Long non-coding RNA AC122108.1 promotes lung adenocarcinoma brain metastasis and progression through the Wnt/β-catenin pathway by directly binding to aldolase A.
Ontology highlight
ABSTRACT: Background
Brain metastasis (BM) is a major pathological subtype of lung adenocarcinoma (LAD), but the pathogenic mechanisms of BM remain unclear. The potential prognostic biomarkers and therapeutic targets for BM of LAD urgently need to be identified. AC122108.1 is a recently discovered new long non-coding ribonucleic acid (RNA).Methods
AC122108 was found to be overexpressed in a LAD BM cell model, and upregulated in 64.52% of LAD BM tissues. AC122108 is an independent factor of BM during LAD development; however, the molecular mechanisms and clinical significance of AC122108.1 in LAD have not yet been established. Additionally, in vitro and in vivo experiments showed that the direct binding of AC122108.1 with aldolase A (ALDOA) enhanced the proliferation, apoptosis, invasiveness, migration, and metastasis of LAD cells.Results
This RNA-protein complex decreased the stability of the β-catenin destruction complex, leading to the accumulation of β-catenin in the cytoplasm and ultimately its translocation into the nucleus to activate Wnt(wingless/integrated)/β-catenin signaling.Conclusions
Overall, AC122108.1 promotes LAD BM and its progression through the Wnt/β-catenin pathway by directly binding to ALDOA. This study provides insights into the regulatory mechanism of the LAD BM. AC122108.1 may serve as a potential therapeutic target and prognostic biomarker of LAD.
SUBMITTER: Feng S
PROVIDER: S-EPMC8743723 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Caveolin-1 (CAV1) has significant roles in many primary tumors and metastasis, despite the fact that malignant cells from different cancer types have different profiles of CAV1 expression. There is little information concerning CAV1 expression and role in hepatocellular carcinoma (HCC) progresion and metastasis. The role of CAV1 in HCC progression was explored in this study. We reported that CAV1 was overexpressed in highly invasive HCC cell lines compared with poorly invasive ones. The immunohistochemical staining was obviously stronger in metastatic HCC samples than in the non-metastatic specimens via tissue microarrays. Furthermore, CAV1 overexpression enhanced HCC cell invasiveness in vitro, and promoted tumorigenicity and lung metastasis in vivo. By contrast, CAV1 stable knockdown markedly reduced these malignant behaviors. Importantly, we found that CAV1 could induce EMT process through Wnt/?-catenin pathway to promote HCC metastasis. We also identify MMP-7 as a novel downstream target of CAV1. We have determined that CAV1 acts as a mediator between hyperactive ERK1/2 signaling and regulation of MMP-7 transcription. Together, these studies mechanistically show a previously unrecognized interplay between CAV1, EMT, ERK1/2 and MMP-7 that is likely significant in the progression of HCC toward metastasis.
| S-EPMC4152279 | biostudies-literature
Project description:BackgroundGlioblastoma (GBM) is a deadly neoplasm of the central nervous system. The molecular mechanisms and players that contribute to GBM development is incompletely understood.MethodsThe expression of PELP1 in different grades of glioma and normal brain tissues was analyzed using immunohistochemistry on a tumor tissue array. PELP1 expression in established and primary GBM cell lines was analyzed by Western blotting. The effect of PELP1 knockdown was studied using cell proliferation, colony formation, migration, and invasion assays. Mechanistic studies were conducted using RNA-seq, RT-qPCR, immunoprecipitation, reporter gene assays, and signaling analysis. Mouse orthotopic models were used for preclinical evaluation of PELP1 knock down.ResultsNuclear receptor coregulator PELP1 is highly expressed in gliomas compared to normal brain tissues, with the highest expression in GBM. PELP1 expression was elevated in established and patient-derived GBM cell lines compared to normal astrocytes. Knockdown of PELP1 resulted in a significant decrease in cell viability, survival, migration, and invasion. Global RNA-sequencing studies demonstrated that PELP1 knockdown significantly reduced the expression of genes involved in the Wnt/β-catenin pathway. Mechanistic studies demonstrated that PELP1 interacts with and functions as a coactivator of β-catenin. Knockdown of PELP1 resulted in a significant increase in survival of mice implanted with U87 and GBM PDX models.ConclusionsPELP1 expression is upregulated in GBM and PELP1 signaling via β-catenin axis contributes to GBM progression. Thus, PELP1 could be a potential target for the development of therapeutic intervention in GBM.
| S-EPMC7147719 | biostudies-literature
Project description:The long non-coding RNA (lncRNA), RP11-480I12.5 is one of the most dysregulated lncRNAs, which is believed to contribute to the progression of cervical carcinoma (CC); however, the exact function of RP11-480I12.5 in human CC remains unknown. The present study aimed to investigate the function and underlying molecular mechanism of RP11-480I12.5 in CC. First, reverse transcription-quantitative PCR was implemented in order to detect differences in the expression of RP11-480I12.5 between normal and CC tissues. The present study used in vitro analysis to establish RP11-480I12.5 stable knockdown and overexpressing cell lines, in order to investigate the function and potential molecular mechanism of RP11-480I12.5 in the progression of CC. RP11-480I12.5 was upregulated in CC tissue compared with normal tissue. Furthermore, RP11-480I12.5 was associated with clinical stage, tumor size and lymph node metastasis. RP11-480I12.5 promoted the proliferation, migration and invasion of CC cell lines. Subsequently, the present study investigated the association between RP11-480I12.5 and the epithelial-to-mesenchymal transition (EMT) and Wnt/β-catenin pathways. RP11-480I12.5 promoted EMT through the Wnt/β-catenin pathway. Overall, the results of the present study demonstrate that RP11-480I12.5 promotes cercical cancer cell migration, invasion and EMT through the Wnt/β-catenin pathway.
