M1 macrophage-derived exosomes containing miR-150 inhibit glioma progression by targeting MMP16.

A large amount of clinical and experimental evidence indicates that M1 macrophages can inhibit tumor progression and expansion; however, the molecular mechanism by which macrophage-derived exosomes inhibit the proliferation of glioblastoma cells has not yet been elucidated. Here, we used M1 macrophage exosomes encapsulating microRNAs to inhibit the proliferation of glioma cells. Exosomes derived from M1 macrophages exhibited high expression levels of miR-150, and the inhibition of glioma cell proliferation mediated by exosomes derived from M1 macrophages was dependent on this microRNA. Mechanistically, miR-150 is transferred to glioblastoma cells through M1 macrophages and binds to MMP16, downregulating its expression and inhibiting glioma progression. Overall, these findings indicate that M1 macrophage-derived exosomes carrying miR-150 inhibit the proliferation of glioblastoma cells through targeted binding to MMP16. This dynamic mutual influence between glioblastoma cells and M1 macrophages provides new opportunities for the treatment of glioma.

Muscle Regeneration in Holothurians without the Upregulation of Muscle Genes.

The holothurian Eupentacta fraudatrix is capable of fully restoring its muscles after transverse dissection. Although the regeneration of these structures is well studied at the cellular level, the molecular basis of the process remains poorly understood. To identify genes that may be involved in the regulation of muscle regeneration, the transcriptome of the longitudinal muscle band of E. fraudatrix has been sequenced at different time periods post-injury. An analysis of the map of biological processes and pathways has shown that most genes associated with myogenesis decrease their expression during the regeneration. The only exception is the genes united by the GO term "heart valve development". This may indicate the antiquity of mechanisms of mesodermal structure transformation, which was co-opted into various morphogeneses in deuterostomes. Two groups of genes that play a key role in the regeneration have been analyzed: transcription factors and matrix metalloproteinases. A total of six transcription factor genes (Ef-HOX5, Ef-ZEB2, Ef-RARB, Ef-RUNX1, Ef-SOX17, and Ef-ZNF318) and seven matrix metalloproteinase genes (Ef-MMP11, Ef-MMP13, Ef-MMP13-1, Ef-MMP16-2, Ef-MMP16-3, Ef-MMP24, and Ef-MMP24-1) showing differential expression during myogenesis have been revealed. The identified genes are assumed to be involved in the muscle regeneration in holothurians.

MMP-16 as a New Biomarker for Predicting Prognosis and Chemosensitivity of Serous Ovarian Cancer: A Study Based on Bioinformatics Analysis.

OBJECTIVE: To explore the prognostic value of MMP-16 expression in patients with serous ovarian cancer and the usefulness of MMP-16 expression to predict sensitivity to chemoradiotherapy. METHODS: The relationship between MMP-16 expression and clinicopathological parameters of serous ovarian cancer was evaluated in The Cancer Genome Atlas (TCGA) database. Cox proportional hazard regression analysis was performed to measure the prognostic significance of MMP-16 in serous ovarian cancer. Dataset GSE51373 was applied to estimate the difference of MMP-16 expression between chemotherapy-sensitive group and resistant group of serous ovarian cancer. Receiver operating characteristic (ROC) curve was also drawn. In addition, the online tool Kaplan-Meier Plotter was used to assess the prognostic value of MMP-16 in patients with serous ovarian cancer. RESULTS: A total of 235 patients with serous ovarian cancer were included in the TCGA database. Cox regression univariate analysis showed that high expression of MMP-16 was not conducive to the overall survival of patients with serous ovarian cancer (hazard ratio [HR] = 1.47, 95% CI: 1.03~2.08; P < 0.05). The results of Cox regression multivariate analysis also demonstrated that there was a statistically significant difference. The results of the online database Kaplan-Meier Plotter analysis showed that the high expression of MMP-16 was not conducive to the progression-free survival (PFS) of patients with serous ovarian cancer (HR = 1.26, 95% CI: 1.06~1.29; P < 0.05). The expression of MMP-16 in the chemotherapy-sensitive group was notably lower than that in the chemotherapy-resistant group, which had a moderate predictive value in predicting the chemosensitivity of serous ovarian cancer (AUC = 0.7187). CONCLUSION: High expression of MMP-16 is not conducive to chemotherapy sensitivity and survival of patients with serous ovarian cancer, and has predictive value for chemotherapy resistance and prognosis.

