NSUN2 modified by SUMO-2/3 promotes gastric cancer progression and regulates mRNA m5C methylation

AbstractThe 5-methylcytosine (m5C) RNA methyltransferase NSUN2 is involved in the regulation of cell proliferation and metastasis formation and is upregulated in multiple cancers. However, the biological significance of NSUN2 in gastric cancer (GC) and the modification of NSUN2 itself have not been fully investigated. Here, we analyzed the expression level of NSUN2 in tissue microarrays containing 403 GC tissues by immunohistochemistry. NSUN2 was upregulated in GC, and that it was a predictor of poor prognosis. NSUN2 promotes the proliferation, migration, and invasion of GC cells in vitro. We also demonstrated that small ubiquitin-like modifier (SUMO)-2/3 interacts directly with NSUN2 by stabilizing it and mediating its nuclear transport. This facilitates the carcinogenic activity of NSUN2. Furthermore, m5C bisulfite sequencing (Bis-seq) in NSUN2-deficient GC cells showed that m5C-methylated genes are involved in multiple cancer-related signaling pathways. PIK3R1 and PCYT1A may be the target genes that participate in GC progression. Our findings revealed a novel mechanism by which NSUN2 functions in GC progression. This may provide new treatment options for GC patients.

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NUSAP1 Promotes Gastric Cancer Progression Through Regulation of Yap Stability

10.21203/rs.3.rs-33883/v1 ◽

2020 ◽

Author(s):

Hui Guo ◽

Jianping Zou ◽

Ling Zhou ◽

Yan He ◽

Miao Feng ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Target Genes ◽

Hippo Pathway ◽

Critical Role ◽

Xenograft Model ◽

Migration And Invasion

Abstract Background:Nucleolar and spindle associated protein (NUSAP1) is involved in tumor initiation, progression and metastasis. However, there are limited studies regarding the role of NUSAP1 in gastric cancer (GC). Methods: The expression profile and clinical significance of NUSAP1 in GC were analysed in online database using GEPIA, Oncomine and KM plotter, which was further confirmed in clinical specimens.The functional role of NUSAP1 were detected utilizing in vitro and in vivo assays. Western blotting, qRT-PCR, the cycloheximide-chase, immunofluorescence staining and Co-immunoprecipitaion (Co-IP) assays were performed to explore the possible molecular mechanism by which NUSAP1 stabilizes YAP protein. Results:In this study, we found that the expression of NUSAP1 was upregulated in GC tissues and correlates closely with progression and prognosis. Additionally, abnormal NUSAP1 expression promoted malignant behaviors of GC cells in vitro and in a xenograft model. Mechanistically, we discovered that NUSAP1 physically interacts with YAP and furthermore stabilizes YAP protein expression, which induces the transcription of Hippo pathway downstream target genes. Furthermore, the effects of NUSAP1 on GC cell growth, migration and invasion were mainly mediated by YAP. Conclusions:Our data demonstrates that the novel NUSAP1-YAP axis exerts an critical role in GC tumorigenesis and progression, and therefore could provide a novel therapeutic target for GC treatment.

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TOP1MT deficiency promotes GC invasion and migration via the enhancements of LDHA expression and aerobic glycolysis

Endocrine Related Cancer ◽

10.1530/erc-17-0058 ◽

2017 ◽

Vol 24 (11) ◽

pp. 565-578 ◽

Cited By ~ 7

Author(s):

Hongqiang Wang ◽

Rui Zhou ◽

Li Sun ◽

Jianling Xia ◽

Xuchun Yang ◽

...

