scholarly journals ATP4B suppresses cell proliferation and migration via mitochondrial/p53/NF-κB pathway in gastric cancer

2020 ◽  
Author(s):  
Yuanming Pan ◽  
Yuqi He ◽  
Shuye Lin ◽  
Min Zhu ◽  
Yangjie Li ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Gastric Mucosa ◽  
Tumor Model ◽  
Suppressor Gene ◽  
Mitochondrial Pathway ◽  
Loss Of Function ◽  
Normal Tissues ◽  
And Migration ◽  
Induced Apoptosis

Abstract Background: Hydrogen/Potassium ATPase β (ATP4B) is a key protein in gastric mucosa barrier acting an essential role in gastric acid secretion. However, the exact role and precise mechanism of ATP4B in gastric cancer (GC) remain obscure. This study aimed to investigate the clinical significance of ATP4B in GC and its biological role in tumor progression.Methods: We evaluated ATP4B expression in GC cell lines and patient specimens via qPCR and Immunofluorescence. The correlations between ATP4B expression level and clinicopathologic parameters, as well as the relevance of ATP4B expression with overall survival were assessed. The functional roles of ATP4B in GC were verified by gain- and loss-of-function cell models and xenograft tumor model. The possible downstream effects of ATP4B were analyzed by iTRAQ‑based quantitative proteomics analysis.Results: A dramatic decrease of ATP4B expression in GC cells and tissues compared with the adjacent normal tissues was observed; Downexpression of ATP4B was associated with the malignant transformation in gastric mucosa lesions and correlated with poor prognosis, high grade of TNM stage, and vessel carcinoma embolus in GC patients. Restoration of ATP4B expression in GC cells significantly inhibited cell proliferation, cell viability, migration, invasion, tumorigenicity and induced apoptosis, whereas ATP4B silencing exerted the opposite effects. Mechanistically, we found a constitutive activation of p53 and inactivation of NF-κB signaling correlated with the mitochondrial pathway in ATP4B-overexpressing GC cells.Conclusion: Our data suggest that ATP4B perform the promising tumor suppressor gene by regulating p53/NF-κB/mitochondrial pathway in GC.

scholarly journals Tumor Suppressor Gene XEDAR Promotes Differentiation and Suppresses Proliferation and Migration of Gastric Cancer Cells Through Upregulating the RELA/LXRα Axis and Deactivating the Wnt/β-Catenin Pathway

2021 ◽  
Vol 30 ◽  
pp. 096368972199634
Author(s):  
Xinwu Zhang ◽  
Di Zhang ◽  
Xiaoli Sun ◽  
Shunle Li ◽  
Yun Sun ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Opposite Effect ◽  
Tumor Necrosis Factor Receptor ◽  
Suppressor Gene ◽  
Gastric Cancer Cells ◽  
Promote Cell Proliferation ◽  
And Migration ◽  
Proliferation And Migration

X-linked ectodermal dysplasia receptor (XEDAR) is a new member of the tumor necrosis factor receptor (TNFR) family that induces cell death. The purpose of this study is to determine the tumor-suppressive potential of XEDAR in the development and differentiation of gastric cancer (GC). XEDAR levels were analyzed in human GC tissues and adjacent normal tissues by immunohistochemistry (IHC), quantitative real-time reverse transcription PCR (RT-qPCR), and Western blot analysis. We found that XEDAR expression was significantly downregulated in GC tissues and further decreased in low differentiated GC tissues. Overexpression of XEDAR in MKN45 and MGC803 cells suppressed the ability of cell proliferation and migration, whereas silencing XEDAR showed the opposite effect. Additionally, XEDAR silencing resulted in the upregulation of the differentiation molecular markers β-catenin, CD44 and Cyclin D1 at the protein levels, whereas XEDAR overexpression showed the opposite effect. Notably, XEDAR positively regulated the expression of liver X receptor alpha (LXRα) through upregulating the RELA gene that was characterized as a transcription factor of LXRα in this study. Inhibition of LXRα by GSK2033 or activation of the Wnt/β-catenin pathway by Wnt agonist 1 impaired the effect of XEDAR overexpression on differentiation of MKN45 cells. Moreover, inhibition of RELA mediated by siRNA could promote cell proliferation/migration and rescue the effect of XEDAR overexpression on cell behaviors and expression of genes. Subsequently, overexpression of XEDAR suppressed the growth of GC cells in vivo. Taken together, our findings showed that XEDAR could promote differentiation and suppress proliferation and invasion of GC cells.

