is the main cause of colon cancer-related death. However, the roles of lncRNAs in colon cancer liver metastasis are still largely unclear. In this study, we identified a novel lncRNA B3GALT5-AS1, which is reduced in colon cancer tissues and further reduced in colon cancer liver metastasis tissues. Reduced expression of B3GALT5-AS1 is associated with liver metastasis and poor outcome of colon cancer patients. Gain-of-function and loss-of-function assays revealed that B3GALT5-AS1 inhibited proliferation but promoted migration and invasion of colon cancer cells. Further investigation revealed that B3GALT5-AS1 directly bound to the promoter of miRNA-203, repressed miR-203 expression, upregulated miR-203 targets ZEB2 and SNAI2, and induced epithelial-to-mesenchymal transition (EMT). In vivo study revealed that B3GALT5-AS1 suppressed colon cancer liver metastasis via its binding on miR-203 promoter and the repression of miR-203. miR-203 is increased and epithelial phenotype is preferred in colon cancer liver metastasis tissues. Collectively, our data revealed the suppressive roles of B3GALT5-AS1/miR-203/EMT regulation axis in colon cancer liver metastasis. Our data suggested that the activating B3GALT5-AS1/miR-203/EMT axis may be potential therapeutic strategy for colon cancer liver metastasis.
| S-EPMC6326654 | biostudies-literature
Project description:Lacking of treatment methods for the patients with triple negative breast cancer (TNBC) underscores the pivotal needs to further understand its biology as well as to find better biomarkers and develop novel therapeutic strategies. Increasing evidences support that aberrantly expressed microRNAs (miRNAs) are involved in tumorigenesis and may serve as biomarkers for diagnostic and prognostic purposes of various cancers. In current study, we found that miR-455-3p and miR-196a-5p were intensively overexpressed in TNBC compared with the hormone receptor (HR) positive breast cancer whereas miR-425-5p was down-regulated by miRNA microarray analysis. qRT-PCR analysis confirmed that the expression of miR-455-3p in TNBC cell lines MDA-MB-231 and MDA-MB-468 was higher than that in HR positive breast cancer cell line MCF-7(p<0.01). Functional experiments in vitro showed that miR-455-3p enhanced cell proliferative, invasive and migrational abilities in TNBC cell lines. miRNA targets prediction showed SMAD2, LTBR and etoposide induced 2.4 (EI24) were potential target genes of miR-455-3p, and then it was confirmed by qRT-PCR assay. Dual luciferase reporter assay showed the specific binding of miR-455-3p to 3' UTR of EI24 in TNBC. Then we found miR-455-3p inhibited the EI24 expression at the levels of mRNA and protein. Through small interfering RNA (siRNA) targeting EI24 gene, there were strengthened capabilities of invasion and migration of TNBC cells, and increased expression of EI24 had the inverse effects. In conclusion, the data suggest that miRNA455-3p promotes invasion and migration by targeting tumor suppressor EI24 and might be a potential prognostic biomarker and therapeutic target in TNBC.
| S-EPMC5386697 | biostudies-literature
Project description:To investigate the effects of higher cellular stanniocalcin 2 (STC2) on suppressing the migration and invasion but promoting the apoptosis of triple-negative breast cancer (TNBC). STC2 in TNBC and the para-carcinoma tissues were analyzed by immunohistochemistry (IHC), while the mRNA level was measured by qPCR. Over-expressing or silencing STC2 was established in MDA-MB-231 cells. Epithelial mesenchymal transition (EMT) related proteins, cell migration, invasion, proliferation and apoptosis were detected. MDA-MB-231 with over-expressing or silencing STC2 were injected into nude mice to formatting tumors, and then EMT related proteins were measured by IHC. Lower STC2 expressed in TNBC tissues than in the para-carcinoma tissues. Silencing STC2 promoted EMT of TNBC cell MDA-MB-231, as well as cell migration, invasion and proliferation, but suppressed MDA-MB-231 apoptosis, while over-expressing STC2 had the opposite results, which might be related to PKC/PI3K/AKT/mTOR pathway. STC2 was the protective gene in TNBC, by suppressing migration and invasion to inhibit MDA-MB-231 cell EMT but promote cell apoptosis, in order to suppress TNBC progression.
| S-EPMC11310179 | biostudies-literature