Keyword(s):

Cancer Progression ◽

Topoisomerase I ◽

Target Genes ◽

Aerobic Glycolysis ◽

Lactate Production ◽

Migration And Invasion ◽

Glucose Transporter 1 ◽

Mesenchymal Transition

Aerobic glycolysis plays an important role in cancer progression. New target genes regulating cancer aerobic glycolysis must be explored to improve patient prognosis. Mitochondrial topoisomerase I (TOP1MT) deficiency suppresses glucose oxidative metabolism but enhances glycolysis in normal cells. Here, we examined the role of TOP1MT in gastric cancer (GC) and attempted to determine the underlying mechanism. Using in vitro and in vivo experiments and analyzing the clinicopathological characteristics of patients with GC, we found that TOP1MT expression was lower in GC samples than in adjacent nonmalignant tissues. TOP1MT knockdown significantly promoted GC migration and invasion in vitro and in vivo. Importantly, TOP1MT silencing increased glucose consumption, lactate production, glucose transporter 1 expression and the epithelial-mesenchymal transition (EMT) in GC. Additionally, regulation of glucose metabolism induced by TOP1MT was significantly associated with lactate dehydrogenase A (LDHA) expression. A retrospective analysis of clinical data from 295 patients with GC demonstrated that low TOP1MT expression was associated with lymph node metastasis, recurrence and high mortality rates. TOP1MT deficiency enhanced glucose aerobic glycolysis by stimulating LDHA to promote GC progression.

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SPON2 Is Upregulated through Notch Signaling Pathway and Promotes Tumor Progression in Gastric Cancer

Cancers ◽

10.3390/cancers12061439 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1439

Author(s):

Hyeon-Gu Kang ◽

Won-Jin Kim ◽

Myung-Giun Noh ◽

Kyung-Hee Chun ◽

Seok-Jun Kim

Keyword(s):

Gastric Cancer ◽

Cell Proliferation ◽

Notch Signaling ◽

Signaling Pathway ◽

Cancer Progression ◽

Notch Signaling Pathway ◽

Migration And Invasion ◽

Gene Assay ◽

Gastric Cancer Progression

Spondin-2 (SPON2) is involved in cancer progression and metastasis of many tumors; however, its role and underlying mechanism in gastric cancer are still obscure. In this study, we investigated the role of SPON2 and related signaling pathway in gastric cancer progression and metastasis. SPON2 expression levels were found to be upregulated in gastric cancer cell lines and patient tissues compared to normal gastric epithelial cells and normal controls. Furthermore, SPON2 silencing was observed to decrease cell proliferation and motility and reduce tumor growth in xenograft mice. Conversely, SPON2 overexpression was found to increase cell proliferation and motility. Subsequently, we focused on regulatory mechanism of SPON2 in gastric cancer. cDNA microarray and in vitro study showed that Notch signaling is significantly correlated to SPON2 expression. Therefore, we confirmed how Notch signaling pathway regulate SPON2 expression using Notch signaling-related transcription factor interaction and reporter gene assay. Additionally, activation of Notch signaling was observed to increase cell proliferation, migration, and invasion through SPON2 expression. Our study demonstrated that Notch signaling-mediated SPON2 upregulation is associated with aggressive progression of gastric cancer. In conclusion, we suggest upregulated SPON2 via Notch signaling as a potential target gene to inhibit gastric cancer progression.

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HER2, NF-κB, and SATB1 Expression Patterns in Gastric Cancer and Their Correlation with Clinical and Pathological Parameters

Disease Markers ◽

10.1155/2019/6315936 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 2

Author(s):

Marta Smolińska ◽

Dariusz Grzanka ◽

Paulina Antosik ◽

Anna Kasperska ◽

Izabela Neska-Długosz ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Statistical Significance ◽