LncRNA NEAT1 regulates MMP-16 by targeting miR-200a/b to aggravate inflammation in asthma.

Asthma is a common respiratory disease which is characterized by persistent airway inflammation. Abnormal expression of long non-coding RNAs (lncRNAs) is observed in asthma. However, whether lncRNA nuclear-enriched abundant transcript 1 (NEAT1) regulates asthmatic inflammation and its mechanism still needs to be further investigated. The expression levels of inflammatory factors (tumour necrosis factor (TNF)-α, interleukin (IL)-4, IL-13, and IL-10) were detected using reverse transcription quantitative real-time PCR (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA). MTT and flow cytometry assays were employed to determine cell proliferation and apoptosis, respectively. Dual luciferase reporter assay was performed to verify the relationship between miR-200a/b and MMP-16 or NEAT1. NEAT1 silencing markedly reduced TNF-α, IL-4, and IL-13 levels, while elevated IL-10 expression, suppressed cell proliferation, and promoted cell apoptosis. However, NEAT1 overexpression elicited the opposite effects on cell proliferation and inflammation cytokines secretion. What is more, NEAT1 negatively regulated miR-200a/b expression, and MMP16 was a target gene of miR-200a/b. miR-200a/b overexpression suppressed inflammation, cell proliferation, and enhanced cell apoptosis through regulation of MMP16. Moreover, MMP-16 overexpression or miR-200a/b inhibition abolished the regulatory effect of sh-NEAT1 on cell inflammation and apoptosis in BEAS-2B cells. NEAT1 acted as the role of sponge for miR-200a/b to regulate MMP-16 expression, thereby promoting asthma progression, suggesting that NEAT1 might have great potential as therapeutic target for asthma.

microRNA-4429-5p suppresses the malignant development of colon cancer by targeting matrix metalloproteinase 16.

Colon cancer has been recognized as the major reason for global cancer-associated mortality. microRNA (miRNA, miR)-4429-5p has been documented to act as a tumor-suppressive miRNA in some cancers, but its effect on colon cancer remains elusive. In this study, the biological effects of miR-4429-5p were investigated both in vitro by MTT, 5-ethynyl-2'-deoxyuridine (EdU), wound healing, and transwell assays and in vivo by a xenograft mice model. Western blot, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and dual-luciferase assay were used to identify the binding of miR-4429-5p on matrix metalloproteinase 16 (MMP16) 3'-UTR. Our results suggested that overexpression of miR-4429-5p hindered colon cancer cell proliferation, migration, and invasion, whereas knockdown of miR-4429-5p exhibited the opposite effect in colon cancer cells. Mechanistically, miR-4429-5p directly bound to the 3'-UTR of MMP16 and led to inhibition of MMP16 protein. Overexpression of miR-4429-5p inhibited colon tumor growth by targeting MMP16. Taken together, our study revealed that miR-4429-5p prevented colon cancer progression through targeting MMP16, indicating miR-4429-5p as a promising target for treatment improvement for colon cancer.

miRNA 146b-5p protects against atherosclerosis by inhibiting vascular smooth muscle cell proliferation and migration.

Aim: To explore the potentially important role of miRNA 146b-5p (miR-146b) during the development of atherosclerosis. Materials & methods: Proliferation, migration and luciferase assays and mouse models were used to determine the functions of miR-146b. Results: miR-146b was identified as substantially upregulated in the aortic plaques of ApoE-/- mice as well as in response to inflammatory cytokines. Overexpression of miR-146b repressed proliferation and migration of vascular smooth muscle cells by downregulating Bag1 and Mmp16, respectively. Adeno-associated virus-mediated miR-146b overexpression inhibited neointima formation after carotid injury and suppressed atherosclerotic plaque formation in Western diet-induced ApoE-/- mice. Conclusion: miR-146b is a novel regulator of vascular smooth muscle cell function induced by inflammatory response, specifically in neointima formation, and offers a novel therapeutic strategy for treating atherosclerosis.

miR-325-3p Overexpression Inhibits Proliferation and Metastasis of Bladder Cancer Cells by Regulating MT3.

