Tumor Cell-Derived Exosomal hsa_circ_0017252 Suppresses the Tumorigenesis of Gastric Cancer Through Suppressing M2 Polarization of Macrophage

Abstract Background: Gastric cancer (GC) is a source of global cancer death. MiR-17-5p is reported to regulate the tumorigenesis of GC. Meanwhile, hsa_circ_0017252 is known to be upregulated in GC. However, the relation between hsa_circ_0017252 and miR-17-5p in GC remains unclear. Methods: Cell viability, migration and invasion were tested by CCK-8 and transwell assay, respectively. Gene expressions were detected by RT-qPCR, and the protein levels in cells or exosomes were tested by western blot. The efficiency of exosomes isolation was investigated by transmission electron microscope (TEM) and nanoparticle tracking analysis (NTA). Meanwhile, cell apoptosis was tested by flow cytometry. In vivo model was constructed to assess the function of MKN45 cells-derived exosomal hsa_circ_0017252 in GC. Results: Hsa_circ_0017252 was verified to be significantly downregulated in GC tissues. Hsa_circ_0017252 upregulation significantly decreased the viability and migration of GC cells, and hsa_circ_0017252 could bind with miR-17-5p. Additionally, exosomal hsa_circ_0017252 reversed the polarization of M2 macrophages, and the polarized macrophages decreased the GC cell invasion. Furthermore, exosomes with upregulated hsa_circ_0017252 suppressed the tumor growth of GC. Conclusion: Delivery of hsa_circ_0017252 by GC cells-derived exosomes inhibits the tumorigenesis of GC through reversing M2 polarization of macrophages. Thus, our finding might provide a new method for GC treatment.

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RUNX2 promotes malignant progression in gastric cancer by regulating COL1A1

Cancer Biomarkers ◽

10.3233/cbm-200472 ◽

2021 ◽

pp. 1-12

Author(s):

Yanlei Li ◽

Ran Sun ◽

Xiulan Zhao ◽

Baocun Sun

Keyword(s):

Gastric Cancer ◽

Human Cancer ◽

Clinical Stage ◽

Collagen Type I ◽

Migration And Invasion ◽

Type I ◽

Aberrant Expression ◽

Invasion And Migration ◽

Protein Levels

BACKGROUND: Runt-related transcription factor 2 (RUNX2) is an important gene that has been implicated in the progression of human cancer. Aberrant expression of RUNX2 predicts gastric cancer (GC) metastasis. However, the molecular mechanism of RUNX2 remains unknown. OBJECTIVE: We hypothesize that RUNX2 promotes GC metastasis by regulating the extracellular matrix component collagen type I alpha 1 (COL1A1). METHODS: The GEPIA database and immunohistochemical staining of 60 GC tissues were used to analyse the correlations between RUNX2 or COL1A1 expression and clinicopathological features, and the Kaplan-Meier method was used to evaluate survival. RT-PCR, western blotting and immunofluorescence were used to detect RUNX2 and COL1A1 expression in GC cells. Migration and invasion assays were performed to assess the influence of RUNX2 and COL1A1 on metastasis. RESULTS: RUNX2 and COL1A1 were highly expressed at both the gene and protein levels in GC, and patients who were positive for RUNX2 and COL1A1 had shorter survival. RUNX2 and COL1A1 expression linearly correlated with each other (r= 0.15, p< 0.01) and with clinical stage and lymph node metastasis (p< 0.05). Overexpressing RUNX2in vitro enhanced COL1A1 expression and promoted GC cell invasion and migration, whereas COL1A1 knockdown inhibited the increase in cell metastatic capacity promoted by RUNX2. In vivo, GC cells overexpressing RUNX2 promoted lung metastasis, and the downregulation of COL1A1 reduced the metastasis promoted by RUNX2. CONCLUSIONS: RUNX2 may promote GC metastasis by regulating COL1A1. RUNX2/COL1A1 can be employed as a novel target for therapy in GC.

