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At least 577 records · Page 32

MicroRNAs let-7b/i suppress human glioma cell invasion and migration by targeting IKBKE directly

We demonstrated that IKBKE is overexpressed in human gliomas and that the downregulation of IKBKE markedly inhibits the proliferative and invasive abilities of glioma cells, which is consistent with the results reported by several different research groups. Therefore, IKBKE represents a promising therapeutic target for the treatment of glioma. In the present study, we verified that the microRNAs let-7b and let-7i target IKBKE through luciferase assays and found that let-7b/i mimics can knock down IKBKE and upregulate E-cadherin through western blot analysis. Moreover, the expression levels of let-7b/i were significantly lower in glioma cell lines than that in normal brain tissues, as determined by quantitative real-time PCR. Furthermore, let-7b/i inhibit the invasion and migration of glioma cells, as determined through wound healing and Transwell assays. The above-mentioned data suggest that let-7b/i inhibit the invasive ability of glioma cells by directly downregulating IKBKE and indirectly upregulating E-cadherin. - Highlights: • Let-7b and let-7i are downregulated in glioma cell lines. • IKBKE is a target gene of let-7b/i. • Let-7b/i inhibit the invasion and migration of glioma cells. • Let-7b/i upregulate E-cadherin by downregulating IKBKE.

60 APPLIED LIFE SCIENCES↗

Long none coding RNA HOTTIP/HOXA13 act as synergistic role by decreasing cell migration and proliferation in Hirschsprung disease

Long noncoding RNAs (lncRNAs) have been confirmed to be associated with various human diseases. However, whether they are associated with Hirschsprung disease (HSCR) progression remains unclear. In this study, we designed the experiment to explore the relationship between lncRNA HOTTIP and HOXA13, and their pathogenicity to HSCR. Quantitative real-time PCR and Western blot were performed to detect the levels of lncRNA, mRNAs, and proteins in colon tissues from 79 patients with HSCR and 79 controls. Small RNA interference transfection was used to study the function experiments in human 293T and SK-N-BE cell lines. The cell viability and activities were detected by the transwell assays, CCK8 assay, and flow cytometry, respectively. LncRNA HOTTIP and HOXA13 were significantly down-regulated in HSCR compared to the controls. Meanwhile, the declined extent of their expression levels makes sense between two main phenotype of HSCR. SiRNA-mediated knock-down of HOTTIP or HOXA13 correlated with decreased levels of each other and both reduced the cell migration and proliferation without affecting cell apoptosis or cell cycle. Our study demonstrates that aberrant reduction of HOTTIP and HOXA13, which have a bidirectional regulatory loop, may play an important role in the pathogenesis of HSCR. - Highlights: • LncRNA HOTTIP and HOXA13 are both down-regulated in HSCR. • HOTTIP and HOXA13 can regulate each other in 293T and SK-N-BE(2) cell lines. • Both HOTTIP and HOXA13 can decrease cell migration and proliferation.

60 APPLIED LIFE SCIENCES↗

Stroma-induced Jagged1 expression drives PC3 prostate cancer cell migration; disparate effects of RIP-generated proteolytic fragments on cell behaviour and Notch signaling

The Notch ligand Jagged1 is subject to regulated intramembrane proteolysis (RIP) which yields a soluble ectodomain (sJag) and a soluble Jagged1 intracellular domain (JICD). The full-length Jagged1 protein enhances prostate cancer (PCa) cell proliferation and is highly expressed in metastatic cells. However, little is known regarding the mechanisms by which Jagged1 or its RIP-generated fragments might promote PCa bone metastasis. In the current study we show that bone marrow stroma (BMS) induces Jagged1 expression in bone metastatic prostate cancer PC3 cells and that this enhanced expression is mechanistically linked to the promotion of cell migration. We also show that RIP-generated Jagged1 fragments exert disparate effects on PC3 cell behaviour and Notch signaling. In conclusion, the expression of both the full-length ligand and its RIP-generated fragments must be considered in tandem when attempting to regulate Jagged1 as a possible PCa therapy. - Highlights: • Bone marrow stroma induces Jagged1 expression in prostate cancer (PCa) PC3 cells. • This enhanced expression of full-length Jagged1 is required for PC3 cell migration. • Proteolytic fragments of Jagged1 exert disparate effects on PC3 cell behaviour. • Effects of fragments on cell behaviour do not correlate with Notch signaling. • Effects of Jagged1 and its fragments on PCa metastasis likely to be complex.

