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

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.

Download Full-text

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.

Download Full-text

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 ◽

Gastric Cancer Progression

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.

Download Full-text

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.

Download Full-text

Long Noncoding RNA LPP-AS2 Promotes Glioma Tumorigenesis via miR-7-5p/EGFR/PI3K/AKT/c-MYC Feedback Loop

10.21203/rs.3.rs-37734/v1 ◽

2020 ◽

Author(s):

Xiaoming Zhang ◽

Wanxiang Niu ◽

Maolin Mu ◽

Shanshan Hu ◽

Chaoshi Niu

Keyword(s):

Cancer Progression ◽

High Throughput ◽

Noncoding Rna ◽

Feedback Loop ◽

Luciferase Reporter ◽

Normal Brain ◽

Clinical Prognosis ◽

Egfr Expression

Abstract Background: Glioma is the most common primary malignant intracranial tumor with poorly clinical prognosis in adults. Accumulating evidences indicate that long non-coding RNAs (lncRNAs) have served as important regulators in cancer progression, including glioma. Here, we identified a new lncRNA LPP antisense RNA-2 (LPP-AS2) and investigated its function and mechanism in the occurrence and development of glioma.Methods: High-throughput RNA sequencing was performed to discriminate the differentially expression lncRNAs and mRNAs between glioma tissues and normal brain tissues. The expression of LPP-AS2, epidermal growth factor receptor (EGFR) and miR-7-5p in glioma tissues and cell lines were detected by real-time quantitative PCR (RT-qPCR). The functions of lncRNA LPP-AS2 in glioma were measured by in vivo and in vitro assays. Insights of the underlying mechanism of competitive endogenous RNAs (ceRNAs) were originated from bioinformatic analysis, dual luciferase reporter assays, RNA pulldown assays, RNA immunoprecipitation (RIP) and rescue experiments. Results: The results of high-throughput RNA-seq indicated that lncRNA LPP-AS2 was upregulated in glioma tissues and further confirmed by RT-qPCR. Higher LPP-AS2 expression was related to poor prognosis of glioma patients. Functional studies illustrated that LPP-AS2 depletion inhibited glioma cell proliferation, invasion and promoted apoptosis in vitro and restrained tumor growth in vivo, whereas overexpression of LPP-AS2 resulted in opposite effects. In addition, LPP-AS2 and EGFR were observed of co-expression networks, and LPP-AS2 functioned as a ceRNA to regulate EGFR expression by sponging miR-7-5p in glioma cells. Result of chromatin immunoprecipitation (ChIP) assay validated that c-MYC was directly bind with promoter region of LPP-AS2. As a downstream protein of EGFR, c-MYC was modulated by LPP-AS2 and in turn increased LPP-AS2 expression. Thus, lncRNA LPP-AS2 promoted glioma tumorigenesis via a miR-7-5p/EGFR/PI3K/AKT/c-MYC feedback loop. Conclusions: Our study elucidated that LPP-AS2 acted as an oncogene through a novel molecular pathway in glioma and might be a potential therapeutic approach for glioma diagnosis, therapy and prognosis.

Download Full-text

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.

Download Full-text

Exosomal miR-122-5p inhibits tumorigenicity of gastric cancer by downregulating GIT1

The International Journal of Biological Markers ◽

10.1177/1724600821990677 ◽

2021 ◽

Vol 36 (1) ◽

pp. 36-46

Author(s):

Yigang Jiao ◽

Li Zhang ◽

Jun Li ◽

Yuqi He ◽

Xin Zhang ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Gastric Cancer Cell ◽

