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At least 343 records · Page 19

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DOE OSTI2015

Sinomenine inhibits breast cancer cell invasion and migration by suppressing NF-κB activation mediated by IL-4/miR-324-5p/CUEDC2 axis

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a vital transcription factor that regulates multiple important biological processes, including the epithelial–mesenchymal transition (EMT) and metastasis of breast cancer. Sinomenine is an isoquinoline well known for its remarkable curative effect on rheumatic and arthritic diseases and can induce apoptosis of several cancer cell types. Recently, sinomenine was reported as a tumor suppressor via inhibiting cell proliferation and inducing apoptosis. However, the role and mechanism of sinomenine in invasion and metastasis of breast cancer are largely unknown. Here, we report that sinomenine suppressed the invasion and migration of MDA-MB-231 and 4T1 breast cancer cells in a dose-dependent manner. We detected binding of NF-κB to the inhibitor of NF-κB (IκB) after the MDA-MB-231 cells were treated with 0.25, 0.5, and 1 mM sinomenine. Co-IP analysis revealed that sinomenine enhanced the binding of NF-κB and IκB in a dose-dependent manner, suggesting that sinomenine had an effect on inactivation of NF-κB. Western blotting and ELISA approaches indicated that the suppression effect was closely associated with the phosphorylation of IκB kinase (IKK) and its negative regulator CUEDC2. Sinomenine treatment decreased miR-324-5p expression, thus increased the level of its target gene CUEDC2, and then blocked the phosphorylation of IKK through altering the upstream axis. Finally, transfection of a miR-324-5p mimic inhibited the suppression of invasion and metastasis of MDA-MB-231 and 4T1 cell by sinomenine, providing evidence that sinomenine treatment suppressed breast cancer cell invasion and metastasis via regulation of the IL4/miR-324-5p/CUEDC2 axis. Our findings reveal a novel mechanism by which sinomenine suppresses cancer cell invasion and metastasis, i.e., blocking NF-κB activation. - Highlights: • Sinomenine reduced invasion and migration of MDA-MB-231 and 4T1 breast cancer cells. • Sinomenine enhanced combination of NF-κB with IκB and blocked NF-κB activation. • Sinomenine promoted CUEDC2 expression and suppressed IκB kinase phosphorylation. • Sinomenine reduced IL-4 and miR-324-5p levels. • MiR-324-5p inhibited the suppression of invasion and metastasis by sinomenine.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

IL-8 interacts with metadherin promoting proliferation and migration in gastric cancer

It has been reported that IL-8 was involved in the promotion of invasion of Gastric Cancer (GC), however the underlying mechanism by which IL-8 was observed to be able to promote invasion remains unknown. Here, in our study, IL-8 was shown to be significantly up-regulated in GC compared with paired normal control tissues whose expression was markedly associated with inferior overall prognosis; and IL-8 was displayed to be capable of directly interacting with metadherin (MTDH), which in turn can up-regulate IL-8 expression. Blockage of IL-8/MTDH using specific mono-antibody can abolish the invasion IL-8 mediated. Taken together, our results may provide a novel explanation of working mechanism of IL-8 in the invasion of GC. - Highlights: • IL-8 was commonly observed to be significantly up-regulated in gastric cancer. • IL-8 was found to be able to be directly interacted with MTDH. • MTDH can up-regulate IL-8 promoting EMT process. • Blockage of IL-8-MTDH complex can abrogate the growth of gastric cancer cells in vitro and in vivo.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

miR-144-3p serves as a tumor suppressor for renal cell carcinoma and inhibits its invasion and metastasis by targeting MAP3K8