BACKGROUND miRNAs have been widely used in cancer treatment. Our study was designed to explore the effects of miR-325-3p in bladder cancer cells. MATERIAL AND METHODS Levels ofd miR-325-3p and MT3 in bladder cancer tissues and cells were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). miR-325-3p mimics were transfected into bladder cancer T24 cells, and cell migration and invasion rates and cell proliferation were assessed by transwell assay and Cell Counting Kit-8 (CCK-8). The target mRNA for miR-325-3p was predicted by Targetscan7.2 and confirmed by dual-luciferase reporter assay. More experiments were performed to confirm the effects of miR-325-3p and MT3 in T24 cells. Additionally, the levels of TIMP-2, MMP9, and E-cadherin were assessed by Western blotting to identify the effects of miR-325-3p and MT3 on epithelial-mesenchymal transition (EMT). RESULTS miR-325-3p expression was reduced and MT3 was increased in bladder cancer tissues and bladder cancer cells. miR-325-3p mimics suppressed cell proliferation ability and invasion and migration rates of T24 cells. Moreover, miR-325-3p was confirmed to target MT3. Further experiments showed that the effects of increased cell proliferation, invasion, migration, and EMT promoted by MT3 overexpression were abolished by miR-325-3p mimics, proving that miR-325-3p is a tumor suppressor through targeting MT3 in bladder cancer cells. CONCLUSIONS Downregulation of miR-325-3p in bladder cancer regulates cell proliferation, migration, invasion, and EMT by targeting MT3. Furthermore, miR-325-3p is a potential therapeutic target in treating bladder cancer.

Role of lncRNA NEAT1 mediated by YY1 in the development of diabetic cataract via targeting the microRNA-205-3p/MMP16 axis.

OBJECTIVE: We aimed at investigating the possible role and mechanism of NEAT1 in the pathogenesis of diabetic cataract. PATIENTS AND METHODS: YY1 and NEAT1 expressions in anterior lens capsule collected from diabetic cataract (DC) patients and normal controls were examined by quantitative real-time polymerase chain reaction (qRT-PCR) analysis, and their correlation was analyzed. The binding site between YY1 and NEAT1 sequences was predicted by JASPAR and detected by Dual-Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. The proliferation and apoptosis of high-glucose-induced cells with NEAT1 knockdown were detected. Potential downstream targets of NEAT1 were predicted by bioinformatics and detected by Dual-Luciferase reporter assay. RESULTS: YY1 and NEAT1 expressions in the anterior capsule tissue of DC lens were remarkably reduced and positively correlated. Dual-Luciferase reporter assay and ChIP confirmed that YY1 could bind to locus 2 of NEAT1. Knockdown of NEAT1 inhibited proliferation while promoted apoptosis under high glucose conditions. Further mechanism studies revealed that knockdown of NEAT1 could upregulate microRNA-205-3p, and MMP16 was a potential target of miR-205. CONCLUSIONS: The low expression of YY1 induces NEAT1 downregulation, which regulates microRNA-205-3p/MMP16 axis and thus participates in the development of DC.

Role of Cyclosporine in Gingival Hyperplasia: An In Vitro Study on Gingival Fibroblasts.

BACKGROUND: Gingival hyperplasia could occur after the administration of cyclosporine A. Up to 90% of the patients submitted to immunosuppressant drugs have been reported to suffer from this side effect. The role of fibroblasts in gingival hyperplasia has been widely discussed by literature, showing contrasting results. In order to demonstrate the effect of cyclosporine A on the extracellular matrix component of fibroblasts, we investigated the gene expression profile of human fibroblasts after cyclosporine A administration. MATERIALS AND METHODS: Primary gingival fibroblasts were stimulated with 1000 ng/mL cyclosporine A solution for 16 h. Gene expression levels of 57 genes belonging to the "Extracellular Matrix and Adhesion Molecules" pathway were analyzed using real-time PCR in treated cells, compared to untreated cells used as control. RESULTS: Expression levels of different genes were significantly de-regulated. The gene CDH1, which codes for the cell adhesion protein E-cadherin, showed up-regulation. Almost all the extracellular matrix metalloproteases showed down-regulation (MMP8, MMP11, MMP15, MMP16, MMP24, MMP26). The administration of cyclosporine A was followed by down-regulation of other genes: COL7A1, the transmembrane receptors ITGB2 and ITGB4, and the basement membrane constituents LAMA2 and LAMB1. CONCLUSION: Data collected demonstrate that cyclosporine inhibits the secretion of matrix proteases, contributing to the accumulation of extracellular matrix components in the gingival connective tissue, causing gingival overgrowth. Patients affected by gingival overgrowth caused by cyclosporine A need to be further investigated in order to determine the role of this drug on fibroblasts.