Cancer Cell Proliferation ◽

Proliferation And Metastasis ◽

Gastric Cancer Cell Proliferation ◽

Gastric Cancer Progression ◽

Cell Proliferation And Metastasis

Background: microRNAs (miRNAs) are non-coding RNAs with important roles in the progression of human cancers, including gastric cancer. Exosomes are extracellular vesicles, which could transfer numerous noncoding RNAs, such as miRNAs. Here, in our study, we intended to investigate the role of exosomal miR-122-5p in gastric cancer progression. Methods: Exosomes were isolated utilizing commercial kit or ultracentrifugation. Biomarkers of exosomes or epithelia-mesenchymal transition (EMT) were monitored by western blot. Expression levels of miR-122-5p and G-protein-coupled receptor kinase interacting protein-1 ( GIT1) were evaluated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) or western blot. Cell proliferation and apoptosis were assessed by colony formation assay, methyl thiazolyl tetrazolium assay and flow cytometry. Cell metastasis was evaluated via Transwell assay. The interaction between miR-122-5p and GIT1 was validated by dual-luciferase reporter assay. Furthermore, tumor growth in vivo was detected by xenograft assay. Results: Exosomes were successfully isolated. MiR-122-5p was downregulated in exosomes derived from the serum of gastric cancer patients. Exosomal miR-122-5p could hinder gastric cancer cell proliferation and metastasis in vitro and tumor growth in vivo. Knockdown of GIT1 also inhibited gastric cancer cell proliferation and metastasis. Exosomal miR-122-5p targeted GIT1 to alter cellular behaviors of gastric cancer cells. Conclusion: Exosomal miR-122-5p suppressed gastric cancer progression by targeting GIT1.

Download Full-text

Decreased expression of ATF3, orchestrated by β-catenin/TCF3, miR-17-5p and HOXA11-AS, promoted gastric cancer progression via increased β-catenin and CEMIP

Experimental & Molecular Medicine ◽

10.1038/s12276-021-00694-9 ◽

2021 ◽

Author(s):

Guohua Xie ◽

Ping Dong ◽

Hui Chen ◽

Ling Xu ◽

Yi Liu ◽

...

Keyword(s):

Gastric Cancer ◽

Wnt Signaling ◽

Cancer Progression ◽

Noncoding Rna ◽

High Throughput Sequencing ◽

Wnt Signaling Pathway ◽

Focal Adhesions ◽

Cell Growth And Migration

AbstractATF3 has been reported to be dysregulated in various cancers and involved in various steps of tumorigenesis. However, the mechanisms underlying the abnormal expression of ATF3 and its biological function in gastric cancer (GC) have not been well investigated. Here, we report ATF3 as one of the key regulators of GC development and progression. Patients with low ATF3 expression had shorter survival and a poorer prognosis. In vitro and in vivo assays investigating ATF3 alterations revealed a complex integrated phenotype that affects cell growth and migration. Strikingly, high-throughput sequencing and microarray analysis of cells with ATF3 silencing or of ATF3-low GC tissues indicated alterations in the Wnt signaling pathway, focal adhesions and adherens junctions. Mechanistically, the expression of β-catenin and cell migration inducing hyaluronidase 1 (CEMIP) was significantly upregulated in GC cells with downregulated ATF3, which was synergistically repressed by the β-catenin/TCF3 signaling axis and noncoding RNA miR-17-5p and HOXA11-AS. In addition, we found that WDR5 expression was promoted by TCF3 and is involved in miR-17-5p and HOXA11-AS activation in GC cells. Taken together, our findings revealed the mechanism of ATF3 downregulation and its biological role in regulating the expression of Wnt signaling-related genes during GC progression, suggesting new informative biomarkers of malignancy and therapeutic directions for GC patients.

Download Full-text

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.

Download Full-text

The LINC00922 aggravates ovarian cancer progression via sponging miR-361-3p

Journal of Ovarian Research ◽

10.1186/s13048-021-00828-7 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Liping Wang ◽