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Downregulation of KIF21B by miR-132-3p suppresses cellular functions in gastric cancer via regulating Wnt/β-catenin signaling pathway

10.21203/rs.3.rs-850811/v1 ◽

2021 ◽

Author(s):

Bingtian Liu ◽

Ling Qiang ◽

Bingxin Guan ◽

Zhipeng Ji

Keyword(s):

Gastric Cancer ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Small Cell Lung ◽

Cellular Functions ◽

Transwell Assay ◽

Microarray Gene Expression ◽

Protein Levels ◽

Normal Tissues ◽

Kinesin Family

Abstract Recently, kinesin family member 21B (KIF21B) has been reported to be an oncogene in non-small cell lung cancer and hepatocellular carcinoma. However, the functional role and related mechanisms underlying gastric cancer (GC) pathogenesis remain largely uncovered. Here, we first found that the expression of KIF21B was upregulated in GC tissues compared with adjunct normal tissues by analysis of Oncomine microarray gene expression datasets and clinical specimens. Knockdown of KIF21B significantly suppressed the proliferation, migration and invasion in GC cell lines using CCK-8 assay and transwell assay. By luciferase reporter assay, KIF21B was confirmed as the target of miR-132-3p in GC cells and suppressed after miR-132-3p overexpression. Moreover, miR-132-3p was down-regulated and inversely correlated with KIF21B expression in GC tissues. Further functional experiments demonstrated that overexpression of KIF21B remarkedly reversed the suppressive effects of miR-132-3p overexpression on GC cell proliferation, migration and invasion. Furthermore, western blot analysis manifested that miR-132-3p overexpression downregulated the protein levels of Wnt1, c-Myc, β-catenin, PCNA and N-cadherin, and upregulated E-cadherin expression in GC cells, which were all alleviated after KIF21B overexpression. In summary, our findings provide the first evidence that down-regulation of KIF21B by miR-132-3p suppresses cellular functions in gastric cancer via regulating Wnt/β-catenin signaling.

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The Interaction Between Long Non-Coding RNA LINC01564 and POU2F1 Promotes the Proliferation and Metastasis of Gastric Cancer

10.21203/rs.3.rs-914479/v1 ◽

2021 ◽

Author(s):

Jixu Wang ◽

Futao Hou ◽

Lusheng Tang ◽

Ke Xiao ◽

Tengfei Yang ◽

...

Keyword(s):

Gastric Cancer ◽

Transcription Factor ◽

Tumor Development ◽

Transcription Activation ◽

Migration And Invasion ◽

Invasion And Migration ◽

Proliferation And Metastasis ◽

And Migration

Abstract Background: An increasing number of studies have demonstrated that long non-coding RNAs (lncRNAs) serve as key regulators in tumor development and progression. However, only a few lncRNAs have been functionally characterized in gastric cancer (GC). Methods: Bioinformatics analysis was conducted to find lncRNAs that are associated with GC metastasis. RNA FISH, RIP, and RNA pull down assays were used to study the complementary binding of LINC01564 complementary to the 3’UTR of transcription factor POU2F1. The transcription activation of LINC01564 by POU2F1 as a transcription factor was examined by ChIP assay. In vitro assays such as MTT, cell invasion assay, and clonogenic assay were conducted to examined the impacts of LINC01564 and POU2F1 on GC cell proliferation and invasion. Experiments in vivo were performed to access the impacts of LINC01564 and POU2F1 on GC metastasis. Results: The results showed that LINC01564 complementary bound to the 3’UTR of POU2F1 to form an RNA duplex, whereby stabilizing POU2F1 mRNA and increasing the enrichment in cells. The level of LINC01564 was also increased by POU2F1 through transcription activation. In vitro assays showed that LINC01564 promoted the proliferation, invasion and migration of GC cells through increasing POU2F1. In vivo experiments indicate the promotion of GC proliferation and metastasis by the interaction between LINC01564 and POU2F1. Conclusion: Taken together, our results indicate that the interaction between LINC01564 and POU2F1 promotes the proliferation, migration and invasion of GC cells.

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MiR-132-3p suppresses cell proliferation and migration in gastric cancer by targeting KIF21B/Wnt/β-catenin signaling pathway

10.21203/rs.3.rs-956317/v1 ◽

2021 ◽

Author(s):

Bingtian Liu ◽

Ling Qiang ◽

Bingxin Guan ◽

Zhipeng Ji

Keyword(s):

Gastric Cancer ◽

Cell Proliferation ◽

Functional Role ◽

Molecular Mechanisms ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Microarray Gene Expression ◽