MiRNA-192-5p attenuates airway remodeling and autophagy in asthma by targeting MMP-16 and ATG7.

Asthma is a chronic lung inflammatory disease with high incidence. MicroRNA-192-5p (miR-192-5p) was down-regulated in asthmatics. However, the role of miR-192-5p in asthma is still unclear. In current study, in vitro, the overexpression of miR-192-5p, matrix metalloproteinase (MMP)-16 and autophagy related 7 (ATG7) was conducted in airway smooth muscle cells (ASMCs). We found that miR-192-5p suppressed cell proliferation, and decreased MMP-16 and ATG7 expression. MMP-16 and ATG7 promoted cell proliferation, and further alleviated the down-regulation of miR-192-5p on proliferation of ASMCs. in vivo, miR-192-5p was down-regulated in asthma mice, and involved in improvement of asthma mice. MiR-192-5p was demonstrated to alleviate inflammation in asthma mice, including decreasing the level of ovalbumin (OVA)-specific IgE, interleukin (IL)-4, IL-5, IL-13, iNOS and COX-2. Moreover, the attenuation of airway remodeling induced by miR-192-5p in asthma mice were expressed by the reduction of fibroblast growth factor-23 (FGF-23) level, decrease in concentrations of MMP-2 and MMP-9 as well as down-regulation of collagen I deposition. Further, miR-192-5p also caused the suppression of autophagy in asthma mice, exhibiting a decrease in LC3II/I, beclin-1 and ATG7, and an increase in p62. Importantly, MMP-16 and ATG7 were confirmed to be targets of miR-192-5p. Therefore, our results indicate that miRNA-192-5p may attenuate airway remodeling and autophagy in asthma via targeting MMP-16 and ATG7.

Chondrocyte sheet in vivo cartilage regeneration technique using miR-193b-3p to target MMP16.

Stable cartilage regeneration has always been a challenge in both tissue engineering research and clinical practice. This study explored the feasibility of using a chondrocyte sheet technique stimulated by microRNAs to regenerate cartilage. We tested the involvement of hsa-miR-193b-3p in the microtia patient remnant auricular chondrocyte extracellular matrix (ECM). We observed in vitro chondrocyte proliferation, ECM synthesis, as well as the increase in the expression of type II collagen (COL2A1) and decrease in the expression of matrix metalloproteinase 16 (MMP16) of the chondrocyte sheets. COL2A1 deposition and MMP16 degradation of regenerative cartilage tissue were examined in vivo. A dual-luciferase reporter showed that the MMP16 gene was the direct target of miR-193b-3p. These results suggested that miR-193b-3p promotes chondrocyte sheet ECM synthesis by inhibiting MMP16. Since the evidence suggests that MMP16 is a critical regulator of chondrocyte ECM, this finding points the way towards a method that both strengthens the ECM and inhibits MMPs.

Sevoflurane suppresses migration and invasion of glioma cells by regulating miR-146b-5p and MMP16.