Expression Patterns ◽

Clinical Information ◽

Tissue Microarrays ◽

Gastric Cancer Tissue ◽

Cancer Tissue ◽

Satb1 Expression

Gastric cancer (GC) is currently recognized as one of the most common and fatal tumor worldwide. The identification of novel biomarkers in relation to clinical information as well as extending the knowledge on a multiple crosstalk between various oncogenic pathways implicated in GC carcinogenesis seems pivotal to limit the disease-associated mortality. Therefore, we assessed the expression of HER2, NF-κB, and SATB1 in a total of 104 gastric adenocarcinomas and 30 normal gastric samples and correlated the expression patterns with each other and with some clinicopathological variables. Protein expression was examined by immunohistochemistry (IHC) on tissue microarrays (TMAs), and fluorescence in situ hybridization (FISH) was employed to detect HER2 amplification. In the studied group, HER2 and SATB1 were found to be overexpressed in gastric cancer tissue in comparison to normal gastric mucosa. The expression status of the former protein was seen to differ according to some clinicopathological features, but without statistical significance, whereas the expression of the latter was not importantly associated with any of them. In turn, the NF-κB protein level was significantly related to the presence of lymph node metastasis. HER2 expression was not significantly correlated with that of other proteins, but a positive correlation was found between the expression of SATB1 and NF-κB. Further studies with a larger group of patients combined with in vitro mechanistic experiments are required to fully elucidate the role and relationship of HER2, NF-κB, and SATB1 expression in gastric cancer progression. However, to the best of our knowledge, this study is the first look at a simultaneous evaluation of these three markers in the samples of gastric cancer patients.

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MiR-223 Promotes Tumor Progression via Targeting RhoB in Gastric Cancer

Journal of Oncology ◽

10.1155/2022/6708871 ◽

2022 ◽

Vol 2022 ◽

pp. 1-10

Author(s):

You Hu ◽

Bin Yi ◽

Xin Chen ◽

Lu Xu ◽

Xiaojun Zhou ◽

...

Keyword(s):

Gastric Cancer ◽

Tumor Progression ◽

Cancer Progression ◽

Tumor Development ◽

Migration And Invasion ◽

Cellular Mechanisms ◽

Borrmann Type ◽

Potential Biomarker

Gastric cancer (GC) is among the most prevalent causes of cancer-related death globally. MiR-223 has been implicated in a variety of cellular mechanisms linked to cancer progression. However, the miR-223 expressions and its function in GC are unknown. We discovered that miR-223 expression was raised in GC tissues in comparison with nearby normal tissues in this investigation. Additionally, multiplied miR-223 expression was strongly linked with TNM stage ( p = 0.022 ), live metastasis ( p = 0.004 ),lymph node metastasis ( p = 0.004 ),and Borrmann type and was associated with an unfavorable prognostic for patients with GC. Furthermore, suppressing miR-223 significantly increased cell death and prevented cell migration and invasion in vitro. Additionally, miR-223 silencing decreased tumor development in vivo. Additionally, we discovered that miR-223 enhanced GC development by specifically targeting RhoB. In summary, our findings reveal that miR-223 increases tumor progression in GC by targeting RhoB, suggesting that it could serve to be a potential biomarker for the prediction of the disease.

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The Interaction Between MiR-141 and lncRNA-H19 in Regulating Cell Proliferation and Migration in Gastric Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000430309 ◽

2015 ◽

Vol 36 (4) ◽

pp. 1440-1452 ◽

Cited By ~ 108

Author(s):

Xiaoying Zhou ◽

Feng Ye ◽

Chengqiang Yin ◽

Ya Zhuang ◽

Ge Yue ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Target Genes ◽

Human Cancer ◽

Luciferase Assay ◽

Gastric Cancer Cells ◽

Mesenchymal Transition ◽

Proliferation And Invasion

Background/Aims: Non-coding RNAs including miRNA and lncRNA had been reported to regulate gene expression and were both related to cancer progression. MicroRNA-141 (miR-141) has been reported to play a role in the epithelial to mesenchymal transition (EMT) process and H19 has also been demonstrated to promote malignancy in various cancers. We aimed to determine the correlation between miR-141 and H19 and their roles in gastric cancer in this study. Methods: H19 and miR-141 expression were detected by qRT-PCR. By bioinformatic analysis and luciferase assay we examined the correlation between H19 and miR-141 in vitro. Results: H19 expression was found to be inversely correlated to miR-141 expression in gastric cancer cells and tissues. H19 promotes malignancy including proliferation and invasion whereas miR-141 suppresses malignancy in human cancer cells. MiR-141 binds to H19 in a sequence specific manner, and suppresses H19 expression and functions including proliferation and invasion. MiR-141 could also regulate H19 target genes and miR-141 inhibitor restores H19 siRNA function, while H19 regulates miR-141 target gene ZEB1. Conclusion: These results were the first to demonstrate that H19 and miR-141 could compete with each other and affect their target genes in gastric cancer, which provide important clues for understanding the key roles of lncRNA-miRNA functional network in cancer.

