scholarly journals E2F2 Inhibition Induces Autophagy to Impair Metastasis via the PI3K/Akt/mTOR Pathway in Gastric Cancer

2021 ◽  
Author(s):  
Hui Li ◽  
Shufen Zhao ◽  
Liwei Shen ◽  
Peige Wang ◽  
Shihai Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Western Blotting ◽  
Cox Regression ◽  
Quantitative Polymerase Chain Reaction ◽  
Mammalian Target Of Rapamycin ◽  
Migration And Invasion ◽  
Poor Overall Survival ◽  
Highly Correlated ◽  
Public Datasets

Abstract BackgroundE2F2 is a member of the E2F transcription factor family and has important but not fully understood biological functions in cancers. The pro- and antitumor functions of E2F2 in some cancer types are controversial. However, the biological role of E2F2 in gastric cancer (GC) remains unclear.MethodsE2F2 expression from multiple gene expression databases was analyzed. Kaplan-Meier plots and Cox regression were used to analyze the prognostic value of E2F2 expression. The correlation between E2F2 and tumor immune infiltration was investigated using the Tumor Immune Estimation Resource (TIMER) database. The functions and pathways of E2F2 and its 50 most highly correlated genes in terms of expression pattern were analyzed using Database Annotation, Visualization, and Integrated Discovery (DAVID) software. We used immunohistochemistry, real-time quantitative polymerase chain reaction, and western blotting to detect the expression level of E2F2 in GC. We further investigated the effects of E2F2 on phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling, autophagy, and the migration and invasion of GC cells by the wound healing assay, Transwell assay, western blotting, and transmission electron microscopy.ResultsE2F2 was highly expressed in both GC tissues and cells compared with normal gastric tissues/cells in public datasets and our validation experiments. High E2F2 expression was associated with poor overall survival (OS). In addition, the expression of E2F2 in GC had a strong correlation with a variety of immune markers. E2F2 overexpression promoted the migration and invasion of GC cells in vitro through the inhibition of PI3K/Akt/mTOR-mediated autophagy. In contrast, inhibition of E2F2 inhibited the migration and invasion of GC cells in vitro by activating PI3K/Akt/mTOR-mediated autophagy.ConclusionThis study provides multilevel evidence for the significance of E2F2 in the pathogenesis of GC and its potential as a biomarker for GC. E2F2 was highly expressed in GC, and high E2F2 expression was associated with the characteristics of invasive tumors and poor prognosis. E2F2 had potential modulatory effects on tumor immunity. We found a novel function of E2F2 in the regulation of PI3K/Akt/mTOR-mediated autophagy and the downstream process of cell migration and invasion. Our results may provide novel targets and strategies for the diagnosis and treatment of GC.

scholarly journals E2F2 inhibition induces autophagy to impair metastasis via the PI3K/Akt/mTOR pathway in gastric cancer

2020 ◽  
Author(s):  
Hui Li ◽  
Shufen Zhao ◽  
Liwei Shen ◽  
Peige Wang ◽  
Shihai Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Migration ◽  
Cox Regression ◽  
Migration And Invasion ◽  
Cell Migration And Invasion ◽  
Kaplan Meier ◽  
Patient Prognosis ◽  
Public Datasets