Background: Glioma is the most common brain tumor with poor prognosis all over the world. Anesthetics have been demonstrated to have important impacts on cell migration and invasion in different cancers. However, the underlying mechanism that allows anesthetics-mediated progression of glioma cells remains elusive. Methods: Sevoflurane (Sev), a class of common anesthetics, was used to expose to U87-MG and U251 cells. The expressions of microRNA-146b-5p (miR-146b-5p) and matrix metallopeptidase 16 (MMP16)were measured by quantitative real-time polymerase chain reaction or western blot. Transfection was performed in glioma cells with miR-146b-5p inhibitor, inhibitor negative control, MMP16 overexpression vector, empty vector, small interfering RNA against MMP16 or scramble. Cell migration and invasion were analyzed by the trans-well assay. The interaction between miR-146b-5p and MMP16 was explored by luciferase activity and RNA immunoprecipitation assays. Results: Sev treatment inhibited migration and invasion of glioma cells. The expression of miR-146b-5p was enhanced and MMP16 protein was decreased in glioma cells after exposure of Sev. Knockdown of miR-146b-5p or overexpression of MMP16 reversed Sev-induced inhibition of migration and invasion of glioma cells. Moreover, MMP16 was indicated as a target of miR-146b-5p and its silencing attenuated the regulatory role of miR-146b-5p abrogationin Sev-treated glioma cells. Conclusion: Sev impeded cell migration and invasion through regulating miR-146b-5p and MMP16 in glioma, indicating a novel theories foundation for the application of anesthetics like Sev in glioma.

Rosmarinic inhibits cell proliferation, invasion and migration via up-regulating miR-506 and suppressing MMP2/16 expression in pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer-related deaths worldwide. However, therapeutic strategies for the treatment of pancreatic cancer are still limited. Therefore, it is urgent for us to develop novel effective therapies for pancreatic cancer. In this study, we explored the effects of rosmarinic acid on pancreatic progression and explored the underlying molecular mechanisms. Rosmarinic acid significantly suppressed cell viability, cell growth, cell invasion and migration as well as epithelial mesenchymal transition (EMT) of pancreatic cancer cells, and induced cell apoptosis in pancreatic cells. In addition, rosmarinic acid significantly up-regulated the expression of miR-506 in pancreatic cancer cells, and knockdown of miR-506 attenuated the suppressive effects of rosmarinic acid on cell growth, cell invasion and migration and EMT, and prevented the enhanced effects of rosmarinic acid on cell apoptosis in pancreatic cancer cells. Mechanistically, the luciferase reporter assay showed that miR-506 targeted the 3' untranslated region of matrix metalloproteinase (MMP)-2/16, and miR-506 overexpression and rosmarinic acid treatment suppressed the expression of MMP2/16 in pancreatic cancer cells. Overexpression of MMP2/16 attenuated the inhibitory effects of rosmarinic acid on pancreatic cell invasion and migration. In vivo studies showed that rosmarinic acid dose-dependently suppressed tumor growth of pancreatic cancer cells, and increased the expression of miR-506, while suppressed the expression of MMP2/16 and Ki-67 in dissected tumor tissues from xenograft nude mice. Collectively, our results for the first time revealed the anti-tumor effects of rosmarinic acid in pancreatic cancer, and the anti-tumor effects of rosmarinic acid were via regulating the miR-506/MMP2/16 axis in pancreatic cancer.

gga-miR-146c Activates TLR6/MyD88/NF-κB Pathway through Targeting MMP16 to Prevent Mycoplasma Gallisepticum (HS Strain) Infection in Chickens.

Mycoplasma gallisepticum (MG), a pathogen that infects chickens and some other birds, triggers chronic respiratory disease (CRD) in chickens, which is characterized by inflammation. The investigation of microbial pathogenesis would contribute to the deep understanding of infection control. Since microribonucleic acids (miRNAs) play a key role in this process, gga-mir-146c, an upregulated miRNA upon MG infection, was selected according to our previous RNA-sequencing data. In this paper, we predicted and validated that MMP16 is one of gga-miR-146c target genes. Results show that MMP16 is the target of gga-miR-146c and gga-miR-146c can downregulate MMP16 expression within limits. gga-miR-146c upregulation significantly increased the expression of TLR6, NF-κB p65, MyD88, and TNF-α, whereas the gga-miR-146c inhibitor led to an opposite result. gga-miR-146c upregulation effectively decreased apoptosis and stimulated DF-1 cells proliferation upon MG infection. On the contrary, gga-miR-146c inhibitor promoted apoptosis and repressed the proliferation. Collectively, our results suggest that gga-miR-146c upregulation upon MG infection represses MMP16 expression, activating TLR6/MyD88/NF-κB pathway, promoting cell proliferation by inhibiting cell apoptosis, and, finally, enhancing cell cycle progression to defend against host MG infection.