60 APPLIED LIFE SCIENCES↗

Downregulated long non-coding RNA MEG3 in breast cancer regulates proliferation, migration and invasion by depending on p53’s transcriptional activity

Long non-coding RNAs (lncRNAs) was found to play critical roles in tumorigenesis, hence, screen of tumor-related lncRNAs, identification of their biological roles is important for understanding the processes of tumorigenesis. In this study, we identified the expressing difference of several tumor-related lncRNAs in breast cancer samples and found that, MEG3, which is downregulated in non-small cell lung cancer (NSCLC) tumor tissues, is also downregulated in breast cancer samples compared with adjacent tissues. For figuring out the effect of MEG3 in breast cancer cells MCF7 and MB231, we overexpressed MEG3 in these cells, and found that it resulted the inhibition of proliferation, colony formation, migration and invasion capacities by enhancing p53’s transcriptional activity on its target genes, including p21, Maspin and KAI1. MEG3 presented similar effects in MB157, which is a p53-null breast cancer cell line, when functional p53 but not p53R273H mutant, which lacks transcriptional activity, was introduced. Surprisingly, overexpression of MEG3 activates p53’s transcriptional activity by decreasing MDM2’s transcription level, and thus stabilizes and accumulates P53. Taken together, our findings indicate that MEG3 is downregulated in breast cancer tissues and affects breast cancer cells’ malignant behaviors, which indicate MEG3 a potential therapeutic target for breast cancer. - Highlights: • MEG3 RNA is widely downregulated in breast tumor tissue. • MEG3 regulates P53 indirectly through transcriptional regulation of MDM2. • Under unstressed condition, MEG3-related P53 accumulation transcriptionally activates p53’s target genes. • MEG3 expression level tightly regulates proliferation, colony formation, migration and invasion in breast tumor cells.

60 APPLIED LIFE SCIENCES↗

Kir2.1 regulates rat smooth muscle cell proliferation, migration, and post-injury carotid neointimal formation

Phenotype switching of vascular smooth muscle cells (VSMC) from the contractile type to the synthetic type is a hallmark of vascular disorders such as atherosclerosis and restenosis after angioplasty. Inward rectifier K{sup +} channel 2.1 (Kir2.1) has been identified in VSMC. However, whether it plays a functional role in regulating cellular transformation remains obscure. In this study, we evaluated the role of Kir2.1 on VSMC proliferation, migration, phenotype switching, and post-injury carotid neointimal formation. Kir2.1 knockdown significantly suppressed platelet-derived growth factor BB-stimulated rat vascular smooth muscle cells (rat-VSMC) proliferation and migration. Deficiency in Kir2.1 contributed to the restoration of smooth muscle α-actin, smooth muscle 22α, and calponin and to a reduction in osteopontin expression in rat-VSMC. Moreover, the in vivo study showed that rat-VSMC switched to proliferative phenotypes and that knockdown of Kir2.1 significantly inhibited neointimal formation after rat carotid injury. Kir2.1 may be a potential therapeutic target in the treatment of cardiovascular diseases, such as atherosclerosis and restenosis following percutaneous coronary intervention.

60 APPLIED LIFE SCIENCES↗

Serum long non coding RNA MALAT-1 protected by exosomes is up-regulated and promotes cell proliferation and migration in non-small cell lung cancer