Protein Levels ◽

Normal Tissues ◽

And Migration

Abstract Background: Recently, kinesin family member 21B (KIF21B) has been reported to be an oncogene in non-small cell lung cancer and hepatocellular carcinoma. However, the functional role and related molecular mechanisms underlying gastric cancer (GC) pathogenesis remain largely uncovered. Methods: The expression of KIF21B was investigated by analysis of Oncomine microarray gene expression datasets and clinical specimens. The association between KIF21B and miR-132-3p was assessed by luciferase reporter assay. CCK-8 assay and transwell assay were performed to analyze the functional role of miR-132-3p/KIF21B in GC cells. Related protein expression levels were evaluated by immunohistochemistry and western blot analysis.Results: We first found that the expression of KIF21B was upregulated in GC tissues compared with adjunct normal tissues. Knockdown of KIF21B significantly suppressed the proliferation, migration and invasion in GC cell lines (AGS and SNU-5). KIF21B was confirmed as the target of miR-132-3p in GC cells. Moreover, miR-132-3p was down-regulated and inversely correlated with KIF21B expression in GC tissues. Further functional experiments demonstrated that overexpression of KIF21B remarkedly reversed the suppressive effects of miR-132-3p overexpression on GC cell proliferation, migration and invasion. Furthermore, miR-132-3p overexpression downregulated the protein levels of Wnt1, c-Myc, β-catenin, PCNA and N-cadherin, and upregulated E-cadherin expression in GC cells, which were all alleviated after KIF21B overexpression. Conclusions: In summary, our findings provide the first evidence that down-regulation of KIF21B by miR-132-3p suppresses cellular functions in GC via regulating Wnt/β-catenin signaling.

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CircGSK3B promotes RORA expression and suppresses gastric cancer progression through the prevention of EZH2 trans-inhibition

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02136-w ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Xianxiong Ma ◽

Hengyu Chen ◽

Lei Li ◽

Feng Yang ◽

Chuanqing Wu ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Gene Expression Regulation ◽

Migration And Invasion ◽

Circular Rnas ◽

Loss Of Function ◽

Invasion And Migration ◽

And Migration

Abstract Background Circular RNAs (circRNAs) are a class of non-coding RNA that play critical roles in the development and pathogenesis of various cancers. The circRNA circGSK3B (hsa_circ_0003763) has been shown to enhance cell proliferation, migration, and invasion in hepatocellular carcinoma. However, the specific functions and underlying mechanistic involvement of circGSK3B in gastric cancer (GC) have not yet been explored. Our study aimed to investigate the effect of circGSK3B on the progression of GC and to identify any potential mechanisms underlying this process. Methods CircRNA datasets associated with GC were obtained from the PubMed, GEO, and ArrayExpress databases, and circRNAs were validated via RT-qPCR and Sanger sequencing. Biotin-labeled RNA pull-down, mass spectrometry, RNA immunoprecipitation, and in vitro binding assays were employed to determine proteins demonstrating interactions with circGSK3B. Gene expression regulation was assessed through RT-qPCR, chromatin immunoprecipitation, and western blot assays. Gain- and loss-of-function assays were used to analyze any effects of circGSK3B and its partner regulatory molecule (EZH2) on the proliferation, invasion, and migration abilities of GC cells both in vitro and in vivo. Results CircGSK3B was mainly identified in the nucleus. This circRNA was present at a reduced concentration in GC tissues and cell lines. Overexpression of circGSK3B was shown to inhibit the growth, invasion, and metastasis of GC cells both in vitro and in vivo. Mechanistically, circGSK3B directly interacted with EZH2, acting to suppress the binding of EZH2 and H3K27me3 to the RORA promoter, and leading to an elevation in RORA expression and ultimately the suppression of GC progression. Conclusions CircGSK3B acts as a tumor suppressor, reducing EZH2 trans-inhibition and GC progression. This demonstrates the potential use of this RNA as a therapeutic target for GC.

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TEAD4 modulated LncRNA MNX1-AS1 contributes to gastric cancer progression partly through suppressing BTG2 and activating BCL2

Molecular Cancer ◽

10.1186/s12943-019-1104-1 ◽

2020 ◽

Vol 19 (1) ◽

Cited By ~ 12

Author(s):

You Shuai ◽

Zhonghua Ma ◽

Weitao Liu ◽

Tao Yu ◽

Changsheng Yan ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Mechanistic Model ◽

Ectopic Expression ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Tissue Samples ◽

