The miR-3648/FRAT1-FRAT2/c-Myc feedback loop modulates the metastasis and invasion of gastric cancer cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE204669 | GEO | 2025/05/20
REPOSITORIES: GEO
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Project description:Although the abnormal expression of miRNAs in cancer cells is a widely accepted phenomenon, the molecular mechanisms underlying miR-3648 progression and metastasis in gastric cancer (GC) remain unclear. miR-3648 expression is downregulated and its ectopic expression in GC cells significantly suppressed cell proliferation and metastasis. Mechanistic analyses indicated that miR-3648 directly targets FRAT1 or FRAT2 and inhibits FRAT1- or FRAT2-mediated invasion and motility in vitro and in vivo. Moreover, FRAT1 physically interacted with FRAT2. Furthermore, FRAT1 overexpression promoted GC cell invasion, whereas siRNA-mediated repression of FRAT2 in FRAT1-overexpressing GC cells reversed its invasive potential. Besides, miR-3648 inactivated the Wnt/β-catenin signalling pathway by downregulating FRAT1 and FRAT2 in GC. Interestingly, c-Myc, a downstream effector of Wnt/β-catenin signalling, was also downregulated by miR-3648 overexpression. In turn, c-Myc negatively regulated miR-3648 expression by binding to the miR-3648 promoter. In addition, miR-3648 expression levels were negatively correlated with c-Myc, FRAT1, and FRAT2 expression in fresh gastric samples. Our studies suggest that miR-3648 acts as a tumour-suppressive miRNA and that the miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop could be a critical regulator of GC progression.
| S-EPMC9586869 | biostudies-literature
Project description:BackgroundMetastasis remains the main cause of cancer-related death for gastric cancer (GC) patients, but the mechanisms are poorly understood. Using The Cancer Genome Atlas (TCGA) data base and bioinformatics analyses, we identified C12orf59 might act as a potential oncogenic protein in GC.MethodsWe investigate the expression pattern and clinical significance of C12orf59 in two independent cohorts of GC samples. In the training cohort, we used the X-tile program software to generate the optimal cutoff value for C12orf59 expression in order to classify patients accurately according to clinical outcome. In the validation cohort, this derived cutoff score was applied to exam the association of C12orf59 expression with survival outcome. A series of in vivo and in vitro assays were then performed to investigate the function of C12orf59 in GC.ResultsC12orf59 was significantly upregulated, and associated with poor survival outcome in two cohorts of GC samples. Gain- and loss of- function studies demonstrated C12orf59 promotes GC cell invasive and metastatic capacity both in vitro and in vivo, and induces epithelial-mesenchymal transition and angiogenesis. Mechanically, C12orf59 exerts oncogenic functions by up-regulating CDH11 expression via NF-κB signaling. Interesting, CDH11 could in turn promote NF-κB bind to C12orf59's promoter and form a positive feedback loop to sustain the metastatic ability of GC cells. Additionally, downregulation of miR-654-5p is another important mechanism for C12orf59 overexpression in GC.ConclusionOur finding suggested the newly identified C12orf59/NF-κB/CDH11 feedback loop may represent a new strategy for GC treatment.