MicroRNAs (miRNAs) are important regulators involved in various cancers, including renal cell carcinoma (RCC). The role of the miRNAs involved in RCC progress and metastasis is largely unknown. Here, miRNA microarray analysis was performed to screen the significant miRNAs involved in RCC progress, and miR-144-3p was chosen for further study. We found that the expression of miR-144-3p was significantly lower in RCC specimens and cell lines. In addition, low expression level of miR-144-3p is correlated with tumor progression and poor survival in RCC patients. Based on in vitro assays, we found that miR-144-3p significantly inhibit cancer cell proliferation and progression. Furthermore, function studies revealed that miR-144-3p was significantly correlated with the metastasis potential by affecting the epithelial-mesenchymal transition (EMT). Moreover, Mitogen-activated protein kinase 8 (MAP3K8) is direct target of miR-144-3p, while the expression levels of MAP3K8 were inversely correlated with the expression levels of miR-144-3p in RCC tissues. Overall, our findings demonstrate that miR-144-3p targeted the MAP3K8 pathway to reduce tumor cells proliferation and metastasis in RCC, suggesting that this axis may provide a novel therapeutic target for RCC therapy. - Highlights: • Downregulation of miR-144-3p expression was significantly associated with the poor survival in RCC patients. • Ectopic expression of miR-144-3p inhibits viability and metastasis of RCC cells in vitro. • miR-144-3p suppresses the epithelial-mesenchymal transition in RCC cells. • MAP3K8 is a direct target of miR-144-3p, and miR-144-3p downregulation is a factor in RCC progression through potentiation of MAP3K8 expression.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

Epigenetic activation of SIN1 promotes NSCLC cell proliferation and metastasis by affecting the epithelial–mesenchymal transition

Stress-activated protein kinase (SAPK) interacting protein 1 (SIN1) is an essential component of mTORC2. Previous studies have shown that SIN1 is a key regulator of Akt pathway which plays an important role in various pathological conditions including cancer. While its effects and mechanisms on the progression of NSCLC remain unknown. In this study, we report that SIN1 is able to promote the growth and migration of NSCLC cells both in vitro and in vivo. Overexpression of SIN1 promoted A549 and H1299 cells proliferation by both MTT and colony formation assays. Consistently, knockdown of SIN1 inhibited the proliferation of these cells. In transwell assay, overexpression of SIN1 increased the migration of A549 and H1299 cells, while SIN1 knockdown reduced their migration. In a tumor xenograft model, overexpression of SIN1 promoted tumor growth of A549 cells in vivo, while SIN1 knockdown suppresses the tumor growth. We also found a mechanistic link between SIN1 and H3K4me3, H3K4me3 is involved in SIN1 upregulation. Moreover, SIN1 can significantly promote the in vitro migration and invasion of NSCLC cells via induction epithelial mesenchymal transition (EMT) process, which subsequently leads to transcriptional downregulation of epithelial marker E-cadherin and upregulation of mesenchymal markers N-cadherin and Vimentin expression. Together, our results reveal that SIN1 plays an important role in NSCLC and SIN1 is a potential biomarker and a promising target in the treatment of NSCLC.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

β-elemene inhibits tumor-promoting effect of M2 macrophages in lung cancer

Macrophages in tumor are mostly M2-polarized and have been reported to promote tumorigenesis, which are also defined as tumor-associated macrophages (TAMs). β-elemene has therapeutic effects against several cancers, however, it remains unknown whether β-elemene could inhibit cancer by targeting TAMs. Herein, we examined the effect of β-elemene on macrophages to elucidate a novel mechanism of β-elemene in tumor therapy. We showed that the conditioned medium of M2 macrophages promoted lung cancer cells to migration, invasion and epithelial mesenchymal transition, which could be inhibited by β-elemene. Moreover, β-elemene regulated the polarization of macrophages from M2 to M1. β-elemene also inhibited the proliferation, migration, invasion of lung cancer cells and enhanced its radiosensitivity. These results indicate β-elemene suppresses lung cancer by regulating both macrophages and lung cancer cells, it is a promising drug for combination with chemotherapy or radiotherapy. - Highlights: • β-elemene inhibits M2 macrophages induced migration and invasion of cancer cells. • β-elemene inhibits M2 macrophages induced EMT in lung cancer cells. • β-elemene transforms macrophages from M2 to M1 phenotype. • This study reveals a novel anti-tumor mechanism of β-elemene.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

Snail transcription factor NLS and importin β1 regulate the subcellular localization of Cathepsin L and Cux1