scholarly journals LncRNA MT1JP Suppresses Gastric Cancer Cell Proliferation and Migration Through MT1JP/MiR-214-3p/RUNX3 Axis

2018 ◽  
Vol 46 (6) ◽  
pp. 2445-2459 ◽  
Author(s):  
Ying Xu ◽  
Guohua Zhang ◽  
Chen Zou ◽  
Heng Zhang ◽  
Zhigang Gong ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Luciferase Reporter ◽  
Loss Of Function ◽  
Ki 67 ◽  
Invasion And Migration ◽  
Tumorigenesis And Progression ◽  
Gastric Cancer Cell Proliferation ◽  
And Migration

Background/Aims: Emerging evidence points towards an important role of long noncoding RNAs (lncRNAs) in the tumorigenesis and progression of gastric cancer (GC). MT1JP has recently been reported to be differentially expressed and act as a tumor suppressor in different tumors, with its mechanisms not fully understood in GC. Methods: RT-qPCR was used to detect the expression of MT1JP, miR-214-3p and RUNX3 in tumor tissues and cell lines of GC. The CCK-8 assay, colony formation, Transwell assay and wound healing assay were used to evaluate the proliferation, invasion and migration of GC cells, respectively. Bioinformatics analysis and luciferase reporter assay were performed to disclose the interaction between MT1JP, miR-214-3p and RUNX3. Western blot and immunofluorescence were applied to assess the downstream signaling of RUNX3. Results: MT1JP was found downregulated in GC tissues and cells. Low expression of MT1JP was significantly correlated with advanced TNM stage and lymphatic metastasis. The expression of plasma MT1JP was also found decreased in GC patients compared to healthy controls, with an area under the ROC curve (AUC) of 0.649 for diagnosis of GC. Gain- and loss-of-function of MT1JP revealed that MT1JP functioned as a ceRNA for miR-214-3p to facilitate RUNX3 expression and then upregulated p21 and Bim levels suppressing GC cell proliferation, invasion and migration, and promoting apoptosis. Furthermore, MT1JP overexpression suppressed tumor growth and inhibited the expression of miR-214-3p and proliferation antigen Ki-67, but increased the expression of RUNX3, p21 and Bim in vivo. Conclusions: Our results suggest a potential ceRNA regulatory network involving MT1JP regulates RUNX3 expression by competitively binding endogenous miR-214-3p in tumorigenesis and progression of GC. This mechanism may contribute to a better understanding of GC pathogenesis and provide potential therapeutic strategy for GC.

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

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.

scholarly journals Suppression of m6A mRNA modification by DNA hypermethylated ALKBH5 aggravates the oncological behavior of KRAS mutation/LKB1 loss lung cancer

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Donghong Zhang ◽  
Jinfeng Ning ◽  
Imoh Okon ◽  
Xiaoxu Zheng ◽  
Ganesh Satyanarayana ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Epigenetic Modification ◽  
Suppressor Gene ◽  
Ctcf Binding ◽  
Binding Motif ◽  
Loss Of Function ◽  
Dna Hypermethylation ◽  
Lung Cancer Patients ◽  
Lkb1 Tumor Suppressor ◽  
And Migration

AbstractOncogenic KRAS mutations combined with the loss of the LKB1 tumor-suppressor gene (KL) are strongly associated with aggressive forms of lung cancer. N6-methyladenosine (m6A) in mRNA is a crucial epigenetic modification that controls cancer self-renewal and progression. However, the regulation and role of m6A modification in this cancer are unclear. We found that decreased m6A levels correlated with the disease progression and poor survival for KL patients. The correlation was mediated by a special increase in ALKBH5 (AlkB family member 5) levels, an m6A demethylase. ALKBH5 gain- or loss-of function could effectively reverse LKB1 regulated cell proliferation, colony formation, and migration of KRAS-mutated lung cancer cells. Mechanistically, LKB1 loss upregulated ALKBH5 expression by DNA hypermethylation of the CTCF-binding motif on the ALKBH5 promoter, which inhibited CTCF binding but enhanced histone modifications, including H3K4me3, H3K9ac, and H3K27ac. This effect could successfully be rescued by LKB1 expression. ALKBH5 demethylation of m6A stabilized oncogenic drivers, such as SOX2, SMAD7, and MYC, through a pathway dependent on YTHDF2, an m6A reader protein. The above findings were confirmed in clinical KRAS-mutated lung cancer patients. We conclude that loss of LKB1 promotes ALKBH5 transcription by a DNA methylation mechanism, reduces m6A modification, and increases the stability of m6A target oncogenes, thus contributing to aggressive phenotypes of KRAS-mutated lung cancer.