| S-EPMC6463669 | biostudies-literature
Project description:The miR-3648/FRAT1-FRAT2/c-Myc feedback loop modulates the metastasis and invasion of gastric cancer cells
| PRJNA841874 | ENA
Project description:BackgroundMetastasis is the leading cause of mortality in patients with breast cancer (BC). Studies demonstrate that circular RNAs (circRNAs) were involved in BC progression, while the molecular mechanisms remain largely unclear.MethodsThe microArray circRNA profiles were used to explore the differential expression circRNAs in BC and paracancerous normal tissues, and the quantitative reverse transcription-polymerase chain reaction was used to validate their expression level in clinical samples and cell lines. Nuclear/cytosolic fractionation and fluorescence in situ hybridization (FISH) assays were performed to examine circRRM2 (hsa_circ_0052582) subcellular location. The scratch wound healing and transwell assays were conducted to evaluate the impact of circRRM2 on BC cell migration and invasion. We predicted miRNAs that might bind with cricRRM2 and the downstream target genes using bioinformatics analysis and explored their expression levels and prognostic value in BC. FISH, RNA immunoprecipitation, Co-immunoprecipitation, Western blot, and rescue experiments were implemented to figure out circRRM2 function and underlying mechanisms in BC.ResultsThe present study revealed several aberrant circRNAs in BC tissues and observed that circRRM2 was upregulated in tumor tissues of 40 patients with BC. High circRRM2 was significantly associated with advanced N stage in patients with BC. Gain- and loss- of function experiments revealed that circRRM2 promoted the migration and invasion of cells and functioned as an oncogene in BC. Mechanism studies showed that circRRM2 competed with miR-31-5p/miR-27b-3p to upregulate the IGF2BP1 expression. Furthermore, IGF2BP1 upregulated the circRRM2 level via interacting with MYC, which functioned as the transcriptional factor of circRRM2. Thus, the positive feedback loop that was composed of circRRM2/IGF2BP1/MYC was identified.ConclusionThis study confirms that upregulated circRRM2 functions an oncogenic role in BC metastasis. The positive feedback loop of circRRM2/IGF2BP1/MYC enforces the circRRM2 expression, which might offer a potential target for BC treatment.
| S-EPMC10039515 | biostudies-literature
Project description:Metastasis is a bottleneck in cancer treatment. Studies have shown the pivotal roles of long noncoding RNAs (lncRNAs) in regulating cancer metastasis; however, our understanding of lncRNAs in gastric cancer (GC) remains limited. RNA-seq was performed on metastasis-inclined GC tissues to uncover metastasis-associated lncRNAs, revealing upregulated small nucleolar RNA host gene 26 (SNHG26) expression, which predicted poor GC patient prognosis. Functional experiments revealed that SNHG26 promoted cellular epithelial-mesenchymal transition and proliferation in vitro and in vivo. Mechanistically, SNHG26 was found to interact with nucleolin (NCL), thereby modulating c-Myc expression by increasing its translation, and in turn promoting energy metabolism via hexokinase 2 (HK2), which facilitates GC malignancy. The increase in energy metabolism supplies sufficient energy to promote c-Myc translation and expression, forming a positive feedback loop. In addition, metabolic and translation inhibitors can block this loop, thus inhibiting cell proliferation and mobility, indicating potential therapeutic prospects in GC.
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Project description:To identify whether the expression of DDX5 was linked to circular RNAs splicing processes, we transfected AGS cell with FLAG-DDX5 or FLAG-tagged empty vector (negative control, NC), and analyzed the differentially expressed circRNAs
2023-04-26 | GSE207636 | GEO
Project description:Our previous study explored the roles of microRNA-424 (miR-424) in the development of endometrial carcinoma (EC) and analyzed the miR-424/E2F7 axis in EC cell growth. In this study, we investigated the status of miR-424 in human endometrial cancer tissues, which were collected from a cohort of Zunyi patients. We found that the expression level of miR-424 was associated with clinical tumor stage, cell differentiation, lymph node metastasis and cell migration ability. Cell function experiments demonstrated that miR-424 overexpression suppressed the invasion and migration abilities of endometrial carcinoma cells in vitro. Bioinformatic predictions and dual-luciferase reporter assays suggested E2F6 as a possible target of miR-424. RT-PCR and western blot assays demonstrated that miR-424 transfection reduced the expression level of E2F6, while inhibiting miR-424 with ASO-miR-424 (antisense oligonucleotides of miR-424) increased the expression level of E2F6. Cell function experiments indicated that E2F6 transfection rescued the EC cell phenotype induced by miR-424. In addition, we also found that E2F6 negatively regulated miR-424 expression in EC cells. In summary, our results demonstrated that the miR-424/E2F6 feedback loop modulates cell invasion, migration and EMT in EC and that the miR-424/E2Fs regulation network may serve as a new and potentially important therapeutic target in EC.