Circulating lncRNAs have been defined as a novel biomarker for non-small cell lung cancer (NSCLC), MALAT-1 was first identified lncRNA that was related to lung cancer metastasis. However, the relationship between exosomal lncRNAs and the diagnosis and prognosis of NSCLC was poorly understood. The aim of this study is to evaluate the clinical significance of serum exosomal MALAT-1 as a biomarker in the metastasis of NSCLC. In this study, we firstly isolated the exosomes from healthy subjects and NSCLC patients. Then we measured the expression levels of MALAT-1 contained in exosomes, and found that exosomal MALAT-1 was highly expressed in NSCLC patients, more importantly, the levels of exosomal MALAT-1 were positively associated with tumor stage and lymphatic metastasis. In addition, we decreased MALAT-1 expression by short hairpin RNA and conducted a series of assays including MTT, cell cycle, colony formation, wound-healing scratch and Annexin/V PI by flow cytometry in human lung cancer cell lines. These in vitro studies demonstrated that serum exosome-derived long noncoding RNA MALAT-1 promoted the tumor growth and migration, and prevented tumor cells from apoptosis in lung cancer cell lines. Taken together, this study shed a light on utilizing MALAT-1 in exosomes as a non-invasive serum-based tumor biomarker for diagnosis and prognosis of NSCLC. - Highlights: • serum MALAT-1 contained in exosomes is upregulated in NSCLC patients. • Exosomal MALAT-1 was positively associated with TNM stage and lymphatic node metastasis. • MALAT-1 knockdown inhibited cell proliferation, colony formation and cell migration. • MALAT-1 knockdown induced cell cycle arrest and cell apoptosis.

60 APPLIED LIFE SCIENCES↗

miR-1236-3p suppresses the migration and invasion by targeting KLF8 in lung adenocarcinoma A549 cells

MicroRNAs (miRNAs) have a great effect on regulating tumor cell migration, invasion, proliferation and prognosis. However, the mechanism of miR-1236-3p on regulating carcinogenesis is still unknown. In this study, the expression of miR-1236-3p was lower in lung adenocarcinoma tissues than that in adjacent normal tissue. In lung adenocarcinoma A549 cell line, miR-1236-3p decreased ability of cell invasion and migration, furthermore, we show that KLF8 is targeted by miR-1236-3p, and expression of miR-1236-3p is negatively correlated with KLF8. Additionally, miR-1236-3p suppressed the expression of KLF8 and EMT (epithelial mesenchymal transition)-related genes. Overexpression of KLF8 can promote EMT-related genes at protein level. In conclusion, our results support the fact that miR-1236-3p acts as a tumor inhibitor in lung adenocarcinoma by suppressing the activity of KLF8, and it may play a critical role in the diagnosis and treatment of lung cancer.

60 APPLIED LIFE SCIENCES↗

D Rhamnose β-hederin inhibits migration and invasion of human breast cancer cell line MDA-MB-231

Highlights: • D Rhamnose β-hederin (DRβ-H) could be a potential therapeutic candidate for treating metastatic breast cancer. • We first report the molecular mechanisms of anti-breast cancer metastasis of DRβ-H. • Up-rugulation of RNPC1 by DRβ-H is essential for its anti-metastatis activities. Many natural products have been shown to have inhibitory effects on the metastatic process of various cancers including breast cancer. An active triterpenoid saponin D Rhamnose β-hederin (DRβ-H) from Clematis ganpiniana, has been known induce the apoptosis of breast cancer cells, but the effect of DRβ-H on the metastasis of breast cancer cells is largely unknown. In this study, we demonstrated that a non-cytotoxic concentration of DRβ-H markedly suppressed wound healing migration, migration through the chamber and invasion through the matrigel. In addition, DRβ-H regulated expression of RNPC1, E-cadherin proteins of MDA-MB-231 cells. Furthermore, RNPC1 knockdown decreased the DRβ-H-induced up-regulation of RNPC1 and E-Cadherin in MDA-MB-231 cells. RNPC1 knockdown reduced the anti-metastasis activities of DRβ-H, meaning that the up-rugulation of RNPC1 by DRβ-H is essential for its anti-metastatis activities. These results suggest that DRβ-H might be a potential therapeutic candidate for the treatment of breast cancer metastasis.