Abstract Background: E2F2 is a member of the E2F family of transcription factors with important yet incompletely understood biological functions in cancer. In some cancer types, controversial tumor-promoting and tumor-suppressive roles of E2F2 have been reported. However, the biological role of E2F2 in gastric cancer (GC) remains to be determined. Methods: We analyzed E2F2 expression via multiple gene expression databases. The prognostic value of the E2F2 was determined by Kaplan-Meier Plotter and Cox regression. The correlations between E2F2 and cancer immune infiltrates were investigated via Tumor Immune Estimation Resource (TIMER). The functions and pathways of E2F2 and its 50 frequently changed genes closely associated with the family members were analyzed using Database for Annotation, Visualization, and Integrated Discovery (DAVID) software. We used immunohistochemistry (IHC), quantitative real-time PCR (qPCR) and western blot to verify the expression level of E2F2 in GC and further studied the effects of E2F2 on PI3K/Akt/mTOR activity; GC cell autophagy, migration, and invasion through wound healing assays, transwell assays, Western blotting, and transmission electron microscopy.Results: We observed that compared with normal gastric tissues/cells, E2F2 is highly expressed in gastric cancer tissues and cells in both the public datasets and in our experimental verification. High E2F2 expression was associated with poorer overall survival (OS). Moreover, E2F2 expression showed strong correlations with diverse immune marker sets in GC. Moreover, E2F2 overexpression promoted GC cell migration and invasion in vitro by inactivating PI3K/Akt/mTOR-mediated autophagy. Conversely, E2F2 inhibition suppressed GC cell migration and invasion in vitro by activating PI3K/Akt/mTOR-mediated autophagy.Conclusions: In conclusion, this study provides multi-level evidence for the importance of E2F2 in gastric carcinogenesis and its potential as a biomarker in GC. We demonstrated that E2F2 is overexpressed in GC and that high E2F2 expression is associated with aggressive tumor features and poorer patient prognosis. Further, our results suggest a potential novel immune regulatory role of E2F2 in tumor immunity. Functionally, we discovered a new role of E2F2 in regulating PI3K/Akt/mTOR-mediated autophagy and the downstream processes of cell migration and invasion. Our results could potentially reveal new targets and strategies for GC diagnosis and treatment.

scholarly journals Exosomal miR-590-5p in Serum as a Biomarker for the Diagnosis and Prognosis of Gastric Cancer

2021 ◽  
Vol 8 ◽  
Author(s):  
Guo-Dian Zheng ◽  
Zhi-Yuan Xu ◽  
Can Hu ◽  
Hang Lv ◽  
Hua-Xia Xie ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cox Regression ◽  
Quantitative Polymerase Chain Reaction ◽  
Characteristic Curve ◽  
Clinical Stage ◽  
Expression Level ◽  
Migration And Invasion ◽  
Serum Samples ◽  
Ki 67 ◽  
Cox Regression Analysis

The purpose of this study is to explore the expression of miRNA-590-5p, an exosome of gastric cancer (GC), and to evaluate the suitability of miR-590-5p, an exosome with its own clinical characteristics. Serum samples from 168 gastric cancer patients and 50 matched controls were collected and exosomal RNAs were extracted. After that, miR-590-5p is analyzed by quantitative polymerase chain reaction (qRT-PCR), which is more related to clinical and pathological parameters and patient monitoring data. MGC-803 and HGC-27 cells were treated by miR-590-5p mimics, and then the changes of cell fluidity and invasiveness were monitored. The results showed that the expression level of miR-590-5p in exosomes of healthy observation group, early (I and II) stage group, and late stage (III) group was 30.34 ± 6.35, 6.19 ± 0.81, and 2.9 ± 0.19, respectively (all p < 0.05). ROC (receiver-operating characteristic curve) showed that the AUC (area under the curve) of exosomal miR-590-5p was 0.810 with 63.7% sensitivity and 86% specificity. The expression of exosomal miR-590-5p in serum was related to clinical stage (p = 0.008), infiltration depth, and the expression level of ki-67 (p < 0.001). In addition, Kaplan-Meier analysis showed that the decrease of explicit level of exosomal miR-590-5p was related to the decrease of overall survival rate (p < 0.001). Cox regression analysis showed that miR-590-5p can be used as an independent predictor. Furthermore, upregulation of miR-590-5p inhibited cell migration and invasion in MGC-803 cells and HGC-27 cells. The serum expression level of exosomal miR-590-5p may be a biomarker, which is potentially useful and noninvasive for early detection and prediction of GC. In addition, miR-590-5p can play a role in eliminating carcinogens by actively regulating the malignant potential of gastric cancer.