Reporter Assays

Abstract Background Gastric cancer (GC) is the third leading cause of cancer-related mortality globally. Long noncoding RNAs (lncRNAs) are dysregulated in obvious malignancies including GC and exploring the regulatory mechanisms underlying their expression is an attractive research area. However, these molecular mechanisms require further clarification, especially upstream mechanisms. Methods LncRNA MNX1-AS1 expression in GC tissue samples was investigated via microarray analysis and further determined in a cohort of GC tissues via quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. Cell proliferation and flow cytometry assays were performed to confirm the roles of MNX1-AS1 in GC proliferation, cell cycle regulation, and apoptosis. The influence of MNX1-AS1 on GC cell migration and invasion was explored with Transwell assays. A xenograft tumour model was established to verify the effects of MNX1-AS1 on in vivo tumourigenesis. The TEAD4-involved upstream regulatory mechanism of MNX1-AS1 was explored through ChIP and luciferase reporter assays. The mechanistic model of MNX1-AS1 in regulating gene expression was further detected by subcellular fractionation, FISH, RIP, ChIP and luciferase reporter assays. Results It was found that MNX1-AS1 displayed obvious upregulation in GC tissue samples and cell lines, and ectopic expression of MNX1-AS1 predicted poor clinical outcomes for patients with GC. Overexpressed MNX1-AS1 expression promoted proliferation, migration and invasion of GC cells markedly, whereas decreased MNX1-AS1 expression elicited the opposite effects. Consistent with the in vitro results, MNX1-AS1 depletion effectively inhibited the growth of xenograft tumour in vivo. Mechanistically, TEAD4 directly bound the promoter region of MNX1-AS1 and stimulated the transcription of MNX1-AS1. Furthermore, MNX1-AS1 can sponge miR-6785-5p to upregulate the expression of BCL2 in GC cells. Meanwhile, MNX1-AS1 suppressed the transcription of BTG2 by recruiting polycomb repressive complex 2 to BTG2 promoter regions. Conclusions Our findings demonstrate that MNX1-AS1 may be able to serve as a prognostic indicator in GC patients and that TEAD4-activatd MNX1-AS1 can promote GC progression through EZH2/BTG2 and miR-6785-5p/BCL2 axes, implicating it as a novel and potent target for the treatment of GC.

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Hispidulin inhibits proliferation, migration, and invasion by promoting autophagy via regulation of PPARγ activation in prostate cancer cells and xenograft models

Bioscience Biotechnology and Biochemistry ◽

10.1093/bbb/zbaa108 ◽

2020 ◽

Author(s):

Yuanyuan Wang ◽

Shanqi Guo ◽

Yingjie Jia ◽

Xiaoyu Yu ◽

Ruiyu Mou ◽

...

Keyword(s):

Prostate Cancer ◽

Flavonoid Compound ◽

Migration And Invasion ◽

Prostate Cancer Cells ◽

Invasion And Migration ◽

Beneficial Effects ◽

Anticancer Properties ◽

Xenograft Models ◽

And Migration

ABSTRACT Prostate cancer (PCa) is one of the important factors of cancer deaths especially in the western countries. Hispidulin (4′,5,7-trihydroxy-6-methoxyflavone) is a phenolic flavonoid compound proved to possess anticancer properties, but its effects on PCa are left to be released. The aims of this study were to investigate the effects and the relative mechanisms of Hispidulin on PCa development. Hispidulin administration inhibited proliferation, invasion, and migration, while accelerated apoptosis in Du145 and VCaP cells, which was accompanied by PPARγ activation and autophagy enhancement. The beneficial effects of Hispidulin could be diminished by PPARγ inhibition. Besides, Hispidulin administration suppressed PCa tumorigenicity in Xenograft models, indicating the anticancer properties in vivo. Therefore, our work revealed that the anticancer properties of Hispidulin might be conferred by its activation on PPARγ and autophagy.

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Loss of PR55α promotes proliferation and metastasis by activating MAPK/AKT signaling in hepatocellular carcinoma

Cancer Cell International ◽

10.1186/s12935-021-01796-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

JiangSheng Zhao ◽

GuoFeng Chen ◽

Jingqi Li ◽

Shiqi Liu ◽

Quan Jin ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Cycle Progression ◽