Circ_002059 suppresses cell proliferation and migration of gastric cancer via miR-182/MTSS1 axis

2021 ◽  
Vol 53 (4) ◽  
pp. 454-462
Author(s):  
Ting Li ◽  
Xiaomin Zuo ◽  
Xiangling Meng
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Luciferase Reporter ◽  
Metastasis Suppressor ◽  
Xenograft Tumor ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Xenograft Tumor Growth ◽  
Proliferation And Migration

Abstract Circular RNAs (circRNAs) play either oncogenic or tumor suppressive roles in gastric cancer (GC). A previous study demonstrated that circ_002059, a typical circRNA, was downregulated in GC tissues. However, the role and mechanism of circ_002059 in GC development are still unknown. In this study, the levels of circ_002059, miR-182, and metastasis suppressor-1 (MTSS1) were examined by real-time quantitative polymerase chain reaction and western blot analysis. Cell proliferation and migration were evaluated by MTT assay and Transwell migration assay, respectively. The interactions between miR-182 and circ_002059 or MTSS1 were analyzed by dual-luciferase reporter assay. A GC xenograft model was established to validate the role of circ_002059 in GC progression in vivo. Overexpression of circ_002059 significantly inhibited, whereas knockdown of circ_002059 notably facilitated, cell proliferation and migration in GC cells. MTSS1 was found to be a direct target of miR-182 and circ_002059 upregulated MTSS1 expression by competitively sponging miR-182. Transfection with miR-182 mimic and MTSS1 silencing abated the inhibitory effect of circ_002059 on GC progression. Circ_002059 inhibited GC cell xenograft tumor growth by regulating miR-182 and MTSS1 expression. Collectively, Circ_002059 inhibited GC cell proliferation and migration in vitro and xenograft tumor growth in mice, by regulating the miR-182/MTSS1 axis.

scholarly journals miR-299-3p suppresses cell progression and induces apoptosis by downregulating PAX3 in gastric cancer

2021 ◽  
Vol 16 (1) ◽  
pp. 266-276
Author(s):  
Zhenfen Wang ◽  
Qing Liu ◽  
Ping Huang ◽  
Guohao Cai
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Western Blot ◽  
Luciferase Reporter ◽  
Reporter System ◽  
Western Blot Assay ◽  
Normal Tissues ◽  
Cell Progression ◽  
Luciferase Reporter System ◽  
Proliferation And Invasion

Abstract Gastric cancer (GC) is ranked the fourth leading cause of cancer-related death, with an over 75% mortality rate worldwide. In recent years, miR-299-3p has been identified as a biomarker in multiple cancers, such as acute promyelocytic leukemia, thyroid cancer, and lung cancer. However, the regulatory mechanism of miR-299-3p in GC cell progression is still largely unclear. Cell viability and apoptosis tests were performed by CCK8 and flow cytometry assay, respectively. Transwell assay was recruited to examine cell invasion ability. The interaction between miR-299-3p and PAX3 was determined by the luciferase reporter system. PAX3 protein level was evaluated by western blot assay. The expression of miR-299-3p was downregulated in GC tissues and cell lines (MKN-45, AGS, and MGC-803) compared with the normal tissues and cells. Besides, overexpression of miR-299-3p significantly suppressed proliferation and invasion and promoted apoptosis in GC. Next, we clarified that PAX3 expression was regulated by miR-299-3p using a luciferase reporter system, qRT-PCR, and western blot assay. Additionally, downregulation of PAX3 repressed GC cell progression. The rescue experiments indicated that restoration of PAX3 inversed miR-299-3p-mediated inhibition on cell proliferation and invasion. miR-299-3p suppresses cell proliferation and invasion as well as induces apoptosis by regulating PAX3 expression in GC, representing desirable biomarkers for GC diagnosis and therapy.

scholarly journals miR-17-5p promotes the invasion and migration of colorectal cancer by regulating HSPB2

2020 ◽  
Author(s):  
Wei fang Yu ◽  
Jia Wang ◽  
Chao Li ◽  
Mingda Xuan ◽  
Shuangshuang Han ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Lymph Node ◽  
Target Genes ◽  
Migration And Invasion ◽  
Invasion And Migration ◽  
Normal Tissues ◽  
Node Metastasis ◽  
Rescue Experiment ◽  
And Migration

