scholarly journals m6A Methylation Mediates LHPP Acetylation as a Tumour Aerobic Glycolysis Suppressor to Improve the Prognosis of Gastric Cancer

2021 ◽  
Author(s):  
Jian-Xian Lin ◽  
Ning-Zi Lian ◽  
You-Xin Gao ◽  
Qing-Zhu Qiu ◽  
Hua-Gen Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cox Regression ◽  
Aerobic Glycolysis ◽  
Prognostic Significance ◽  
Predictive Biomarker ◽  
Human Gastric Cancer ◽  
Gastric Cancer Cells ◽  
Cox Regression Analysis

Abstract BackgroundLHPP, a histidine phosphatase, has been implicated in tumor progression. However, its role, underlying mechanisms, and prognostic significance in human gastric cancer (GC) are elusive. MethodsWe obtained GC tissues and corresponding normal tissues from 8 patients and identified LHPP as a downregulated gene via RNA-seq. qRT-PCR and western blotting were applied to examine LHPP levels in normal and GC tissues. The prognostic value of LHPP was elucidated using tissue microarray and IHC analyses in two independent GC cohorts. The functional roles and mechanistic insights of LHPP in GC growth and metastasis were evaluated in vitro and in vivo. ResultsThe results showed that LHPP expression was significantly decreased in GC tissues at both the mRNA and protein level. Multivariate Cox regression analysis revealed that LHPP was an independent prognostic factor and effective predictor in patients with GC. The low expression of LHPP was significantly related to the poor prognosis and chemotherapy sensitivity of gastric cancer patients. Moreover, elevated LHPP expression effectively suppressed GC growth and metastasis in vitro and in vivo. Mechanistically, the m6A modification of LHPP mRNA by METTL14 represses its expression; LHPP inhibits the phosphorylation of GSK3b through acetylation, and mediates HIF1A to inhibit glycolysis, proliferation, invasion and metastasis of gastric cancer cells. ConclusionLHPP is regulated by m6A methylation and regulates the metabolism of GC by changing the acetylation level. Thus, LHPP is a potential predictive biomarker and therapeutic target for GC.

scholarly journals Regulation of Apelin Is Associated with Proliferation and Angiogenesis in Gastric Cancer

2020 ◽  
Author(s):  
LiJun Tian ◽  
Hong-Zhi Liu ◽  
Qiang Zhang ◽  
Dian-Zhong Geng ◽  
Jing Yang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Cox Regression ◽  
Human Gastric Cancer ◽  
Gastric Cancer Cells ◽  
Normal Tissues ◽  
Underlying Mechanisms

Abstract Background: Apelin is an emerging endogenous ligand, which is involved in proliferation and angiogenesis in certain cancers. However, few studies have reported its functions and underlying mechanisms in human gastric cancer (GC). Therefore, the present study aimed to investigate the effect of Apelin expression in human GC and the underlying mechanisms of Apelin in the promotion of proliferation both in vitro and in vivo.Methods: A total of 178 patients diagnosed with GC under postoperative care were enrolled for the study to investigate clinicopathological and immunohistochemical factors of Apelin expression. Survival of patients was analyzed using the Kaplan-Meier method and Cox regression model. We adopted quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR), western blot and ELISA to analyze human GC specimens and cell lines. The role and mechanisms of Apelin were evaluated by performing in vitro and in vivo experiments to analyze exogenous Apelin and its overexpression in human GC cells. Results: The expression of Apelin was higher in human gastric cancer cells than in adjacent normal tissues. Apelin, which was overexpressed in vessel invasion (P <0.01), lymph node metastasis (P <0.01), late-staged tumor (T) status (P <0.05), pathological type (P <0.05) and nerve invasion (P <0.05), also exhibited a positive correlation with vascular endothelial growth factor (VEGF). Apelin overexpression or exogenous Apelin activated downstream of ERK/Cyclin D1/MMP-9 signaling pathway to promote MGC-803 cell proliferation and invasion in vitro. Apelin overexpression promoted angiogenesis aiming at accelerating growth of subcutaneous xenograft in vivo.Conclusions: This study has elucidated the relationship between Apelin and its clinicopathological features in human GC, and the role of Apelin in tumor cell proliferation in human GC cell lines. This is the first study to elucidate underlying mechanisms of Apelin in the proliferation of GC. Apelin can be a potential therapeutic target for human GC.

