LncRNA HOXA-AS3 Promotes Gastric Cancer Progression by Regulating miR-29a-3p/LTβR and Activating NF-κB Signaling

Proliferation And Invasion

Abstract Background: Gastric cancer (GC) is among the most common and deadliest cancers globally. While many long non-coding RNAs (lncRNAs) are key regulators of GC pathogenesis, the role of HOXA-AS3 in this oncogenic context remains to be defined. Methods: Levels of HOXA-AS3 expression in GC were quantified, after which the functional role of this lncRNA in vitro and in vivo was assessed via HOXA-AS3 knockdown. The localization of HOXA-AS3 within cells was also confirmed, and predicted microRNA (miRNA) targets of this lncRNA and its ability to modulate downstream NF-κB signaling in GC cells were evaluated.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 migration, proliferation, 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.

ELK4-mediated lncRNA SNHG22 promotes gastric cancer progression through interacting with EZH2 and regulating miR-200c-3p/Notch1 axis

10.21203/rs.3.rs-494915/v1 ◽

2021 ◽

Author(s):

Xiaqiong Mao ◽

Tao Ji ◽

Aiguo Liu ◽

Yunqi Weng

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Tumor Suppressor Genes ◽

Luciferase Reporter ◽

Diagnosis And Prognosis ◽

Reporter Assays ◽

Non Coding Rnas ◽

Proliferation And Invasion

Abstract Background Long non-coding RNAs (lncRNAs) play important regulatory roles in the initiation and progression of various cancers. However, the biological roles and the potential mechanisms of lncRNAs in gastric cancers remain unclear. Methods The expression of SNHG22 in gastric cancer was analyzed in public databases (TCGA) and validated via qRT-PCR. SNHG22 knockdown cell lines were construced, and cell proliferation and invasion were analyzed. CHIP and luciferase reporter assays were performed to clarify the transcriptional role of ELK4. RNA pull-down followed MS and RIP assays were employed to identify the interaction between SNHG22 and EZH2. Luciferase reporter assays and RIP assays were used to confirm the regulation of SNHG22 on Notch1 by sponging miR-2003-3p. Results Knockdown of SNHG22 inhibited the proliferation and invasion ability of GC cells. Moreover, we identified that the transcriptional factor, ELK4, could promote SNHG22 expression in GC cells. In addition, using RNA pull-down followed MS assay, we found that SNHG22 directly bound to EZH2 to suppress the expression of tumor suppressor genes. At the same time, SNHG22 sponged miR-200c-3p to increase Notch1 expression. Conclusions Taken together, our findings demonstrated the role of SNHG22 on promoting proliferation and invasion of GC cells. And we revealed a new regulatory mechanism of SNHG22 in GC cells. SNHG22 is a promising lncRNA biomarker for diagnosis and prognosis and a potential target for GC treatment.

MiR-124-3p/ZC3H15 Regulates Gastric Cancer Progression by Blocking FBXW7 Mediated Degradation of c-Myc

10.21203/rs.3.rs-48782/v1 ◽

2020 ◽

Author(s):

Jianbing Hou ◽

Yudong Liu ◽

Du Yan ◽

Pan Huang ◽

Zhongze Wang ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Biological Role ◽

Potential Biomarker ◽

Proliferation And Metastasis ◽

Cell Proliferation And Metastasis

Abstract BACKGROUND: Zinc finger CCCH-type containing 15 (ZC3H15), a highly conserved eukaryotic protein, was involved in tumorigenesis and may be a potential biomarker in hepatocellular carcinoma (HCC) and acute myeloid leukemia (AML). However, the biological role of ZC3H15 in gastric cancer (GC) is unclear.METHODS: The potential correlation between ZC3H15 expression and GC prognosis was assessed based on the patient data analysis. The biological role of ZC3H15 in regulating cell proliferation and metastasis was evaluated in vitro and in vivo. In addition, the potential mechanism of ZC3H15 was investigated. RESULTS: we found that ZC3H15 expression was positively correlated with GC progression, including cell growth, metastasis and cancerogenesis. Through further investigations, we found that ZC3H15 could modulate c-Myc protein stability via suppressing the transcription of FBXW7, which was mainly responsible for c-Myc degradation. In addition, we revealed that miR-124-3p, a tumor suppressor of GC, was negatively associated with ZC3H15. We revealed that miR-124-3p was a critical upstream modulator of ZC3H15 in GC.CONCLUSIONS: Taken together, our studies unearth the important roles of ZC3H15 in GC development and suggest that miR-124-3p/ZC3H15/c-Myc axis may be a potential target for the treatment of GC.