scholarly journals The Novel Role of LINC01235 in Metastasis of Gastric Cancer Cells by Inducing Epithelial-mesenchymal Transition

2020 ◽  
Author(s):  
Cheng Zhang ◽  
Yu Liang ◽  
Chun-Dong Zhang ◽  
Dong-Qiu Dai
Keyword(s):  
Gastric Cancer ◽  
Cox Regression ◽  
Migration And Invasion ◽  
Rna Seq ◽  
Pcr Assay ◽  
Cox Regression Analysis ◽  
Qrt Pcr ◽  
Overall Survival Analysis

Abstract BackgroundLncRNAs play a vital role in the tumorigenesis of gastric cancer (GC). The present study aims to explore the role of LINC01235 in clinical significance, prognostic prediction and GC metastasis.MethodsWe identified differentially expressed lncRNAs using stomach adenocarcinoma RNA-Seq data from The Cancer Genome Atlas (TCGA). The expression of LINC01235 in GC cell lines and tissues were confirmed by qRT-PCR assay. The overall survival analysis and univariate/ multivariate Cox regression analysis were performed to explore the prognostic value of LINC01235. In vitro assays were utilized to assess the effect of LINC01235 in cell migration and invasion. Western blotting measured the expression of EMT-induced proteins.ResultsThis study determined that LINC01235 expression has a higher fold changes by analyzing TCGA RNA-Seq data. qRT-PCR assay confirmed that LINC01235 is significantly over-expressed in GC cells and tissues. Additionally, the overall survival analysis showed that patients with a higher LINC01235 expression had a poorer prognosis than those with a lower LINC01235 expression. Univariate Cox regression analysis indicated that high LINC01235 expression is positively correlated with poor prognosis. Moreover, LINC01235 was an independent poor prognostic marker for GC in multivariate Cox analysis. In vitro assays suggested that LINC01235 knockdown suppresses GC cell migration and invasion. GSEA revealed that high LINC01235 expression is strongly enriched in EMT pathway. Western blotting results revealed that LINC01235 silencing decreases the expression of EMT-induced proteins.ConclusionLINC01235 could promote GC cell metastasis via EMT and function as a prognostic biomarker.

scholarly journals SMG9 Serves as an Oncogene to Promote the Tumor Progression via EMT and Wnt/β-Catenin Signaling Pathway in Hepatocellular Carcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Xing Jin ◽  
Jie Yin ◽  
Hongling Zhu ◽  
Weikang Li ◽  
Kewei Yu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Proportional Hazards ◽  
Cox Regression ◽  
Quantitative Polymerase Chain Reaction ◽  
Mrna Level ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion ◽  
Apoptosis Resistance

Background/Aims: SMG9 participates in the nonsense-mediated mRNA decay process that degrades mRNA harboring nonsense mutations introduced either at the level of transcription or RNA processing. However, little is known about the role of SMG9 in hepatocellular carcinoma (HCC). The objective of this research was to clarify the effects of SMG9 expression on HCC progression.Methods: Microarray data were acquired from NCBI Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database to bioinformatically analyze the differential expression of SMG9 between HCC patients and normal controls. SMG9 mRNA level was measured in sixteen sets of fresh tumor tissues and adjacent non-cancerous liver tissues (ANLTs) via reverse transcription-quantitative polymerase chain reaction (RT-qPCR). SMG9 protein expression was analyzed in ninety-five sets of paired formalin-fixed and paraffin-embedded tissue specimens by immunohistochemistry (IHC). In addition, clinicopathological features of SMG9 in HCC were checked. For in vitro studies, small interfering RNA (siRNA) was used to silence SMG9 expression for exploring biological functions and underlying mechanisms of SMG9 in SMMC-7721 and HepG2.Results: We found that SMG9 was upregulated in HCC tissues and SMG9 levels were closely related to TNM stage, tumor number and tumor size. Cox regression and Kaplan–Meier proportional hazards analyses showed that high expression of SMG9 was associated with poor patient survival. Furthermore, proliferation, apoptosis resistance, migration and invasion of both SMMC-7721 and HepG2 cells were suppressed by SMG9 inhibition. In addition, EMT and the Wnt/β-catenin signaling pathway were involved in SMG9-mediated HCC progression.Conclusions: SMG9 may serve as a potential novel prognostic biomarker and therapeutic target in HCC patients.