Several recent studies have highlighted an additional unexpected localization and site of action for Cathepsin L (Cat L) protease within the nucleus in breast, colon and prostate cancer, however, its role in the nucleus was unclear. It was proposed to mediate proteolytic processing of the transcription factor CCAAT-displacement protein/cut homeobox transcription factor (Cux1) from the full-length p200 isoform to generate the p110 and p90 isoforms, of which the p110 isoform was shown to act as a cell cycle regulator to accelerate entry into the S phase. The p110 isoform has also been shown to bind to the promoter regions of Snail and E-cadherin to activate Snail and inactivate E-cadherin transcription, thus promoting epithelial mesenchymal transition (EMT). Mechanistic studies on what drives Cat L nuclear localization have not been reported. Our hypothesis is that Snail shuttles into the nucleus with Cat L through binding to importin-β. Snail knockdown with siRNA in MDA-MB-468 breast cancer cells led to nuclear to cytoplasmic shuttling of Cat L and decreased levels of Cux1, while overexpression of Snail in MCF-7 breast cancer cells or HEK-293 human embryonic kidney cells led to increased nuclear expression of both Cat L and Cux1. Additionally, transient transfection of Snail NLS mutants not only abrogated Snail nuclear localization but also nuclear localization of Cat L and Cux1. Interestingly, importin β1 knockdown with siRNA decreased Snail and Cux1 levels, as well as nuclear localization of Cat L. Therefore, we show for the first time that the nuclear localization of Cat L and its substrate Cux1can be positively regulated by Snail NLS and importin β1, suggesting that Snail, Cat L and Cux1 all utilize importin β1 for nuclear import. - Highlights: • Snail expression is associated with increased nuclear expression of Cathepsin L (Cat L) and Cux1. • Snail NLS is required for nuclear localization of Cat L and Cux1. • Importin β1 is required for Snail, Cat L and Cux1 expression/nuclear localization.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

Upregulation of SOX2 activated LncRNA PVT1 expression promotes breast cancer cell growth and invasion

Increasing evidences indicated that Long noncoding RNAs (lncRNAs) played pivotal roles during tumorigenesis in multiple types of cancers, including breast cancer. This study aimed to investigate the role and function of long noncoding RNA PVT1 in the progression of breast cancer and explore the transcription factor which contributes to the regulation of PVT1 in breast cancer. Our results indicated that the expression of PVT1 was significantly upregulated in breast cancer tissues, compared with adjacent normal tissues (ANTs). And the increasing expression of PVT1 was associated with clinical stage, lymph nodes metastasis, and overall survival in breast cancer patients. Using computational screening, a transcriptional factor binding site was found between SOX2 and PVT1 promoter and the interaction between each other was further verified by chromatin immunoprecipitation (ChIP) analysis. In addition, ectopically overexpression of SOX2 can enhance breast cancer cell proliferation and invasion, while knockdown of SOX2 or PVT1 can severely attenuate this effect both in epithelial and mesenchymal types of breast cancer cells. Further evidences confirmed that overexpression of SOX2 can promote breast cancer cell EMT process; while silencing SOX2 or PVT1 expression can undermine this effect. These data suggest that elevated expression of SOX2 can activate lncRNA PVT1 expression promoted breast cancer tumorigenesis and progression. PVT1 may be a prognostic predictive biomarker for breast cancer, and the interaction of PVT1-SOX2 could be a therapeutic target in breast cancer. - Highlights: • SOX2 can bind to the promoter of LncRNA PVT1 and promotes it transcription in breast cancer cells. • Overexpression of SOX2 can activate PVT1 expression promote breast cancer cell growth and invasion. • PVT1 might be a prognostic biomarker in breast cancer.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Up-regulated lnc-SNHG1 contributes to osteosarcoma progression through sequestration of miR-577 and activation of WNT2B/Wnt/β-catenin pathway