Abstract Background: MicroRNA (miRNA) can affect tumor progression by regulating cell proliferation, apoptosis and metastasis. After miRNA microarray chip analysis of colorectal cancer (CRC) tissues and adjacent normal tissues, a significant upregulation of miR-17-5p expression was found in CRC tissues. However, the underlying mechanism of miR-17-5p in CRC is still unclear.Methods: The levels of miR-17-5p in 47 paired CRC and adjacent normal tissue samples were determined by quantitative real-time PCR (qRT-PCR). CCK-8, colony formation, flow cytometry and transwell assays were used to explore the biological effects of miR-17-5p on CRC cells. In addition, the transcriptome sequencing and miRNA target prediction software were employed to identify targets of miR-17-5p. Luciferase reporter detection was used to demonstrate the direct binding of target genes by miR-17-5p. The rescue experiment was conducted to investigate the biological function of target genes and regulatory mechanism of miR-17-5p on target genes.Results: The expression of miR-17-5p was significantly higher in CRC tissues than in adjacent normal tissues. In CRC group, the expression of miR-17-5p in cancer tissues with lymph node metastasis was higher compared with those without lymph node metastasis. Overexpression of miR-17-5p inhibited CRC cell apoptosis, as well as promoting proliferation, migration and invasion. We hypothesized that HSPB2 might be a target gene of miR-17-5p and validated for the first time that miR-17-5p binds directly to the 3’-UTR of HSPB2. In the rescue experiment, the tumor suppressive effect of HSPB2 was detected and miR-17-5p could promote cell proliferation, migration and invasion by targeting HSPB2.Conclusion: MiR-17-5p promotes invasion and migration by inhibiting HSPB2 in CRC, thereby implicating its potential as a novel diagnostic biomarker and therapeutic target for CRC.

scholarly journals Centromere Protein I (CENP-I) Is Upregulated in Gastric Cancer, Predicts Poor Prognosis, and Promotes Tumor Cell Proliferation and Migration

2021 ◽  
Vol 20 ◽  
pp. 153303382110455
Author(s):  
Jiahui Wang ◽  
Xin Liu ◽  
Hong-jin Chu ◽  
Ning Li ◽  
Liu-ye Huang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Poor Prognosis ◽  
Cellular Function ◽  
Mesenchymal Transition ◽  
Qrt Pcr ◽  
Lauren Classification ◽  
Centromere Protein ◽  
Laurén Classification ◽  
And Migration

This study aimed to investigate the expression and cellular function of the centromeric family of proteins (CENPs), especially centromere protein I (CENP-I), in gastric cancer (GC) and identified its clinical significance and cellular functions. CENP-I expression in GC was studied by cDNA microarray, quantitative real-time PCR (qRT-PCR), and immunohistochemistry (IHC), and using datasets from The Cancer Genome Atlas (TCGA), UALCAN, and Gene Expression Omnibus (GEO) databases. Microarray and bioinformatic analyses identified upregulated CENP-A/E/F/H/I/K/P/W and HJURP in stomach adenocarcinoma (STAD), but not in signet ring cell carcinoma (SRCC). Significantly higher CENP-I mRNA expression was also confirmed in 40 pairs of GC tissues than in paired normal gastric tissues by qRT-PCR ( P<.001). IHC showed that elevated CENP-I expression was associated with higher tumor stage, lymph node invasion, increased HER2-positive rate (36.7% vs 10.0%), and intestinal Lauren classification in 69 GC samples compared to paired paracancerous normal tissues. The survival of the high-CENP-I group members was poor compared with that of the low-CENP-I group ( P = .0011). Cox univariate regression analysis identified tumor size ( P = .008), HER2 status ( P = .027), and CENP-I expression ( P = .049) were independent prognostic factors of GC. The cellular function of CENP-I was studied in MKN45 and MKN28 GC cell lines in vitro. Cell proliferation, migration, and apoptosis were determined using CCK-8, transwell assay, TUNEL assay, and flow cytometry. Our results showed that CENP-I promoted GC cell proliferation, inhibited apoptosis, facilitated cell migration, and induced epithelial–mesenchymal transition (EMT), possibly by activating the AKT pathway. CENP-I expression was correlated with genetic signatures of the proliferative subtype of GC, characterized by intestinal Lauren classification, HER2 amplification, and TP53 mutation. In conclusion, this study revealed an elevated CENP-I expression in GC, which was associated with malignant features and poor prognosis of GC patients, and identified its function in modulating cell proliferation, apoptosis, and migration.

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