scholarly journals A novel mechanism for C1GALT1 in the regulation of gastric cancer progression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xiaoxia Dong ◽  
Chunli Chen ◽  
Xinzhou Deng ◽  
Yongyu Liu ◽  
Qiwen Duan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Progression ◽  
Critical Role ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Poor Overall Survival ◽  
Downstream Target ◽  
Integrin Α5

Abstract Background Gastric cancer (GC) is a highly aggressive and lethal disease around the world. High expression of core 1 β 1, 3-galactosyltransferase 1 (C1GALT1), the primary enzyme responsible for protein O-glycosylation, plays a critical role in gastric carcinogenesis. However, proteins that can be O-glycosylated by C1GALT1 in GC have not been completely elucidated. Also, the mechanism leading to its upregulation in GC is currently unknown. Results Using public databases and our patient samples, we confirmed that C1GALT1 expression was upregulated at both the mRNA and protein levels in GC tissues. Elevated expression of C1GALT1 protein was closely associated with advanced TNM stage, lymph node metastasis, tumor recurrence, and poor overall survival. With gain- and loss-of-function approaches, we demonstrated that C1GALT1 promoted GC cell proliferation, migration, and invasion. By employing lectin pull-down assay and mass spectrometry, integrin α5 was identified as a new downstream target of C1GALT1 in GC. C1GALT1 was able to modify O-linked glycosylation on integrin α5 and thereby modulate the activation of the PI3K/AKT pathway. Functional experiments indicated that integrin α5 inhibition could reverse C1GALT1-mediated tumor growth and metastasis both in vitro and in vivo. Moreover, transcription factor SP1 was found to bind to the C1GALT1 promoter region and activated its expression. Further investigation proved that miR-152 negatively regulated C1GALT1 expression by directly binding to its 3′ -UTR. Conclusions Our findings uncover a novel mechanism for C1GALT1 in the regulation of GC progression. Thus, C1GALT1 may serve as a promising target for the diagnosis and treatment of GC.

scholarly journals MicroRNA-937 is overexpressed and predicts poor prognosis in patients with colon cancer

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Huiya Liu ◽  
Lin Ma ◽  
Ling Wang ◽  
Yizuo Yang
Keyword(s):  
Colon Cancer ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Cox Regression ◽  
Quantitative Polymerase Chain Reaction ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Prognostic Impact ◽  
Cancer Tissues

Abstract Background Colon cancer is a heterogeneous tumor and a leading cause of cancer-related mortality. MicroRNA (miRNA) has been proposed as the biomarker in cancers. The aim of this study was to investigate the clinical significance and potential functional role of miR-937 in colon cancer. Methods In the present study, reverse transcription-quantitative polymerase chain reaction (qRT-PCR) was conducted to examine the expression levels of miR-937 in colon cancer tissues and cell lines. Kaplan-Meier curve and Cox regression analyses were used to determine the prognostic impact of miR-937 on survival. Cell Counting Kit-8 and Transwell assays were performed to examine cell proliferation, migration, and invasion, respectively. Results miR-937 was significantly upregulated in colon cancer tissues and cell lines. Clinical analysis results showed that miR-937 expression was associated with lymph node metastasis and TNM stage. Patients with high miR-937 expression predicted a shorter overall survival rate. Functionally, overexpression of miR-937 promoted cell proliferation, migration, and invasion, while inhibition of miR-937 inhibited these cellular behaviors in vitro. Conclusions These results suggested that miR-937 may act as a prognostic biomarker and a potential target for therapeutic strategy, as well as promote proliferation, migration, and invasion of colon cancer.

