Legumain Promotes Gastric Cancer Progression Through Tumor-associated Macrophages In vitro and In vivo

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.

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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 ◽

Gastric Cancer Progression

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.

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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 ◽

Gastric Cancer Progression

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.

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N6-methyladenosine-dependent pri-miR-17-92 maturation suppresses PTEN/TMEM127 and promotes sensitivity to everolimus in gastric cancer

Cell Death and Disease ◽

10.1038/s41419-020-03049-w ◽

2020 ◽

Vol 11 (10) ◽

Author(s):

Yiting Sun ◽

Song Li ◽

Wenbin Yu ◽

Zeyi Zhao ◽

Jing Gao ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Rna Modification ◽

Non Coding Rna ◽

Low Levels ◽

Poor Outcomes ◽

Gastric Cancer Progression ◽

Dependent Mechanism

Abstract N6-methyladenosine (m6A) is the most common epigenetic RNA modification with essential roles in cancer progression. However, roles of m6A and its regulator METTL3 on non-coding RNA in gastric cancer are unknown. In this study, we found elevated levels of m6A and METTL3 in gastric cancer. Increased METTL3 expression indicated poor outcomes of patients and high malignancy in vitro and in vivo. Mechanically, m6A facilitated processing of pri-miR-17-92 into the miR-17-92 cluster through an m6A/DGCR8-dependent mechanism. The m6A modification that mediated this process occurred on the A879 locus of pri-miR-17-92. The miR-17-92 cluster activated the AKT/mTOR pathway by targeting PTEN or TMEM127. Compared with those with low levels of METTL3, METTL3-high tumors showed preferred sensitivity to an mTOR inhibitor, everolimus. These results reveal a perspective on epigenetic regulations of non-coding RNA in gastric cancer progression and provide a theoretical rationale for use of everolimus in the treatment of m6A/METTL3-high gastric cancer.

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Circ-HuR suppresses HuR expression and gastric cancer progression by inhibiting CNBP transactivation

Molecular Cancer ◽

10.1186/s12943-019-1094-z ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 21

Author(s):

Feng Yang ◽

Anpei Hu ◽

Dan Li ◽

Jianqun Wang ◽

Yanhua Guo ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Real Time ◽

Cancer Progression ◽

Rt Pcr ◽

Invasion And Metastasis ◽

Gastric Cancer Cells ◽

Gastric Cancer Progression

Abstract Background Circular RNAs (circRNAs), a subclass of non-coding RNAs, play essential roles in tumorigenesis and aggressiveness. Our previous study has identified that circAGO2 drives gastric cancer progression through activating human antigen R (HuR), a protein stabilizing AU-rich element-containing mRNAs. However, the functions and underlying mechanisms of circRNAs derived from HuR in gastric cancer progression remain elusive. Methods CircRNAs derived from HuR were detected by real-time quantitative RT-PCR and validated by Sanger sequencing. Biotin-labeled RNA pull-down, mass spectrometry, RNA immunoprecipitation, RNA electrophoretic mobility shift, and in vitro binding assays were applied to identify proteins interacting with circRNA. Gene expression regulation was observed by chromatin immunoprecipitation, dual-luciferase assay, real-time quantitative RT-PCR, and western blot assays. Gain- and loss-of-function studies were performed to observe the impacts of circRNA and its protein partner on the growth, invasion, and metastasis of gastric cancer cells in vitro and in vivo. Results Circ-HuR (hsa_circ_0049027) was predominantly detected in the nucleus, and was down-regulated in gastric cancer tissues and cell lines. Ectopic expression of circ-HuR suppressed the growth, invasion, and metastasis of gastric cancer cells in vitro and in vivo. Mechanistically, circ-HuR interacted with CCHC-type zinc finger nucleic acid binding protein (CNBP), and subsequently restrained its binding to HuR promoter, resulting in down-regulation of HuR and repression of tumor progression. Conclusions Circ-HuR serves as a tumor suppressor to inhibit CNBP-facilitated HuR expression and gastric cancer progression, indicating a potential therapeutic target for gastric cancer.

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Onco-miR-21 Promotes Stat3-Dependent Gastric Cancer Progression

Cancers ◽

10.3390/cancers14020264 ◽

2022 ◽

Vol 14 (2) ◽

pp. 264

Author(s):

Janson Tse ◽

Thomas Pierce ◽

Annalisa L. E. Carli ◽

Mariah G. Alorro ◽

Stefan Thiem ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Functional Restoration ◽

Matrix Remodeling ◽

Mesenchymal Transition ◽

Therapeutic Benefits ◽

Solid Malignancies ◽

Gastric Cancer Progression

MicroRNA-21 (miR-21) is a small, non-coding RNA overexpressed in gastric cancer and many other solid malignancies, where it exhibits both pro-and anti-tumourigenic properties. However, the pathways regulating miR-21 and the consequences of its inhibition in gastric cancer remain incompletely understood. By exploiting the spontaneous Stat3-dependent formation of inflammation-associated gastric tumors in Gp130F/F mice, we functionally established miR-21 as a Stat3-controlled driver of tumor growth and progression. We reconciled our discoveries by identifying several conserved Stat3 binding motifs upstream of the miR-21 gene promoter, and showed that the systemic administration of a miR-21-specific antisense oligonucleotide antagomir reduced the established gastric tumor burden in Gp130F/F mice. We molecularly delineated the therapeutic benefits of miR-21 inhibition with the functional restoration of PTEN in vitro and in vivo, alongside an attenuated epithelial-to-mesenchymal transition and the extracellular matrix remodeling phenotype of tumors. We corroborated our preclinical findings by correlating high STAT3 and miR-21 expression with the reduced survival probability of gastric cancer patients. Collectively, our results provide a molecular framework by which miR-21 mediates inflammation-associated gastric cancer progression, and establish miR-21 as a robust therapeutic target for solid malignancies characterized by excessive Stat3 activity.

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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 ◽

Gastric Cancer Progression ◽

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.

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

10.21203/rs.3.rs-136419/v1 ◽

2020 ◽

Author(s):

Feng Qu ◽

Bin Zhu ◽

Yi-Lin Hu ◽

Qin-Sheng Mao ◽

Ying Feng

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Lymph Node Status ◽

Non Coding Rnas ◽

Novel Target ◽

Gastric Cancer Progression ◽

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.

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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 ◽

Gastric Cancer Progression ◽

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.

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