Chenchen Ren ◽

Yajuan Xu ◽

Li Yang ◽

Yannan Chen ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Noncoding Rna ◽

Luciferase Reporter ◽

Comprehensive Strategy ◽

Repressive Effect ◽

Underlying Mechanisms

Abstract Background Long noncoding RNA (lncRNA) LINC00922 has been reported to promote tumorigenesis of lung and breast cancer. However, the functions and mechanisms of LINC00922 in ovarian cancer (OC) remain unclarified. The current study aims to clarify the detailed functions and underlying mechanisms of LINC00922 in the progression of OC. Methods LINC00922 expression in OC tissues and cells was identified by a comprehensive strategy of data miming, computational biology and quantitative real-time polymerase chain reaction (RT-qPCR) experiment. In vitro CCK-8, wound healing, transwell invasion, western blotting and in vivo tumorigenesis assays LINC00922 were conducted to evaluate the functions of LINC00992. Subsequently, bioinformatics technology and dual luciferase reporter assay were performed to confirm the between miR-361-3p and LINC00922 or CLDN1. Finally, rescue experiments were performed to confirm whether LINC00922 effect functions of OC cells through regulation of miR-361-3p. Results LINC00922 was significantly upregulated in OC tissues and cell lines, which is significantly positively corelated with the poor prognosis of patients with OC. LINC00922 knockdown inhibited proliferation and tumorigenesis of OC cells in vitro and vivo. In addition, LINC00922 knockdown suppressed migration, invasion, and EMT of OC cells in vitro. Mechanically, LINC00922 could competitively bind with miR-361-3p to relieve the repressive effect of miR-361-3p on its target gene CLDN1 in OC cells. In addition, silencing miR-361-3p promoted OC cell proliferation, migration, invasion, EMT and Wnt/β-catenin signaling, while LINC00922 knockdown inhibited Wnt/β-catenin signaling by upregulating miR-361-3p. Rescue experiments revealed that LINC00922 knockdown inhibited OC cell proliferation, migration, invasion and EMT by regulating miR-361-3p. Conclusion This study suggested that LINC00922 could competitively bind with miR-361-3p to promote the CLDN1 expression and activate Wnt/β-catenin signaling in OC progression, which providing a promising therapeutically target for OC.

Download Full-text

Long noncoding RNA LPP-AS2 promotes glioma tumorigenesis via miR-7-5p/EGFR/PI3K/AKT/c-MYC feedback loop

10.21203/rs.3.rs-37734/v2 ◽

2020 ◽

Author(s):

Xiaoming Zhang ◽

Wanxiang Niu ◽

Maolin Mu ◽

Shanshan Hu ◽

Chaoshi Niu

Keyword(s):

Cancer Progression ◽

High Throughput ◽

Noncoding Rna ◽

Feedback Loop ◽

Luciferase Reporter ◽

Normal Brain ◽

Clinical Prognosis ◽

Egfr Expression

Abstract Background: Glioblastoma is the most common primary malignant intracranial tumor with poor clinical prognosis in adults. Accumulating evidence indicates that long non-coding RNAs (lncRNAs) function as important regulators in cancer progression, including glioblastoma. Here, we identified a new lncRNA LPP antisense RNA-2 (LPP-AS2) and investigated its function and mechanism in the development of glioma.Methods: High-throughput RNA sequencing was performed to discriminate differentially expressed lncRNAs and mRNAs between glioma tissues and normal brain tissues. Expression of LPP-AS2, epidermal growth factor receptor (EGFR) and miR-7-5p in glioma tissues and cell lines was detected by real-time quantitative PCR (RT-qPCR), and the functions of lncRNA LPP-AS2 in glioma were assessed by in vivo and in vitro assays. Insight into the underlying mechanism of competitive endogenous RNAs (ceRNAs) was obtained via bioinformatic analysis, dual luciferase reporter assays, RNA pulldown assays, RNA immunoprecipitation (RIP) and rescue experiments. Results: The results of high-throughput RNA-seq indicated lncRNA LPP-AS2 was upregulated in glioma tissues and further confirmed by RT-qPCR. Higher LPP-AS2 expression was related to a poor prognosis in glioma patients. Based on functional studies, LPP-AS2 depletion inhibited glioma cell proliferation, invasion and promoted apoptosis in vitro and restrained tumor growth in vivo, overexpression of LPP-AS2 resulted in the opposite effects. In addition, LPP-AS2 and EGFR were observed in co-expression networks. LPP-AS2 was found to function as a ceRNA to regulate EGFR expression by sponging miR-7-5p in glioma cells. The result of chromatin immunoprecipitation (ChIP) assays validated that c-MYC binds directly to the promoter region of LPP-AS2. As a downstream protein of EGFR, c-MYC was modulated by LPP-AS2 and in turn enhanced LPP-AS2 expression. Thus, lncRNA LPP-AS2 promoted glioma tumorigenesis via a miR-7-5p/EGFR/PI3K/AKT/c-MYC feedback loop.Conclusions: Our study elucidated that LPP-AS2 acted as an oncogene through a novel molecular pathway in glioma and might be a potential therapeutic approach for glioma diagnosis, therapy and prognosis.

Download Full-text