Highlights: • Up-regulated Lnc-SNHG1 is positively correlatedwith tumor size, TNM stage and lymph node metastasis. • Lnc-SNHG1 overexpression promoted malignantphenotype in vitro and in vivo. • MiR-577 could act as a ceRNA of lnc-SNHG1 andtarget WNT2B in OS cells. • The lnc-SNHG1/miR-577/WNT2B/Wnt/β-catenin axisregulatory network might provide a potential new therapeutic strategy for OStreatment. Long noncoding RNA small nucleolar RNA host gene 1 (lnc-SNHG1) was reported to play an oncogenic role in the progression of cancers. However, the roles of SNHG1 and its molecular mechanism in osteosarcoma (OS) cells are largely unknown. In present study, we found that the expression of SNHG1 was up-regulated in OS tissues and cell lines. OS patients with the high SNHG1 expression were positively correlated with tumor size, TNM stage and lymph node metastasis. In addition, SNHG1 overexpression promoted cell proliferation, cell migration and EMT process in U2OS and MG63 cells and tumor growth in vivo. Furthermore, we also found that miR-577 could act as a ceRNAof SNHG1 in OS cells and the promotion of OS progression induced by lnc-SNHG1 overexpression required the inactivity of miR-577. Besides, we identified that WNT2B acted as a target of miR-577, and WNT2B played the oncogenic role in OS cells by activating Wnt/β-catenin pathway. In short, our study suggested that lnc-SNHG1 could promote OS progression via miR-577 and WNT2B. The lnc-SNHG1/miR-577/WNT2B/Wnt/β-catenin axis regulatory network might provide a potential new therapeutic strategy for OS treatment.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Downregulation of Bit1 expression promotes growth, anoikis resistance, and transformation of immortalized human bronchial epithelial cells via Erk activation-dependent suppression of E-cadherin

Highlights: • Downregulation of Bit1 potentiates cell growth, anoikis resistance, and anchorage-independent potential of BEAS-2B cells. • Loss of Bit1 induced E-cadherin repression contributes to enhanced malignant phenotype of Bit1 knockdown cells. • Increased Erk activation in Bit1 knockdown cells promotes TLE1-mediated transcriptional repression of E-cadherin. The mitochondrial Bit1 protein exerts tumor-suppressive function in NSCLC through induction of anoikis and inhibition of EMT. Having this dual tumor suppressive effect, its downregulation in the established human lung adenocarcinoma A549 cell line resulted in potentiation of tumorigenicity and metastasis in vivo. However, the exact role of Bit1 in regulating malignant growth and transformation of human lung epithelial cells, which are origin of most forms of human lung cancers, has not been examined. To this end, we have downregulated the endogenous Bit1 expression in the immortalized non-tumorigenic human bronchial epithelial BEAS-2B cells. Knockdown of Bit1 enhanced the growth and anoikis insensitivity of BEAS-2B cells. In line with their acquired anoikis resistance, the Bit1 knockdown BEAS-2B cells exhibited enhanced anchorage-independent growth in vitro but failed to form tumors in vivo. The loss of Bit1-induced transformed phenotypes was in part attributable to the repression of E-cadherin expression since forced exogenous E-cadherin expression attenuated the malignant phenotypes of the Bit1 knockdown cells. Importantly, we show that the loss of Bit1 expression in BEAS-2B cells resulted in increased Erk activation, which functions upstream to promote TLE1-mediated transcriptional repression of E-cadherin. These collective findings indicate that loss of Bit1 expression contributes to the acquisition of malignant phenotype of human lung epithelial cells via Erk activation-induced suppression of E-cadherin expression.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

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↗

DOE OSTI2018

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↗

DOE OSTI2018

ELK1-induced upregulation of lncRNA HOXA10-AS promotes lung adenocarcinoma progression by increasing Wnt/β-catenin signaling

In recent years, increasing number of lncRNAs have been studied in lung adenocarcinoma (LAD). LncRNA HOXA10-AS was found to be upregulated in LAD tissues. Based on the data of TCGA database, HOXA10-AS was a prognostic factor for lung adenocarcinoma. This study aims to reveal the biological function of HOXA10-AS in LAD. qRT-PCR was applied to test expression levels of HOXA10-AS in both LAD tissues and cell lines. Next, transcription factor ELK1 was demonstrated to upregulate HOXA10-AS in LAD cells through performing bioinformatics analysis and dual luciferase activity. Loss of function assays were performed in two different LAD cell lines. Silenced HOXA10-AS was proved to inhibit LAD progression by affecting cell proliferation, cell apoptosis and cell metastasis and EMT progress. Western blot analysis revealed that HOXA10-AS increased Wnt/β-catenin signaling in LAD cell lines. Finally, rescue assays were carried out to identify the biological function of HOXA10-AS-Wnt/β-catenin signaling in LAD progression. In conclusion, ELK1-induced upregulation of HOXA10-AS improved LAD progression through increasing Wnt/β-catenin signaling.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Over-expression of lysyl oxidase is associated with poor prognosis and response to therapy of patients with lower grade gliomas