60 APPLIED LIFE SCIENCES↗

miR-455-3p serves as prognostic factor and regulates the proliferation and migration of non-small cell lung cancer through targeting HOXB5

MicroRNAs (miRs) have been reported to play significantly roles in the initiation and progression of human cancers. miR-455-3p has been recently found could function as tumor suppressor in various human cancers. However, its expression and biological role in non-small cell lung cancer (NSCLC) remains elusive. In this study, we found miR-455-3p was markedly downregulated in NSCLC tissues and cell lines. Chi-square test to analyze the correlations between miR-455-3p expression and clinicopathological features revealed that miR-455-3p expression was correlated with poorly differentiated cancer and advanced tumor stage (P P = 0.029). Univariate and multivariate analyses identified low miR-455-3p expression was an unfavorable prognostic factor for overall survival. Gain-of-function and loss-of-function studies revealed that miR-455-3p inhibits cell proliferation and migration in vitro. Computer algorithm and dual-luciferase reporter assay revealed that miR-455-3p directly targets and suppresses HOXB5 in NSCLC. Further studies demonstrated that knockdown of HOXB5 attenuated the effect of miR-455-3p downregulation on cell proliferation and migration. Taken together, our results for the first time suggested that miR-455-3p was downregulated in NSCLC and was correlated with the poor prognosis of NSCLC patients. Also, miR-455-3p functions as tumor suppressor by directly targeting HOXB5 in NSCLC progression and may be used as a potential target for NSCLC treatment.

60 APPLIED LIFE SCIENCES↗

Long noncoding RNA SNHG15 promotes human breast cancer proliferation, migration and invasion by sponging miR-211-3p

Long non-coding RNAs (lncRNA) have been demonstrated to act as essential regulators in the development and progression of breast cancer. In our study, we found that long noncoding RNA SNHG15 was highly expressed in breast cancer tissues and cell lines. And the expression of SNHG15 was correlated with TNM stage, lymphnode metastasis and survival in breast cancer patients. SNHG15 knockdown significantly inhibited the proliferation and induced apoptosis in breast cancer cells in vitro and in vivo. Besides, SNHG15 downregulation suppressed cell migration and invasion in MCF-7 and BT-20 cells, and inhibited epithelial-mesenchymal transition (EMT). In mechanism, we found that SNHG15 acted as a competing endogenous RNA to sponge miR-211-3p, which was downregulated in breast cancers and inhibited cell proliferation and migration. Our results showed that there was a negative correlation between SNHG15 and miR-211-3p expression in breast cancer patients. Collectively, we, for the first time, revealed the functions of SNHG15 and miR-211-3p in breast cancer.

60 APPLIED LIFE SCIENCES↗

High expression of diffuse panbronchiolitis critical region 1 gene promotes cell proliferation, migration and invasion in pancreatic ductal adenocarcinoma

Highlights: • DPCR1 is overexpressed in PDAC and correlates with prognosis of PDAC patients. • Inhibition of DPCR1 suppresses PDAC cell proliferation in vitro and in vivo. • Inhibition of DPCR1 suppresses PDAC cell migration and invasion. • DPCR1 may promote tumor progression by regulating NF-κB pathway. Diffuse panbronchiolitis critical region 1 (DPCR1) is located in the major histocompatibility complex (MHC) class I. It was reported to be downregulated in invasive pituitary adenoma compared with that in non-invasive tumors, but upregulated in the precursor of gastric carcinogenesis. However, the direct effect of DPCR1 on cancer cells has rarely been reported, and the role DPCR1 in pancreatic ductal adenocarcinoma (PDAC) remains unclear. The clinical sample validation and public data analysis of the present study demonstrated that DPCR1 was upregulated markedly in PDAC and this high expression was negatively correlated with the patient prognosis. Functionally, knocking down DPCR1 in PDAC cell lines inhibited cell proliferation, migration and invasion in vitro. Tumor xenograft experiments further showed that suppression of DPCR1 inhibited tumor growth in vivo. In addition, the results of RNA deep sequencing and qRT-PCR assay showed that DPCR1 participated in PADC progression by regulating nuclear factor-kappa B signaling pathway, suggesting that it might be a novel oncogene in tumor progression and a potential therapeutic target in PDAC as well.