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LncRNA HOXA-AS3 promotes gastric cancer progression by regulating miR-29a-3p/LTβR and activating NF-κB signaling

Cancer Cell International ◽

10.1186/s12935-021-01827-w ◽

2021 ◽

Vol 21 (1) ◽

Cited By ~ 1

Author(s):

Feng Qu ◽

Bin Zhu ◽

Yi-Lin Hu ◽

Qin-Sheng Mao ◽

Ying Feng

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Tumor Model ◽

Model Systems ◽

Immunofluorescent Staining ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Lymph Node Status

Abstract Background Gastric cancer (GC) is among the most common and deadliest cancers globally. Many long non-coding RNAs (lncRNAs) are key regulators of GC pathogenesis. This study aimed to define the role of HOXA-AS3 in this oncogenic context. Methods Levels of HOXA-AS3 expression in GC were quantified via qPCR. The effects of HOXA-AS3 knockdown on GC cells function were evaluated in vitro using colony formation assays, wound healing assays and transwell assays. Subcutaneous xenograft and tail vein injection tumor model systems were generated in nude mice to assess the effects of this lncRNA in vivo. The localization of HOXA-AS3 within cells was confirmed by subcellular fractionation, and predicted microRNA (miRNA) targets of this lncRNA and its ability to modulate downstream NF-κB signaling in GC cells were evaluated via luciferase-reporter assays, immunofluorescent staining, and western blotting. Results GC cells and tissues exhibited significant HOXA-AS3 upregulation (P < 0.05), and the levels of this lncRNA were found to be correlated with tumor size, lymph node status, invasion depth, and Helicobacter pylori infection status. Knocking down HOXA-AS3 disrupted GC cell proliferation, migration, and invasion in vitro and tumor metastasis in vivo. At a mechanistic level, we found that HOXA-AS3 was able to sequester miR-29a-3p, thereby regulating the expression of LTβR and modulating NF-κB signaling in GC. Conclusion HOXA-AS3/miR-29a-3p/LTβR/NF-κB regulatory axis contributes to the progression of GC, thereby offering novel target for the prognosis and treatment of GC.

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Overexpression of NELFE contributes to gastric cancer progression via Wnt/β-catenin signaling-mediated activation of CSNK2B expression

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01848-3 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Shijun Yu ◽

Li Li ◽

Hui Cai ◽

Bin He ◽

Yong Gao ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Target Genes ◽

Mrna Level ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Loss Of Function ◽

Mice Model ◽

Qrt Pcr

Abstract Background Accumulating evidence has highlighted the importance of negative elongation factor complex member E (NELFE) in tumorigenesis. However, the relationship between NELFE and gastric cancer (GC) remains unclear. This study aimed to explore the expression pattern and specific function of NELFE in GC. Methods NELFE expression was evaluated by immunohistochemistry and qRT-PCR in GC tissues, respectively. Cell proliferation, migration and invasion were measured by CCK-8, colony formation, transwell assays, and nude mice model. Bioinformatics analysis was performed to search potential target genes of NELFE, and a Cignal Finder 10-Pathway Reporter Array was used to explore potential signaling pathways regulated by NELFE. Dual-luciferase reporter assays, qRT-PCR and western blotting were conducted to verify their regulatory relationship. The expression correlations among NELFE, β-catenin and CSNK2B were further explored by immunohistochemistry on consecutive resections. Results NELFE was significantly overexpressed in GC tissues both in protein and mRNA level and negatively correlated with the prognosis of GC patients. Gain- and loss-of-function experiments showed that NELFE potentiated GC cell proliferation and metastasis in vitro and in vivo. CSNK2B was identified as a downstream effector of NELFE. Wnt/β-catenin signaling may mediate the regulation of CSNK2B by NELFE. In addition, NELFE, β-catenin and CSNK2B were all remarkably upregulated in tumor tissues compared with adjacent normal tissues, and their expression levels in GC were positively correlated with each other. Conclusion Our findings reveal a new NELFE-Wnt/β-catenin-CSNK2B axis to promote GC progression and provide new candidate targets against this disease.