Targeting miR-148b-5p Inhibits Immunity Microenvironment and Gastric Cancer Progression

Frontiers in Immunology ◽

10.3389/fimmu.2021.590447 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuyu Zhang ◽

Wei Huo ◽

Lidi Sun ◽

Jie Wu ◽

Chengbin Zhang ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Immune Microenvironment ◽

Anti Cancer ◽

Direct Target ◽

Metabolic Properties ◽

Proliferation And Invasion

BackgroundMicroRNAs (miRNAs) have been discovered to dictate the development of various tumors. However, studies on the roles of miRNAs in the progression of gastric cancer (GC) are still lacking.MethodsHerein, by analyzing GC cell lines and patients samples, we observed that miR-148b-5p was significantly downregulated in GC. We also confirmed that miR-148b-5p overexpression significantly inhibited GC cell proliferation and invasion in vitro and in vivo.ResultsOverexpression of miR-148b-5p not only reprogrammed the metabolic properties of GC but also regulated the immune microenvironment by shifting lymphocyte and myeloid populations. Mechanistically, ATPIF1, an important glycolysis-associated gene, was identified as a direct target of miR-148b-5p and mediated the effect of miR-148b-5p. Notably, the low level of miR-148b-5p was significantly related with poor prognosis of GC patients (P < 0.001). Importantly, the levels of miR-148b-5p significantly changed the sensitivity of GC cells to several anti-cancer drugs (Doxorubicin, P < 0.05, Paclitaxel, P < 0.01, Docetaxel, P < 0.05).ConclusionsTargeting miR-148b-5p inhibits immunity microenvironment and gastric cancer progression.

Revealing the Role of lncRNA CCDC144NL-AS1 and LINC01614 in Gastric Cancer via Integrative Bioinformatics Analysis and Experimental Validation

Frontiers in Oncology ◽

10.3389/fonc.2021.769563 ◽

2022 ◽

Vol 11 ◽

Author(s):

Weiwei Sheng ◽

Weihong Zhou ◽

Yundi Cao ◽

Yuejiao Zhong

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Gastric Cancer Cells ◽

Non Coding Rnas ◽

Cellular Pathways ◽

And Migration ◽

Long non-coding RNAs (lncRNAs) are key regulators in the pathophysiology of gastric cancer, and lncRNAs have been regarded as potential biomarkers and therapeutic targets for gastric cancer. The present study performed the WGCNA analysis of the GSE70880 dataset and aimed to identify novel lncRNAs associated with gastric cancer progression. Based on the WGCNA, the lncRNAs and mRNA co-expression network were constructed. A total of four modules were identified and the eigengenes in different modules were involved in various key signaling pathways. Furthermore, the co-expression networks were constructed between the lncRNAs and mRNA; this leads to the identification of 6 modules, which participated in various cellular pathways. The survival analysis showed that high expression of CCDC144NL antisense RNA 1 (CCDC144NL-AS1) and LINC01614 was positively correlated with the poor prognosis of patients with gastric cancer. The in vitro validation results showed that CCDC144NL-AS1 and LINC01614 were both up-regulated in the gastric cancer cells. Silence of CCDC144NL-AS1 and LINC01614 both significantly suppressed the cell proliferation and migration of gastric cancer cells, and also promoted the chemosensitivity of gastric cancer cells to 5-fluorouracil. Collectively, our results suggested that the newly identified two lncRNAs (CCDC144NL-AS1 and LINC01614) may act as oncogenes in gastric cancer.