60 APPLIED LIFE SCIENCES↗

LncRNA CCND2-AS1 promotes proliferation, migration, and invasion in papillary thyroid carcinoma

In decades, a lot of long non-coding RNAs (LncRNAs) have been proven to exert influences on tumorigenesis in vitro and in vivo. Many lncRNAs have been reported as effective therapeutic targets and biomarkers in various cancers. However, whether LncRNAs are associated with the progression of PTC remains largely unknown. In this study, we measured the expression of CCND2-AS1 in PTC cell lines by quantitative real-time polymerase chain reaction (qRT-PCR).We found that CCND2-AS1 expression was significantly over-expressed in PTC cell lines compared to normal thyroid epithelial cells. Gain-and loss-of-function experiments were performed to investigate the role of CCND2-AS1 in PTC cells. In vitro experiments, we proved that CCND2-AS1 knockdown in TPC1 significantly suppressed cell proliferation, migration, and invasion, while CCND2-AS1 overexpression in BCPAP had the opposite effects. Meanwhile, we also found that CCND2-AS1 could regulate N-cadherin and Vimentin expression, which may influence invasion and migration. Our findings indicate that the lncRNA CCND2-AS1 is a gene associated with PTC and might become a potential therapeutic target.

60 APPLIED LIFE SCIENCES↗

AIM2 regulates vascular smooth muscle cell migration in atherosclerosis

Highlights: • Our study demonstrated that AIM2 is involved in the progression of atherosclerosis in ApoE−/− mice for the first time. • We first found AIM2 could affect VSMCs migration and MMP2 expression. • We first found that AIM2 could active the TGF-β/SMAD signaling in VSMCs. Atherosclerosis (AS) is a common pathological basis of various cardiovascular and cerebrovascular diseases. Plaque formation is initiated and triggered by vascular smooth musclecells (VSMCs) migration in vascular wall, which gradually aggravates atherosclerosis progression. Absent in melanoma 2 (AIM2), a member of HIN-200 family, plays an important role in activating inflammasome. However, the role of AIM2 in atherosclerotic plaque progression outside of the inflammasome has not yet been reported.

60 APPLIED LIFE SCIENCES↗

GATA3 acetylation at K119 by CBP inhibits cell migration and invasion in lung adenocarcinoma

Highlights: • GATA3 interacts with and is acetylated by the acetyltransferase CBP. • The major acetylated site of GATA3 in lung adenocarcinoma cells is lysine 119. • GATA3 is deacetylated by Class I deacetylases HDAC1, HDAC2 and HDAC3. • The acetylation status of GATA3-K119 is critical to lung adenocarcinoma progression. GATA3 is a transcriptional factor involved in the development of multiple organs. Post translational modifications of GATA3 are critical to its function. Here, we report that GATA3 interacts with and is acetylated by the acetyltransferase CBP. Class I deacetylases HDAC1, HDAC2 and HDAC3 deacetylate GATA3. The major acetylated site of GATA3 in lung adenocarcinoma cells was determined at lysine 119 (AcK119). Functionally, GATA3-acetylation mimics K119Q mutant was found to inhibit lung adenocarcinoma cell migration and invasion with concomitant downregulation of EMT-controlling transcriptional factors Slug, Zeb1 and Zeb2. Taken together, we demonstrated that GATA3 acetylation at lysine 119 by CBP hinders the migration and invasion of lung adenocarcinoma cells.

60 APPLIED LIFE SCIENCES↗

Chlamydia pneumoniae infection promotes monocyte transendothelial migration by increasing vascular endothelial cell permeability via the tyrosine phosphorylation of VE-cadherin

Highlights: • C. pneumoniae infection promotes monocyte TEM through increasing VEC permeability. • C. pneumoniae infection stimulates VE-cadherin tyrosine phosphorylation by Src. • VE-cadherin phosphorylation is involved in VE-cadherin internalization. • VE-cadherin phosphorylation is involved in EC hyperpermeability caused by infection. • VE-cadherin phosphorylation is associated with the infection-induced monocyte TEM. Migration of monocytes into the subendothelial layer of the intima is one of the critical events in early atherosclerosis. Chlamydia pneumoniae (C. pneumoniae) infection has been shown to promote monocyte transendothelial migration (TEM). However, the exact mechanisms have not yet been fully clarified. In this study, we tested the hypothesis that C. pneumoniae infection increases vascular endothelial cell (VEC) permeability and subsequent monocyte TEM through stimulating the tyrosine phosphorylation of vascular endothelial-cadherin (VE-cadherin). Here, we demonstrated that C. pneumoniae infection promoted monocyte TEM in a TEM assay possibly by increasing the permeability of a VEC line EA.hy926 cell as assessed by measuring the passage of FITC-BSA across a VEC monolayer. Subsequently, Western blot analysis showed that C. pneumoniae infection induced VE-cadherin internalization. Our further data revealed that Src-mediated VE-cadherin phosphorylation at Tyr658 was involved in C. pneumoniae infection-induced internalization of VE-cadherin, VEC hyperpermeability and monocyte TEM. Taken together, our data indicate that C. pneumoniae infection promotes monocyte TEM by increasing VEC permeability via the tyrosine phosphorylation and internalization of VE-cadherin in VECs.