scholarly journals PLXDC2 Enhances Invadopodium Formation to Promote Invasion and Metastasis of Gastric Cancer Cells via Iteracting with PTP1B

2021 ◽  
Author(s):  
Bin Wu ◽  
Yan-xia Wang ◽  
Jun-jie Wang ◽  
Dong-fang Xiang ◽  
Meng-si Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Cox Regression ◽  
Tyrosine Phosphatase ◽  
Invasion And Metastasis ◽  
Gastric Cancer Cells ◽  
Cox Regression Analysis

Abstract Background: Plexin-domain containing 2 (PLXDC2) has been reported as an oncoprotein in several human malignancies. However, its expression and roles in gastric cancer remain largely unclear. Methods: The expression of PLXDC2 in 170 gastric cancer specimens was measured by using immunohistochemical staining and its clinical relevance was statistically analyzed. Matrigel-transwell invasion assays and mouse intraperitoneal metastasis models with PLXDC2-silencing and -overexpressing gastric cells were performed to explore the biological functions of PLXDC2 in gastric cancer cells. RNA-Seq, immunofluorescence and Co-IP analyses were used to investigate the potential molecular mechanisms of PLXDC2 action in gastric cancer. Results: PLXDC2 was highly expressed in gastric cancer tissues, and the expression levels were positively correlated with clinicopathological features, but negatively with the patients’ outcome. Cox regression analysis identified PLXDC2 as an independent prognostic indicator for the patients. Knockdown of PLXDC2 markedly suppressed the in vitro invasion and in vivo metastasis of gastric cancer cells, while overexpression of PLXDC2 resulted in opposite effects. Mechanistically, PLXDC2 inhibited dephosphorylation of phosphorylated Cortactin by physically interacting with PTP1B, an important tyrosine phosphatase, thereby promoting the formation of invadopodium. Conclusions: PLXDC2 contributes to the invasion and metastasis of gastric cancer by inhibiting PTP1B to facilitate the invadopodium formation, and may serve as a potential prognostic biomarker and a therapeutic target for this disease.

METTL3-mediated m6A modification of HDGF mRNA promotes gastric cancer progression and has prognostic significance

Gut ◽  
2019 ◽  
Vol 69 (7) ◽  
pp. 1193-1205 ◽  
Author(s):  
Qiang Wang ◽  
Chen Chen ◽  
Qingqing Ding ◽  
Yan Zhao ◽  
Zhangding Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Liver Metastasis ◽  
Cancer Progression ◽  
Tumour Growth ◽  
Cox Regression ◽  
Prognostic Significance ◽  
Tumour Angiogenesis ◽  
Cox Regression Analysis

ObjectiveN6-methyladenosine (m6A) RNA methylation and its associated methyltransferase METTL3 are involved in tumour initiation and progression via the regulation of RNA function. This study explored the biological function and clinical significance of METTL3 in gastric cancer (GC).DesignThe prognostic value of METTL3 expression was evaluated using tissue microarray and immunohistochemical staining analyses in a human GC cohort. The biological role and mechanism of METTL3 in GC tumour growth and liver metastasis were determined in vitro and in vivo.ResultsThe level of m6A RNA was significantly increased in GC, and METTL3 was the main regulator involved in the abundant m6A RNA modification. METTL3 expression was significantly elevated in GC tissues and associated with poor prognosis. Multivariate Cox regression analysis revealed that METTL3 expression was an independent prognostic factor and effective predictor in human patients with GC. Moreover, METTL3 overexpression promoted GC proliferation and liver metastasis in vitro and in vivo. Mechanistically, P300-mediated H3K27 acetylation activation in the promoter of METTL3 induced METTL3 transcription, which stimulated m6A modification of HDGF mRNA, and the m6A reader IGF2BP3 then directly recognised and bound to the m6A site on HDGF mRNA and enhanced HDGF mRNA stability. Secreted HDGF promoted tumour angiogenesis, while nuclear HDGF activated GLUT4 and ENO2 expression, followed by an increase in glycolysis in GC cells, which was correlated with subsequent tumour growth and liver metastasis.ConclusionsElevated METTL3 expression promotes tumour angiogenesis and glycolysis in GC, indicating that METTL3 expression is a potential prognostic biomarker and therapeutic target for human GC.