Lower grade gliomas (LGGs) have highly diverse clinical phenotypes. The histological grade and type are insufficient to accurately predict the clinical outcomes of patients with LGGs. Therefore, identification of biomarkers that can facilitate the prediction of clinical outcomes in LGGs is urgently needed. Gene expression of LOX has been identified as a biomarker for various cancers. However, the clinical significance of LOX expression in LGGs has not been investigated. In this study, we analyzed the glioma RNA-seq dataset from TCGA (The Cancer Genome atlas) and identified lysyl oxidase (LOX) as a potential biomarker for LGGs. Kaplan-Meier survival analysis revealed that high LOX expression is associated with worse overall survival and recurrence free survival in LGG patients. Besides, high LOX expression is associated with poor response to primary therapy, follow-up treatment, targeted molecular therapy, and radiation therapy. Univariate and multivariate Cox regression analyses further confirmed LOX expression as an independent prognostic factor for LGG patients. Finally, we observed that LOX expression is significantly correlated with EMT (epithelial to mesenchymal transition) and IDH1 status in LGGs. In conclusion, our analyses suggest that LOX expression is a potential biomarker for prognosis and therapeutic response in LGGs.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

PAFAH1B2 is a HIF1a target gene and promotes metastasis in pancreatic cancer

Platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B2) plays important roles in inflammation and anaphylaxis. However, its primary function in pancreatic cancer remains unclear. In the current study, we report that PAFAH1B2 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and correlated inversely with patient survival. PAFAH1B2 overexpression induced epithelial–mesenchymal transition (EMT), migration and invasion in vitro and metastasis in vivo. Conversely, silencing PAFAH1B2 inhibited these aggressive phenotypes. Moreover, PAFAH1B2 overexpression in PDAC cells was directly mediated by HIF1a. PAFAH1B2 expression in PDAC clinical specimens correlated positively with HIF1a expression. Overall, our results defined PAFAH1B2 as a target gene of HIF1a and a critical driver of PDAC metastatic behaviors.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

LSINCT5 activates Wnt/β-catenin signaling by interacting with NCYM to promote bladder cancer progression

Highlights: • LSINCT5 promotes bladder cancer. • LSINCT5 interacts with NCYM. • LSINCT5 activates Wnt/β-catenin signaling by NCYM. Accumulating evidence has indicated that long non-coding RNAs (lncRNAs) are critically involved in tumor progression. In current study, we reported a novel lncRNA signature correlated with bladder cancer development. Particularly, the lncRNA long stress-induced noncoding transcript 5 (LSINCT5) is significantly upregulated in human bladder cancer cell lines and tumor specimens. Meanwhile, high LSINCT5 expression correlates with poor prognosis, enhances tumor sphere formation and invasion in vitro. In vivo xenograft tumor growth is also elevated by LSINCT5 overexpression. Mechanistic investigations showed that LSINCT5 could physically interact with NCYM, a de novo gene product from the MYCN cis-antisense RNA and inhibit GSK3β activity leading to enhanced Wnt/β-catenin signaling activation and epithelial mesenchymal transition (EMT). Taken together, our findings have created a novel LSINCT5 mediated process which facilitates bladder cancer progression and may provide a potential target for therapeutic intervention.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

TGF-β1 induced fascin1 expression facilitates the migration and invasion of kidney carcinoma cells through ERK and JNK signaling pathways

Highlights: • In 769-P and OSRC cell lines, TGF-β1 can increase the expression of fascin1. • TGF-β1 promoted the invasive and migratory capabilities of the two cell lines via increased the expression of fascin1. • TGF-β1 induced fascin1 expression through ERK and JNK signal pathways. Transforming growth factor-β1 (TGF-β1) plays a crucial role in the signaling network that controls cellular invasion and motility capability during tumor development. To investigate whether fascin1 plays a crucial role in TGF-β1-facilitated invasion and migration of kidney cancer cells (KCC), real-time PCR and western blotting were used to test the fascin1 expression after TGF-β1 treatment (10 ng/ml) in 769-P and OSRC cells. Fascin1 was silenced using the small interfering RNA (siRNA) technique. Cytoskeleton staining was used to test the change of Cytoskeleton. Cell migration and invasion changes were measured by wound-healing and Transwell assay. The results indicate that mRNA and protein levels of fascin1 were dramatically increased after treatment with 10 ng/ml TGF-β1 in 769-P and OSRC cells. TGF-β1 promoted the occurrence of EMT (Epithelial-Mesenchymal Transition) and the invasive and migratory capabilities of the two cell lines after treatment with 10 ng/ml TGF-β1. In addition, fascin1 siRNA dramatically attenuated the invasiveness and migration induced by TGF-β1. Furthermore, we identified that specific inhibitors of ERK and JNK signaling pathways, FR180204 and SP600125, can suppress TGF-β1-induced fascin1 expression. In conclusion, these results reveal that fascin1 is an important mediator of TGF-β1-induced invasion and migration of KCC through ERK and JNK signal pathways.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Influence and mechanism of Angiotensin 1-7 on biological properties of normal prostate epithelial cells