scholarly journals lncRNA LUCAT1 acts as a potential biomarker and demonstrates malignant biological behaviors in gastric cancerlncRNA LUCAT1 acts as a potential biomarker and demonstrates malignant biological behaviors in gastric cancer

2020 ◽  
Author(s):  
YangYang Teng ◽  
HeJie Yu ◽  
LeYi Ni ◽  
GuangRong Lu ◽  
YueSheng Zhu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Expression Profiles ◽  
Quantitative Polymerase Chain Reaction ◽  
Phase Cell ◽  
Migration And Invasion ◽  
Tumor Diameter ◽  
Potential Biomarker ◽  
Lymphnode Metastasis

Abstract Gastric cancer(GC) remains the fourth-leading malignancy worldwide and has a high mortality rate.Accumulating evidence reveals that long noncoding RNAs (lncRNAs) play essential roles in tumorigenesis and metastasis and can be used as potential biomarkers for diagnosis and prognosis. The current study sought to define the lncRNA LUCAT1 and verify its malignant biological behaviors in GC. We conducted bioinformatic analysis to screen differentially expressed lncRNAs between GC tissue and paracancerous tissue. Gene expression profiles were downloaded from the National Center of Biotechnology Information Gene Expression Omnibus(GEO). Real-time quantitative polymerase chain reaction (RT-qPCR) was carried out to verify LUCAT1 expression in both GC tissue and paracancerous tissue. Furthermore, the associations between LUCAT1 and clinical features were analyzed. In addition, the malignant behaviors of LUCAT1 in GC were investigated by knocking down LUCAT1 expression in the SGC7901 and AGS cell lines. The results indicated that LUCAT1 expression was obviously upregulated in GC samples compared with paracancerous tissue samples. Moreover, the expression pattern of LUCAT1 showed close correlations with tumor diameter (P<0.001), differentiation grade (P=0.026), and lymphnode metastasis(LNM)status (P=0. 020). In vitro, shRNA-mediated knockdown of LUCAT1 expression inhibited proliferation, migration, and invasion and led to S-phase cell cycle arrest and apoptosisin GC cells. Thus, the lncRNA LUCAT1 may be used as a potential biomarker for early signs of LNM in GC and may play a crucial role in the development of GC.

OSI-027 alleviates oxaliplatin chemoresistance in gastric cancer cells by suppressing P-gp induction

2020 ◽  
Vol 20 ◽  
Author(s):  
En Xu ◽  
Hao Zhu ◽  
Feng Wang ◽  
Ji Miao ◽  
Shangce Du ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Mammalian Target Of Rapamycin ◽  
Cell Counting ◽  
Gastric Cancer Cells ◽  
Ags Cells ◽  
Dual Inhibitor ◽  
Induced Apoptosis

: Gastric cancer is one of the most common malignancies worldwide and the third leading cause of cancer-related death. In the present study, we investigated the potential activity of OSI-027, a potent and selective mammalian target of rapamycin complex 1/2 (mTOR1/2) dual inhibitor, alone or in combination with oxaliplatin against gastric cancer cells in vitro. Cell counting kit-8 assays and EdU staining were performed to examine the proliferation of cancer cells. Cell cycle and apoptosis were detected by flow cytometry. Western blot was used to detect the elements of the mTOR pathway and Pgp in gastric cancer cell lines. OSI-027 inhibited the proliferation of MKN-45 and AGS cells by arresting the cell cycle in the G0/G1 phase. At the molecular level, OSI-027 simultaneously blocked mTORC1 and mTORC2 activation, and resulted in the downregulation of phosphor-Akt, phpspho-p70S6k, phosphor-4EBP1, cyclin D1, and cyclin-dependent kinase4 (CDK4). Additionally, OSI-027 also downregulated P-gp, which enhanced oxaliplatin-induced apoptosis and suppressed multidrug resistance. Moreover, OSI-027 exhibited synergistic cytotoxic effects with oxaliplatin in vitro, while a P-gp siRNA knockdown significantly inhibited the synergistic effect. In summary, our results suggest that dual mTORC1/mTORC2 inhibitors (e.g., OSI-027) should be further investigated as a potential valuable treatment for gastric cancer.