60 APPLIED LIFE SCIENCES↗

LncRNA FABP5P3/miR-589-5p/ZMYND19 axis contributes to hepatocellular carcinoma cell proliferation, migration and invasion

Hepatocellular carcinoma (HCC) contributes to cancer-related deaths greatly every year in the world. However, there is still no radical method for HCC treatment. Here we screened out a lncRNA FABP5P3 that was up-regulated in HCC tissues. Patients with higher FABP5P3 expression displayed poorer survival rate. FABP5P3 depletion in HCC cell lines and sample cells remarkably inhibited the abilities of proliferation, migration and invasion. In mechanism, we showed that FABP5P3 bond to miR-589-5p which served as a tumor suppressor. MiR-589-5p targeted directly the mRNA of ZMYND19 whose function has not been defined in HCC. FABP5P3 promoted HCC development and progression by sponging miR-589-5p and up-regulating ZMYND19 expression. In sum, we showed that FABP5P3/miR-589-5p/ZMYND19 axis regulates cell proliferation and migration in HCC, which may serve as a new target for HCC treatment.

60 APPLIED LIFE SCIENCES↗

MicroRNA-585 suppresses tumor proliferation and migration in gastric cancer by directly targeting MAPK1

Highlights: • MiR-585 is down-regulated in gastric cancer tissues. • Down-regulation of miR-585 indicates poor prognosis for GC patients. • MiR-585 inhibits GC cell proliferation and migration by targeting MAPK1. Increasing evidence reveals that microRNA contributes to the development and progression of gastric cancer (GC), but the roles of miR-585 in GC remain unclear. In this study, we confirmed that miR-585 was down-regulated in GC tissues and cell lines and that miR-585 expression was related to extent of invasion, TNM stage, lymph node invasion and poor prognosis. Our results showed that miR-585 inhibits the proliferation and migration of GC, and MAPK1 is a direct and functional target of miR-585. Our study sheds light on the role of miR-585 as a suppressor for tumor growth and metastasis and raises the intriguing possibility that miR-585 may serve as a new potential marker for monitoring and treating GC.

60 APPLIED LIFE SCIENCES↗

MiR-615 inhibits cell proliferation, migration and invasion by targeting EGFR in human glioblastoma

Highlights: • MiR-615 is decreased in GBM. • MiR-615 is a tumor suppressor. • MiR-615 targets EGFR 3′-UTR. MiR-615 and epidermal growth factor receptor (EGFR) are associated with a number of disease processes and pathogenesis. However, little is known about the mechanisms of miR-615 and EGFR in human glioblastoma multiforme (GBM). Here, we found that down-regulation of miR-615 expression occurred in GBM tissues and cells, and was inversely correlated with overall survival, relapse-free survival, WHO grade as well as EGFR expression. We further determined that miR-615 functions as a tumor suppressor by inhibiting GBM cell proliferation, cell cycle, migration and invasion, and promoting cell apoptosis. In-vivo assay validated the inhibition effect of miR-615 on tumor growth and EGFR expression. Luciferase reporter assays demonstrated that miR-615 targeted the 3′-untranslated region (3′-UTR) of EGFR. Besides, over-expression of EGFR reversed the inhibition effects of miR-615, while silencing of EGFR aggravated these inhibition effects. In conclusions, we identified that miR-615 plays a tumor suppressor role in GBM cell proliferation, migration and invasion by targeting EGFR expression, and miR-615 may act as a novel biomarker for early diagnosis or therapeutic targets of GBM.

60 APPLIED LIFE SCIENCES↗