KLF5 activates lncRNA DANCR and inhibits cancer cell autophagy accelerating gastric cancer progression

npj Genomic Medicine ◽

10.1038/s41525-021-00207-7 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Zhiyi Cheng ◽

Guiyuan Liu ◽

Chuanjiang Huang ◽

Xiaojun Zhao

Keyword(s):

Gastric Cancer ◽

Cancer Cell ◽

Cancer Progression ◽

Growth Regulation ◽

Bioinformatics Analysis ◽

Potential Therapeutic Target ◽

AbstractCancer cell autophagy has been associated with the progression of gastric cancer (GC), but involvement of long noncoding RNAs (lncRNAs) remains unclear. Initial bioinformatics analysis has identified abnormally highly expressed KLF5 in GC, as well as the predicted regulatory mechanism associating with lncRNA DANCR, miR-194, and AKT2. The expression of KLF5, DANCR, and AKT2 in GC tissue was upregulated, and the expression of miR-194 was downregulated. We knocked KLF5 down and manipulated the expression of DANCR, miR-194, and AKT2 to characterize their roles in GC cell viability, autophagy, and apoptosis. The mechanistic investigations revealed that KLF5 activated the transcription of DANCR in the promoter region and elevated its expression. DANCR acted as a miR-194 sponge to repress its expression in GC. MiR-194 targeted and inhibited AKT2 expression. Silencing KLF5 augmented GC cell autophagy, apoptosis and impeded its viability through the DANCR/miR-194/AKT2 axis. The tumor-inhibiting properties of KLF5 knockdown were substantiated in vivo. Together, our study uncovered the oncogenic role of KLF5-dependent lncRNA DANCR transcription in GC in vivo and in vitro, which implicates the miR-194/AKT2 axis in tumor growth regulation, and it may be a potential therapeutic target for human GC.

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.

Mevalonate Pathway Enzyme HMGCS1 Contributes to Gastric Cancer Progression

Cancers ◽

10.3390/cancers12051088 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1088 ◽

Cited By ~ 2

Author(s):

I-Han Wang ◽

Tzu-Ting Huang ◽

Ji-Lin Chen ◽

Li-Wei Chu ◽

Yueh-Hsin Ping ◽

...

Keyword(s):

Gastric Cancer ◽

Endoplasmic Reticulum ◽

Cancer Cells ◽

Cancer Progression ◽

Nuclear Translocation ◽

Mevalonate Pathway ◽

Gastric Cancer Cells ◽

The 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) is a potential regulatory node in the mevalonate pathway that is frequently dysregulated in tumors. This study found that HMGCS1 expression is upregulated in stomach adenocarcinoma samples of patients and tumorspheres of gastric cancer cells. HMGCS1 elevates the expression levels of the pluripotency genes Oct4 and SOX-2 and contributes to tumorsphere formation ability in gastric cancer cells. HMGCS1 also promotes in vitro cell growth and progression and the in vivo tumor growth and lung metastasis of gastric cancer cells. After blocking the mevalonate pathway by statin and dipyridamole, HMGCS1 exerts nonmetabolic functions in enhancing gastric cancer progression. Furthermore, the level and nuclear translocation of HMGCS1 in gastric cancer cells are induced by serum deprivation. HMGCS1 binds to and activates Oct4 and SOX-2 promoters. HMGCS1 also enhances the integrated stress response (ISR) and interacts with the endoplasmic reticulum (ER) stress transducer protein kinase RNA-like endoplasmic reticulum kinase (PERK). Our results reveal that HMGCS1 contributes to gastric cancer progression in both metabolic and nonmetabolic manners.

miR-125b Suppresses Proliferation and Invasion by Targeting MCL1 in Gastric Cancer

BioMed Research International ◽

10.1155/2015/365273 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 19

Author(s):

Shihua Wu ◽

Feng Liu ◽

Liming Xie ◽

Yaling Peng ◽

Xiaoyuan Lv ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Clinical Stage ◽