scholarly journals HDAC4 promotes nasopharyngeal carcinoma progression and serves as a therapeutic target

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Chun Cheng ◽  
Jun Yang ◽  
Si-Wei Li ◽  
Guofu Huang ◽  
Chenxi Li ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Tumor Growth ◽  
Therapeutic Target ◽  
Histone Deacetylases ◽  
Migration And Invasion ◽  
Poor Overall Survival ◽  
Mesenchymal Transition ◽  
E Cadherin

AbstractHistone deacetylases (HDACs) are involved in tumor progression, and some have been successfully targeted for cancer therapy. The expression of histone deacetylase 4 (HDAC4), a class IIa HDAC, was upregulated in our previous microarray screen. However, the role of HDAC4 dysregulation and mechanisms underlying tumor growth and metastasis in nasopharyngeal carcinoma (NPC) remain elusive. Here, we first confirmed that the HDAC4 levels in primary and metastatic NPC tissues were significantly increased compared with those in normal nasopharyngeal epithelial tissues and found that high HDAC4 expression predicted a poor overall survival (OS) and progression-free survival (PFS). Functionally, HDAC4 accelerated cell cycle G1/S transition and induced the epithelial-to-mesenchymal transition to promote NPC cell proliferation, migration, and invasion in vitro, as well as tumor growth and lung metastasis in vivo. Intriguingly, knockdown of N-CoR abolished the effects of HDAC4 on the invasion and migration abilities of NPC cells. Mechanistically, HDAC3/4 binds to the E-cadherin promoter to repress E-cadherin transcription. We also showed that the HDAC4 inhibitor tasquinimod suppresses tumor growth in NPC. Thus, HDAC4 may be a potential diagnostic marker and therapeutic target in patients with NPC.

scholarly journals Overexpressed P75CUX1 promotes EMT in glioma infiltration by activating β-catenin

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Anqi Xu ◽  
Xizhao Wang ◽  
Jie Luo ◽  
Mingfeng Zhou ◽  
Renhui Yi ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Tumor Grade ◽  
Prognostic Indicator ◽  
Migration And Invasion ◽  
Poor Overall Survival ◽  
Mesenchymal Transition ◽  
Kaplan Meier ◽  
Homeobox Protein

AbstractThe homeobox protein cut-like 1 (CUX1) comprises three isoforms and has been shown to be involved in the development of various types of malignancies. However, the expression and role of the CUX1 isoforms in glioma remain unclear. Herein, we first identified that P75CUX1 isoform exhibited consistent expression among three isoforms in glioma with specifically designed antibodies to identify all CUX1 isoforms. Moreover, a significantly higher expression of P75CUX1 was found in glioma compared with non-tumor brain (NB) tissues, analyzed with western blot and immunohistochemistry, and the expression level of P75CUX1 was positively associated with tumor grade. In addition, Kaplan–Meier survival analysis indicated that P75CUX1 could serve as an independent prognostic indicator to identify glioma patients with poor overall survival. Furthermore, CUX1 knockdown suppressed migration and invasion of glioma cells both in vitro and in vivo. Mechanistically, this study found that P75CUX1 regulated epithelial–mesenchymal transition (EMT) process mediated via β-catenin, and CUX1/β-catenin/EMT is a novel signaling cascade mediating the infiltration of glioma. Besides, CUX1 was verified to promote the progression of glioma via multiple other signaling pathways, such as Hippo and PI3K/AKT. In conclusion, we suggested that P75CUX1 could serve as a potential prognostic indicator as well as a novel treatment target in malignant glioma.

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