scholarly journals The Significance of MET Expression and Strategies of Targeting MET Treatment in Advanced Gastric Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Haiyan Liao ◽  
Tiantian Tian ◽  
Yuling Sheng ◽  
Zhi Peng ◽  
Zhongwu Li ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Molecular Mechanisms ◽  
Predictive Biomarker ◽  
Mapk Signaling ◽  
Human Gastric Cancer ◽  
Gastric Cancer Cells ◽  
Met Amplification ◽  
Before And After

BackgroundAccurate assessment of predictive biomarker expression is critical in patient selection in clinical trials or clinical practice. However, changes in biomarker expression may occur after treatment. The aim of the present study was to evaluate the effects of chemotherapy on MET expression in gastric cancer (GC).MethodsMET expression was examined immunohistochemically before and after treatment in 122 patients with unresectable or recurrent GC, and was evaluated according to H-score or the scoring criteria used in the MetMAb trial. MET gene amplification was assessed by chromogenic in situ hybridization (CISH). The antitumor effect of MET targeted therapy was investigated in human gastric cancer cells in vitro and in vivo, and the underlying molecular mechanisms were analyzed by western blot.ResultsMET expression was associated with Lauren classification as well as tumor differentiation by either scoring system. MET amplification was not associated with clinical characteristics. Of the 71 patients who had paired pre- and post-treatment tumor tissues, 28 patients (39%) were initially positive for MET expression, and 43 (61%) were negative. Twenty-five patients (35%) showed significant changes in MET expression after treatment (P=0.007). Additionally, there was a concomitant overexpression of MET and HER2 in a subset of GC patients. MET inhibitor volitinib could significantly inhibit cell proliferation and xenograft growth in vitro and in vivo in MKN45 cells with MET and phosphorylated MET (pMET) high expressions via suppressing downstream PI3K/Akt and MAPK signaling pathways. Furthermore, combination therapy targeting both MET and HER2 demonstrated a synergistic antitumor activity.ConclusionsMET expression is altered post chemotherapy and MET status should be evaluated in real-time. Both MET and pMET expressions might need to be considered for patients suitable for volitinib treatment.

scholarly journals Apelin Over-Expression Promotes Proliferation and Angiogenesis of Gastric Cancer Cells

2021 ◽  
Author(s):  
Li-Jun Tian ◽  
Hong-Zhi Liu ◽  
Qiang Zhang ◽  
Dian-Zhong Geng ◽  
Jing Yang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Cox Regression ◽  
Gastric Cancer Cells ◽  
Over Expression ◽  
Normal Tissues

Abstract Background: Apelin is a recently identified endogenous ligand associated with proliferation and angiogenesis of several cancers. However, only few studies have reported on the functions and the role of apelin in gastric cancer (GC). Therefore, in the present study, we investigated the association and the mechanisms underlying Apelin expression and proliferation of GC cells both in vitro and in vivo.Methods: We enrolled 178 postoperative care GC patients to investigate clinicopathological and immunohistochemical factors associated with Apelin expression. The relationship between Survival of patients and apelin expression was evaluated using Kaplan-Meier method and Cox regression analyses. The expression of apelin mRNA and its proteins in GC tissues and cell lines were analyzed using quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR), western blot and ELISA. The role and mechanisms underlying regulation of Apelin expression in human GC cells were evaluated through several in vitro and in vivo experiments. Results: Apelin was over expressed in human GC cells, relative to adjacent normal tissues. The over expression of apelin was associated with vessel invasion (P <0.01), lymph node metastasis (P <0.01), late-staged tumor (T) (P <0.05), worse pathological type (P <0.05), nerve invasion (P <0.05). In addition, expression of apelin strongly and positively correlated with that of vascular endothelial growth factor (VEGF). Over-expression of apelin promoted proliferation and invasion of MGC-803 cell via the ERK/Cyclin D1/MMP-9 signaling pathway. Apelin over-expression also promoted angiogenesis of GC cells, accelerating growth of subcutaneous xenograft of the cancer cells in vivo.Conclusions: Over-expression of apelin promotes proliferation and metastasis of GC cells via the ERK/Cyclin D1/MMP-9 signaling pathway and is associated with adverse events of the cancer. Consequently, apelin is a potential therapeutic target for human GC.