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Project description:Laryngeal cancer is one of the most common head and neck malignant tumors and is commonly resistant to X-ray-based radiotherapy. NF-κB interacting lncRNA (NKILA) has been reported to serve as a tumor suppressor in several cancers through combining with NF-κB: IκB complex thereby inhibiting NF-κB activation. Herein, we demonstrated a low NKILA expression in laryngeal cancer and its correlation with shorter overall survival in patients with laryngeal cancer. NKILA serves as a tumor suppressor in laryngeal cancer by suppressing laryngeal cancer cell viability and migration, whereas promoting cell apoptosis; NKILA knockdown reverses the cytotoxicity of X-ray radiation on laryngeal cancer cells through combining with NF-κB: IκB complex to inhibit IκB phosphorylation, inhibit p65 nuclear translocation, and finally inhibit NF-κB activation. NF-κB binds to the promoter region of NKILA to activate its transcriptional activity, upregulated NKILA then inhibits IκB phosphorylation and NF-κB activation, thus forming a negative feedback loop to sensitize laryngeal cancer cell to X-ray radiation. In conclusion, NKILA can serve as a promising agent of enhancing the cytotoxicity of X-ray radiation on laryngeal cancer and addressing the radioresistance of laryngeal cancer.
| S-EPMC5943486 | biostudies-literature
Project description:DC-SIGN is previously focused on its physiologic and pathophysiologic roles in immune cells. Little is known about whether DC-SIGN is expressed in malignant epithelial cells and how DC-SIGN participates in tumor progression. Here we showed that DC-SIGN expression was increased in metastatic colorectal cancer (CRC) cell lines and patient tissues. The overall survival in CRC patients with positive DC-SIGN was remarkably reduced. Gain of DC-SIGN function facilitated the CRC metastases both in vitro and in vivo, and this effect was reversed by miR-185. DC-SIGN and Lyn interacted physically, and Lyn maintained the stability of DC-SIGN in cells. DC-SIGN activation recruited Lyn and p85 to form the DC-SIGN-Lyn-p85 complex, which promoted CRC metastasis by increasing PI3K/Akt/β-catenin signaling in tyrosine kinase Lyn-dependent manner. Furthermore, activation of DC-SIGN promoted the transcription of MMP-9 and VEGF by increasing PI3K/Akt/β-catenin signaling, and induced TCF1/LEF1-mediated suppression of miR-185. Our findings reveal the presence of the DC-SIGN-TCF1/LEF1-miR-185 loop in cancer cells with metastatic traits, implying that it may represent a new pathogenic mechanism of CRC metastasis. This character of the loop promises to provide new targets for blocking CRC invasive and metastatic activity.
| S-EPMC7205996 | biostudies-literature
Project description:BackgroundGastric cancer (GC) is one of the most prevalent and deadly malignancies worldwide. Accumulating reports have indicated the participation of long non-coding RNAs (lncRNAs) in the onset and progression of GC.MethodsGSE109476 data was utilized to screen out lncRNAs dysregulated in GC. Gene expressions were determined by qRT-PCR and western blot. Both in vitro and in vivo experiments were carried out to assess the function of HOXC-AS1 in GC. The association between genes was verified via RIP, ChIP, CoIP, RNA pull down and luciferase reporter assays, as appropriate.ResultsHOXC-AS1 was discovered to be upregulated in GC and located both in cytoplasm and in nucleus in GC cells. Functionally, inhibition of HOXC-AS1 restrained GC cell growth and metastasis both in vitro and in vivo. Moreover, HOXC-AS1 was proved to be trans-activated by c-MYC in GC. In return, HOXC-AS1 positively regulated MYC expression in GC through targeting miR-590-3p/MYC axis in cytoplasm and modulating BRG1/β-catenin complex-activated MYC transcription in nucleus. Furthermore, the rescue assays verified that MYC mediated HOXC-AS1-affected GC progression.ConclusionOur research illustrated a feedback loop of HOXC-AS1-MYC in aggravating GC cell growth and metastasis, highlighting HOXC-AS1 as a promising target for GC diagnosis and treatment.
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