Overexpression of Aiolos promotes epithelial-mesenchymal transition and cancer stem cell-like properties in lung cancer cells.

Aiolos/Ikaros family zinc finger 3 (IKZF3), a member of the Ikaros family of lymphocyte maturation-driving transcription factors, is highly expressed in hematopoietic malignancies. However, its role in epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-like properties in lung cancer remains unknown. Human lung cancer cell lines H1299 with overexpressing Aiolos (H1299-Aiolos) and A549 with overexpressing Aiolos (A549-Aiolos) were generated by stable transfection. Cell migration and invasion assays were done to demonstrate their invasion and migration ability. Sphere formation assay was used to determine their tumor-initiating capability. Aiolos overexpression induced EMT and increased migration/invasiveness in H1299 and A549 cells. Aiolos overexpression also increased metastatic ability in vivo. Aiolos overexpression upregulated the expression of Twist and matrix metalloproteinase 16 (MMP16). By using knockdown of Twist or an inhibitor of phosphatidylinositol (PI) 3-kinase, EMT, migration/invasiveness ability, and MMP16 expression were reversed in H1299-Aiolos and A549-Aiolos cells. Overexpression of Aiolos upregulated the CSC-like properties in lung cancer cells, and were also reversed by an inhibitor of PI 3-kinase. For lung cancer cells, Aiolos overexpression promotes EMT and CSC-like properties through upregulating the PI 3-kinase/Akt pathway. The information is helpful for developing therapeutic strategies targeting Aiolos expression for lung cancer treatment.

Pb(ii) binding to the brain specific mammalian metallothionein isoform MT3 and its isolated αMT3 and ßMT3 domains.

The toxicity of lead, one of the most ubiquitous toxic metals, is well known. Some of its pathological effects are related to its preference for the sulfhydryl groups of proteins. Metallothioneins (MT) are a particular family of metalloproteins characterized by their high Cys content that, among other functions, are linked to the detoxification of heavy metals. In mammals, 4 MT isoforms have been found. The MT3 isoform, also called "neuronal growth inhibitory factor", is mainly synthesized in the brain and contains several structural differences that may contribute to important functional differences between it and other MT isoforms. The abilities of recombinant MT3 and its individual αMT3 and ßMT3 fragments to bind Pb(ii) have been investigated here, under different pH conditions, by means of spectroscopy, mass spectrometry and isothermal titration calorimetry. The results obtained show that the binding of Pb(ii) to the intact MT3 protein is relatively unaffected by pH, while the individual domains interact with Pb(ii) in a pH-sensitive manner. The mass spectrometry data reveal the evolution with time of the initially formed Pb-MT complexes. In the case of the full length protein, Pb(ii) remains bound for a long period of time. With the isolated fragments, the lead is eventually released. The Pb-species formed depend on the amount of Pb(ii) present in solution. The thermodynamic data recorded, as measured by ITC, for the replacement of Zn(ii) by Pb(ii) in reactions with Zn-MT3, Zn-αMT3 and Zn-ßMT3 are all similar, and in all cases, the displacement of Zn(ii) by Pb(ii) is thermodynamically favorable. Zn-Replete and Pb-replete MT3 have distinctive circular dichroism spectra, suggestive of structural differences with different metallation status.

MiR-155 promotes the proliferation and migration of breast cancer cells via targeting SOCS1 and MMP16.