Oleanolic acid induces autophagic death in human gastric cancer cells in vitro and in vivo

2016 ◽  
Vol 40 (7) ◽  
pp. 770-778 ◽  
Author(s):  
Hao Nie ◽  
Yu Wang ◽  
Yong Qin ◽  
Xing-Guo Gong
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Oleanolic Acid ◽  
Human Gastric Cancer ◽  
Gastric Cancer Cells

scholarly journals Increased Thioredoxin-1 Expression Promotes Cancer Progression and Predicts Poor Prognosis in Patients with Gastric Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Wenjing Shang ◽  
Zhongdong Xie ◽  
Fengying Lu ◽  
Daoquan Fang ◽  
Tianbin Tang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Growth ◽  
Poor Prognosis ◽  
Prognostic Significance ◽  
Migration And Invasion ◽  
Human Gastric Cancer ◽  
Antitumor Effects ◽  
Thioredoxin 1

Background. Thioredoxin-1 (Trx-1) is a small redox protein, which plays an important role in many biological processes. Although increased expression of Trx-1 in various solid tumors has been reported, the prognostic significance and function of Trx-1 in human gastric cancer (GC) are still unclear. Here, we investigated the clinical and prognostic significance of Trx-1 expression and the function and mechanism of Trx-1 in human GC. Methods. We analyzed Trx-1 mRNA expression from the GEO database and Trx-1 protein expression in 144 GC tissues using immunohistochemistry. Effects of Trx-1 on GC cell were assessed in vitro and in vivo through Trx-1 knockdown or overexpression. The antitumor effects of the Trx-1 inhibitor, PX-12, on GC cells were investigated. PTEN and p-AKT expressions were evaluated by Western blotting. Results. Increased Trx-1 expression was found in GC tissues and associated with poor prognosis and aggressive clinicopathological characteristics in patients with GC. High Trx-1 expression predicted poor prognosis, and its expression was an independent prognostic factor for overall survival of GC patients. Knockdown of Trx-1 expression inhibited GC cell growth, migration, and invasion in vitro and tumor growth and lung metastasis in vivo. Conversely, overexpression of Trx-1 promoted GC cell growth, migration, and invasion. We also found that PX-12 inhibited GC cell growth, migration, and invasion. Overexpression of Trx-1 caused a decrease in PTEN and increase in p-AKT levels whereas silencing Trx-1 caused an increase in PTEN and decrease in p-AKT levels in GC cells. Inhibition of AKT signaling pathway by MK2206 also inhibited GC cell growth, migration, and invasion. Conclusion. Our results indicate that Trx-1 may be a promising prognostic indicator and therapeutic target for GC patients.

scholarly journals Adenovirus mediated p53 tumour suppressor gene therapy for human gastric cancer cells in vitro and in vivo

Gut ◽  
1999 ◽  
Vol 44 (3) ◽  
pp. 366-371 ◽  
Author(s):  
M Ohashi ◽  
F Kanai ◽  
H Ueno ◽  
T Tanaka ◽  
K Tateishi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gene Therapy ◽  
P53 Gene ◽  
Human Gastric Cancer ◽  
Wild Type ◽  
Gastric Cancer Cells ◽  
Gastric Cancer Cell Lines ◽  
Wild Type P53

BACKGROUND/AIMSGastric cancer is one of the most prevalent forms of cancer in East Asia. Point mutation of the p53 gene has been reported in more than 60% of cases of gastric cancer and can lead to genetic instability and uncontrolled cell proliferation. The purpose of this investigation was to evaluate the potential of p53 gene therapy for gastric cancer.METHODSThe responses of human gastric cancer cell lines, MKN1, MKN7, MKN28, MKN45, and TMK-1, to recombinant adenoviruses encoding wild type p53 (AdCAp53) were analysed in vitro. The efficacy of the AdCAp53 treatment for MKN1 and MKN45 subcutaneous tumours in nude mice was assessed in vivo.RESULTSp53-specific growth inhibition was observed in vitro in two of four gastric cancer cell lines with mutated p53, but not in the wild type p53 cell line. The mechanism of the killing of gastric cancer cells by AdCAp53 was found, by flow cytometric analysis and detection of DNA fragmentation, to be apoptosis. In vivo studies showed that the growth of subcutaneous tumours of p53 mutant MKN1 cells was significantly inhibited by direct injection of AdCAp53, but no significant growth inhibition was detected in the growth of p53 wild type MKN45 tumours.CONCLUSIONSAdenovirus mediated reintroduction of wild type p53 is a potential clinical utility in gene therapy for gastric cancers.

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