Highlights: • Ang1-7 inhibit proliferation and EMT of prostate epithelial cells by inactivation of PI3K axis. • Ang1-7 can counteract oxidant stress in prostate by inhibition of VEGF and upregulation of NOS3. • Ang1-7 increase the mRNA level of antiapoptotic genes: BIRC5 and BCL-2 in PNT1A cells. • Ang1-7 can upregulate not only AT1-7/MAS expression but also classic angiotensin receptors. • Ang1-7 can upregulate the AR and ESR2 receptor but dowregulate ESR1 in PNT1A. The ACE2/Ang1-7/MAS axis was involved in the cell proliferation, migration and apoptosis of many types of reproductive tissues. The research was conducted on prostate epithelial cells, immortalized by Simian Virus 40. We examined the influence of Ang 1–7 on biological properties of PNT1A cells after 24- or 48-h treatment. The employed selective antagonists of angiotensin receptors allowed evaluation of the receptor mediating Ang1-7 action. Our data clearly indicate that Ang1-7 can decrease cell proliferation and epithelial-to-mesenchymal transition of PNT1A cells via inactivation of PI3K axis and modulation of expression of the NF-kB gene family. Furthermore, it counteracts oxidant stress and inflammation in prostate cells by inhibition of VEGF expression and MMPs activation as well as by modulating the level of ERα and ERβ. On the other hand, this heptapeptide can promote cell survival by alteration of expression of anti- and pro-apoptotic members as well as compensatory up-regulation of AR expression. Summary, the results confirm the existence of a complicated dependence networks between the various elements of the local RAS and steroid hormone receptor pathways in prostate gland. Furthermore, shows the chances of using ACE2/Ang1-7/MAS pathway as a novel therapeutic target in prevention and treatment of prostate diseases.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

MicroRNA-124-3p represses cell growth and cell motility by targeting EphA2 in glioma

Highlights: • miR-124-3p inhibits glioma cell proliferation. • miR-124-3p inhibits glioma cell motility. • miR-124-3p suppresses glioma cell EMT. • EphA2 is a candidate target of miR-124-3p. MiR-124-3p and EphA2 are aberrantly expressed in glioma tissue specimens. In the present study, we firstly investigated that miR-124-3p inhibits EphA2 expression mediated by binding its 3′-UTR to regulate the progression of human glioma. The U87MG and LN229 cells were transfected with miR-124-3p mimics and/or siRNA-EphA2, and then the role of miR-124-3p and EphA2 in the colony-formation, cell-cycle, migration and invasion of glioma cells in vitro were examined. Proteins involved in the epithelial-mesenchymal transition were examined using western blot. The results showed that miR-124-3p was significantly downregulated in glioma tissues, whereas a marked upregulation of EphA2 expression was found. Colony-formation and flow cytometry assays demonstrated that EphA2 downregulation or miR-124-3p mimics caused growth and cell-cycle inhibition in glioma. Transwell migration and invasion assays demonstrated that EphA2 downregulation or miR-124-3p mimics suppressed the migration and invasion of glioma cells. EphA2 downregulation or miR-124-3p mimics reduced the level of vimentin in U87MG and LN229 cells. In conclusion, miR-124-3p was found to suppress the growth, migration and invasion of glioma cells in vitro via EphA2. Furthermore, we validated miR-124-3p enforced its biological modulation via targeting EphA2 through the rescue experiment. Conclusively, our study proclaimed that miR-124-3p can counteract the malignant phenotypes of glioma cells by the inhibitory effect of the EphA2.

60 APPLIED LIFE SCIENCES↗