OBJECTIVE: The aim of this study was to investigate the effect of miR-155 on the proliferation and migration of breast cancer cells, and to explore the underlying mechanism. MATERIALS AND METHODS: The breast cancer cell line MDA-MB-231 was transfected with miR-155 mimics, inhibitor or negative control, respectively. The expression level of miR-155 was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Subsequently, the proliferation of MDA-MB-231 cells was detected by multi-cellular tumor spheroid (MTS) and colony formation assay. Cell migration was examined by transwell assay and scratch test. In addition, qRT-PCR was performed to analyze the expression of matrix metallopeptidase 16 (MMP16) after miR-155 mimics or inhibitor transfection in MDA-MB-231 cells. Meanwhile, Western blot was used to evaluate the protein expression levels of suppressor of cytokine signaling 1 (SOCS1) and MMP16 after miR-155 mimics or inhibitor transfection. RESULTS: QRT-PCR results showed that miR-155 mimics significantly increased the expression of miR-155 in MDA-MB-231 cells, whereas miR-155 inhibitor markedly decreased miR-155 expression (p < 0.05). Meanwhile, MTS and colony formation assay indicated that the proliferation of MDA-MB-231 cells was remarkably increased after miR-155 mimics transfection. However, miR-155 inhibitor transfection exhibited the opposite result in cell proliferation (p < 0.05). Moreover, miR-155 overexpression significantly increased the migration of MDA-MB-231 cells (p < 0.05). Western blot further confirmed that miR-155 overexpression down-regulated the expression level of target protein SOCS1 and upregulated the expression level of MMP16. CONCLUSIONS: We found that miR-155 significantly enhanced the proliferation and migration of MDA-MB-231 cells, which might serve as an oncogene in breast cancer. Therefore, it is preliminarily believed that miR-155 plays an important role in the proliferation and migration of breast cancer cells via down-regulating the expression of SOCS1 and up-regulating the expression of MMP16.

HOXA11-AS promotes the growth and invasion of renal cancer by sponging miR-146b-5p to upregulate MMP16 expression.

Recently, increasing studies showed that long noncoding RNAs (lncRNAs) play critical roles in tumor progression. However, the function and underlying mechanism of HOMEOBOX A11 antisense RNA (HOXA11-AS) on renal cancer remain unclear. In the current study, our data showed that the expression of HOXA11-AS was significantly upregulated in clear cell renal cell carcinoma (ccRCC) tissues and cell lines. High HOXA11-AS expression was associated with the advanced clinical stage, tumor stage, and lymph node metastasis. Function assays showed that HOXA11-AS inhibition significantly suppressed renal cancer cells growth, invasion, and ETM phenotype. In addition, underlying mechanism revealed that HOXA11-AS could act as a competing endogenous RNA (ceRNA) that repressed miR-146b-5p expression, which regulated its downstream target MMP16 in renal cancer. Taken together, our findings suggested that HOXA11-AS could promote renal cancer cells growth and invasion by modulating miR-146b-5p-MMP16 axis. Thus, our findings suggested that HOXA11-AS could serve as potential therapeutic target for the treatment of renal cancer.

MT3-MMP Promotes Excitatory Synapse Formation by Promoting Nogo-66 Receptor Ectodomain Shedding.

Cell-surface molecules are dynamically regulated at the synapse to assemble and disassemble adhesive contacts that are important for synaptogenesis and for tuning synaptic transmission. Metalloproteinases dynamically regulate cellular behaviors through the processing of cell surface molecules. In the present study, we evaluated the role of membrane-type metalloproteinases (MT-MMPs) in excitatory synaptogenesis. We find that MT3-MMP and MT5-MMP are broadly expressed in the mouse cerebral cortex and that MT3-MMP loss-of-function interferes with excitatory synapse development in dissociated cortical neurons and in vivo We identify Nogo-66 receptor (NgR1) as an MT3-MMP substrate that is required for MT3-MMP-dependent synapse formation. Introduction of the shed ectodomain of NgR1 is sufficient to accelerate excitatory synapse formation in dissociated cortical neurons and in vivo Together, our findings support a role for MT3-MMP-dependent shedding of NgR1 in regulating excitatory synapse development.SIGNIFICANCE STATEMENT In this study, we identify MT3-MMP, a membrane-bound zinc protease, to be necessary for the development of excitatory synapses in cortical neurons. We identify Nogo-66 receptors (NgR1) as a downstream target of MT3-MMP proteolytic activity. Furthermore, processing of surface NgR1 by MT3-MMP generates a soluble ectodomain fragment that accelerates the formation of excitatory synapses. We propose that MT3-MMP activity and NgR1 shedding could stimulate circuitry remodeling in the adult brain and enhance functional connectivity after brain injury.