Gastric Cancer Cells ◽

Understanding the molecular mechanisms underlying gastric cancer progression contributes to the development of novel targeted therapies. In this study, we found that the expression levels of miR-125b were strongly downregulated in gastric cancer and associated with clinical stage and the presence of lymph node metastases. Additionally, miR-125b could independently predict OS and DFS in gastric cancer. We further found that upregulation of miR-125b inhibited the proliferation and metastasis of gastric cancer cells in vitro and in vivo. miR-125b elicits these responses by directly targeting MCL1 (myeloid cell leukemia 1), which results in a marked reduction in MCL1 expression. Transfection of miR-125b sensitizes gastric cancer cells to 5-FU-induced apoptosis. By understanding the function and molecular mechanisms of miR-125b in gastric cancer, we may learn that miR-125b has the therapeutic potential to suppress gastric cancer progression and increase drug sensitivity to gastric cancer.

Long Noncoding RNA EGFR-AS1 Promotes Cell Proliferation by Increasing EGFR mRNA Stability in Gastric Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000492883 ◽

2018 ◽

Vol 49 (1) ◽

pp. 322-334 ◽

Cited By ~ 15

Author(s):

Jiaojiao Hu ◽

Yingying Qian ◽

Lipan Peng ◽

Ling Ma ◽

Tianzhu Qiu ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Mrna Stability ◽

Noncoding Rna ◽

Synthesis Inhibitor ◽

Egfr Expression ◽

Background/Aims: LncRNA EGFR-AS1 is an antisense transcript of EGFR, which plays a key role in gastric cancer progression. This study was aimed to explore the effects of lncRNA EGFR-AS1 on GC and the underling mechanisms. Methods: The silencing of EGFR-AS1 expression was performed by using EGFR-AS1 shRNA lentivirus in MGC803 and SGC-7901 GC cell. The levels of lncRNA EGFR-AS1 and EGFR were detected by qPCR and western blot. Cell proliferation was assessed by CCK-8, EdU, and colony formation assays. The EGFR mRNA stability was explored by using RNA synthesis inhibitor α-amanitin. Results: In our study, EGFR-AS1 significantly up-regulated in GC tissues and correlated with tumor size. And the expression of EGFR-AS1 positively correlated with EGFR in tissues. Moreover, knock-down of EGFR-AS1 inhibited the proliferation of GC cells via suppressing EGFR-dependent PI3K/AKT pathway in vitro and in vivo. Mechanismly, depletion of EGFR-AS1 was found to decrease EGFR expression by reduction of EGFR mRNA stability. Conclusion: Our findings suggested that EGFR-AS1 might have an oncogenic effect on GC and serve as a potential target of GC.

EDD1 predicts prognosis and regulates gastric cancer growth in vitro and in vivo via miR-22

Biological Chemistry ◽

10.1515/hsz-2015-0279 ◽

2016 ◽

Vol 0 (0) ◽

Author(s):

Min Yang ◽

Nan Jiang ◽

Qi-wei Cao ◽

Qing Sun

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Patient Survival ◽

Underlying Mechanism ◽

Gastric Cancer Cells ◽

Cancer Tissues

Abstract Gastric cancer is the most common digestive malignant tumor worldwild. EDD1 was reported to be frequently amplified in several tumors and played an important role in the tumorigenesis process. However, the biological role and potential mechanism of EDD1 in gastric cancer remains poorly understood. In this study, we are aim to investigate the effect of EDD1 on gastric cancer progression and to explore the underlying mechanism. The results showed the significant up-regulation of EDD1 in -gastric cancer cell tissues and lines. The expression level of EDD1 was also positively associated with advanced clinical stages and predicted poor overall patient survival and poor disease-free patient survival. Besides, EDD1 knockdown markedly inhibited cell viability, colony formation, and suppressed tumor growth. Opposite results were obtained in gastric cancer cells with EDD1 overexpression. EDD1 knockdown was also found to induce gastric cancer cells apoptosis. Further investigation indicated that the oncogenic role of EDD1 in regulating gastric cancer cells growth and apoptosis was related to its PABC domain and directly through targeting miR-22, which was significantly down-regulated in gastric cancer tissues. Totally, our study suggests that EDD1 plays an oncogenic role in gastric cancer and may be a potential therapeutic target for gastric cancer.