Lung Metastases ◽

Cell Counting ◽

Migration And Invasion ◽

Signal Pathways ◽

And Migration ◽

Healthy Liver

Abstract Background PR55α plays important roles in oncogenesis and progression of numerous malignancies. However, its role in hepatocellular carcinoma (HCC) is unclear. This study aims to characterize the functions of PR55α in HCC. Methods PR55α expressions in HCC tissues and paired healthy liver samples were evaluated using Western blot and tissue microarray immunohistochemistry. We knocked down the expression of PR55α in SMMC-7721 and LM3 cell lines via small interfering and lentivirus. In vitro cell counting, colony formation, migration and invasion assays were performed along with in vivo xenograft implantation and lung metastases experiments. The potential mechanisms involving target signal pathways were investigated by RNA-sequencing. Results PR55α expression level was suppressed in HCC tissues in comparison to healthy liver samples. Decreased PR55α levels were correlated with poorer prognosis (P = 0.0059). Knockdown of PR55α significantly promoted cell proliferation and migration, induced repression of the cell cycle progression and apoptosis in vitro while accelerating in vivo HCC growth and metastasis. Mechanistic analysis indicated that PR55α silencing was involved with MAPK/AKT signal pathway activation and resulted in increased phosphorylation of both AKT and ERK1/2. Conclusions This study identifies PR55α to be a candidate novel therapeutic target in the treatment of HCC.

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Visfatin facilitates gastric cancer malignancy by targeting snai1 via the NF-κB signaling

Human & Experimental Toxicology ◽

10.1177/09603271211006168 ◽

2021 ◽

pp. 096032712110061

Author(s):

D Cao ◽

L Chu ◽

Z Xu ◽

J Gong ◽

R Deng ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Migration ◽

Western Blot ◽

Blot Analysis ◽

Western Blot Analysis ◽

Epithelial Mesenchymal Transition ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Cell Migration And Invasion ◽

Protein Levels

Background: Visfatin acts as an oncogenic factor in numerous tumors through a variety of cellular processes. Visfatin has been revealed to promote cell migration and invasion in gastric cancer (GC). Snai1 is a well-known regulator of EMT process in cancers. However, the relationship between visfatin and snai1 in GC remains unclear. The current study aimed to explore the role of visfatin in GC. Methods: The RT-qPCR and western blot analysis were used to measure RNA and protein levels, respectively. The cell migration and invasion were tested by Trans-well assays and western blot analysis. Results: Visfatin showed upregulation in GC cells. Additionally, Visfatin with increasing concentration facilitated epithelial-mesenchymal transition (EMT) process by increasing E-cadherin and reducing N-cadherin and Vimentin protein levels in GC cells. Moreover, endogenous overexpression and knockdown of visfatin promoted and inhibited migratory and invasive abilities of GC cells, respectively. Then, we found that snai1 protein level was positively regulated by visfatin in GC cells. In addition, visfatin activated the NF-κB signaling to modulate snai1 protein expression. Furthermore, the silencing of snai1 counteracted the promotive impact of visfatin on cell migration, invasion and EMT process in GC. Conclusion: Visfatin facilitates cell migration, invasion and EMT process by targeting snai1 via the NF-κB signaling, which provides a potential insight for the treatment of GC.

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A novel design of HA-coated nanoparticles co-encapsulating plasmid METase and 5-Fu shows enhanced application in targeting gastric cancer stem cells

Biological Chemistry ◽

10.1515/hsz-2017-0208 ◽

2018 ◽

Vol 399 (3) ◽

pp. 293-303 ◽

Cited By ~ 3

Author(s):

Weifeng Yang ◽

Houting Zhang ◽

Lin Xin

Keyword(s):

Gastric Cancer ◽

Tumor Growth ◽

Precipitation Method ◽

Inhibition Effect ◽

Coated Nanoparticles ◽

Transmission Electron ◽

Targeted Drug ◽

Gastric Cancer Stem Cells ◽

Novel Design

AbstractNanoparticles (NPs) are recognized as an attractive vehicles for cancer treatment due to their targeted drug release. Gastric cancer is an important killer disease, and its therapy methods still need improvement. The NPs were prepared using a precipitation method, and were evaluated using transmission electron microscopy (TEM). MTT and Transwell assays were used to determine cell viability and apoptosis.In vivoexperiments were performed to validate the effects of NPs on tumor growth. Methioninase (METase)/5-Fu co-encaspulated NPs showed highest ζ size and lowest ζ potential than other NPs. The migration and tumorsphere formation ability of CD44(+) was stronger than CD44(−). The effects of METase/5-Fu co-encaspulated NPs on inhibition cell growth was stronger than that of 5-Fu encaspulated NPs, while HA coated NPs showed significant target ability than that NPs without HA. METase supplementation promoted the inhibition effect of 5-Fu on thymidylate synthetase (TS), as well as cell apoptosis. Thein vivoexperiments demonstrated that HA coated NPs significantly inhibited tumor growth. It was concluded that HA-coated NPs enhance the target ability, while METase/5-Fu co-encaspulated NPs promote the inhibition effects on tumor growth in gastric cancer.

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