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LncRNA LINC00342 promotes gastric cancer progression by targeting the miR-545-5p/CNPY2 axis

BMC Cancer ◽

10.1186/s12885-021-08829-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Run Liu ◽

Xianwu Yang

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Cell Counting ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Growth Factor Signaling ◽

Ags Cells

Abstract Background This study aimed to explore the role and underlying molecular mechanisms of long non-coding RNA (lncRNA) LINC00342 in gastric cancer (GC). Methods The expression of LINC00342 in GC tissues was evaluated by Quantitative reverse transcription polymerase chain reaction (qRT-PCR). Silencing of LINC00342 was conducted to investigate the effect of LINC00342 in vitro and in vivo. The underlying molecular mechanisms of LINC00342 were determined by dual luciferase reporter assay, Western blotting analysis and rescue experiments. Biological functions of LINC00342 were evaluated by cell counting kit-8 (CCK-8) assay, colony formation assay, wound healing assay and Transwell assays. In addition, a tumor model was used to verify the effect of LINC00342 in tumorigenesis in vivo. Results LINC00342 was significantly upregulated in GC tissues and cell lines. Silencing of LINC00342 efficiently inhibited proliferation, migration and invasion of AGS cells in vitro, and also suppressed the tumorigenesis of GC in vivo. Functional experiments showed that LINC00342 regulated the expression of canopy fibroblast growth factor signaling regulator 2 (CNPY2) by competitively sponging miR-545-5p. Rescue experiments showed that inhibition of miR-545-5p and overexpression of CNPY2 significantly reversed cell phenotypes caused by silencing of LINC00342. Conclusion LINC00342 plays a potential oncogenic role in GC by targeting the miR545-5p/CNPY2 axis, and might act as a novel therapeutic target for GC.

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NUSAP1 Promotes Gastric Cancer Tumorigenesis and Progression by Stabilizing the YAP1 Protein

Frontiers in Oncology ◽

10.3389/fonc.2020.591698 ◽

2021 ◽

Vol 10 ◽

Author(s):

Hui Guo ◽

Jianping Zou ◽

Ling Zhou ◽

Min Zhong ◽

Yan He ◽

...

Keyword(s):

Gastric Cancer ◽

Target Genes ◽

Hippo Pathway ◽

Therapeutic Targets ◽

Xenograft Model ◽

Migration And Invasion ◽

Aberrant Expression ◽

Downstream Target ◽

Tumorigenesis And Progression

The Yes-associated protein (YAP1) is a main effector of the canonical Hippo pathway, which contributes greatly to tumor initiation, progression, and metastasis in multiple cancers, including gastric cancer (GC). Due to limited knowledge of YAP1 upregulation in cancer, it is a great challenge of therapeutic targets toward the Hippo–YAP1 pathway. Here, we identify nucleolar spindle-associated protein 1 (NUSAP1) as a novel binding partner of YAP1. The upregulation of NUSAP1 is associated with unfavorable clinical outcomes in GC patients, and NUSAP1 depletion impairs its oncogenic properties in vitro and in a xenograft model. Mechanistically, we discovered that NUSAP1 functions as a positive regulator of YAP1 protein stability, thereby inducing the transcription of Hippo pathway downstream target genes, such as CTGF and CYR61. More interestingly, we find that the cancer-promoting effects of NUSAP1 on GC cell growth, migration, and invasion are mainly mediated by YAP1. Furthermore, aberrant expression of NUSAP1 and YAP1 is highly correlated in GC cell lines and tissues. We herein clarify the role of the oncogenic NUSAP1–YAP1 axis in GC tumorigenesis and progression and, therefore, provide novel therapeutic targets for GC treatment.

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