| S-EPMC6923895 | biostudies-literature
Project description:BackgroundLung adenocarcinoma (LUAD) is a heavy social burden worldwide. Because the mechanisms involved in LUAD remain unclear, the prognosis of LUAD remains poor. Consequently, it is urgent to investigate the potential mechanisms of LUAD. Junctional adhesion molecule-like protein (JAML), is recognized as a tumorigenesis molecule in gastric cancer. However, the role of JAML in LUAD is still unclear. Here we aimed to evaluate the role of JAML in LUAD.MethodsqRT-PCR, Western blotting and immunohistochemistry were conducted to investigate the expression of JAML in LUAD tissues. JAML was knocked down and overexpressed in LUAD cells using transient transfection by siRNA and plasmids or stable transfection by lentivirus. Proliferation potential of LUAD cells were detected by Cell Counting Kit-8, EdU incorporation and Colony formation assay. Migration and invasion abilities of LUAD cells were determined by wound healing, transwell migration and invasion assays. Cell cycle and cell apoptosis were detected by flow cytometry. The effects of JAML in vivo were studied in xenograft tumor models. Western blotting was used to explore the molecular mechanisms of JAML function. In addition, rescue experiments were performed to verify the possible mechanisms.ResultsJAML expression was elevated in LUAD tissues compared with peritumor tissues, and this upregulation was positively related to pT and pTNM. Furthermore, both in vitro and in vivo, JAML silencing markedly repressed malignant behaviors of LUAD cells and vice versa. Knockdown of JAML also mediated cell cycle arrest at G0/G1 phase and promoted apoptosis in LUAD cells. Mechanistically, silencing JAML repressed the process of epithelial-mesenchymal transition by inactivating the Wnt/β-catenin pathway in LUAD cells. Effects of JAML can be rescued by Wnt/β-catenin pathway activator in A549 cells.ConclusionsOur data reveal the oncogenic role of JAML in LUAD, indicating that JAML may be a predictive biomarker and novel therapeutic target for LUAD.
| S-EPMC9171988 | biostudies-literature
Project description:Tumor endothelial marker 8 (TEM8), also known as ANTXR1, was highly expressed in cancers, and was identified as a biomarker for early diagnosis and prognosis in some cancers. However, the clinical role and molecular mechanisms of TEM8 in lung adenocarcinoma (LUAD) are still unclear. The present study aimed to explore its clinical value and the molecular mechanisms of TEM8 underlying the progression of LUAD. Our study found the elevation of TEM8 in LUAD cell lines and tissues. What's more, we observed that the TEM8 expression level was associated with tumor size, primary tumor, and AJCC stage, and LUAD patients with high TEM8 expression usually have a poor prognosis. Then, we conducted a series of experiments by the strategy of loss-of-function and gain-of-function, and our results suggested that the knockdown of TEM8 suppressed proliferation, migration, and invasion and induced apoptosis in LUAD whereas overexpression of TEM8 had the opposite effect. Molecular mechanistic investigation showed that TEM8 exerted its promoting effects mainly through activating the Wnt/β-catenin signaling pathway. In short, our findings suggested that TEM8 played a crucial role in the progression of LUAD by activating the Wnt/β-catenin signaling pathway and could serve as a potential therapeutic target for LUAD.
| S-EPMC8552045 | biostudies-literature
Project description:BackgroundBreast cancer (BrCa) is the most common female malignancy worldwide and has the highest morbidity among all cancers in females. Unfortunately, the mechanisms of BrCa growth and metastasis, which lead to a poor prognosis in BrCa patients, have not been well characterized.MethodsImmunohistochemistry (IHC) was performed on a BrCa tissue microarray (TMA) containing 80 samples to evaluate ubiquitin protein ligase E3C (UBE3C) expression. In addition, a series of cellular experiments were conducted to reveal the role of UBE3C in BrCa.ResultsIn this research, we identified UBE3C as an oncogenic factor in BrCa growth and metastasis for the first time. UBE3C expression was upregulated in BrCa tissues compared with adjacent breast tissues. BrCa patients with high nuclear UBE3C expression in tumors showed remarkably worse overall survival (OS) than those with low nuclear expression. Knockdown of UBE3C expression in MCF-7 and MDA-MB-453 BrCa cells inhibited cell proliferation, migration and invasion in vitro, while overexpression of UBE3C in these cells exerted the opposite effects. Moreover, UBE3C promoted β-catenin nuclear accumulation, leading to the activation of the Wnt/β-catenin signaling pathway in BrCa cells.ConclusionCollectively, these results imply that UBE3C plays crucial roles in BrCa development and progression and that UBE3C may be a novel target for the prevention and treatment of BrCa.
| S-EPMC7789303 | biostudies-literature
Project description:Abnormal stratifin (SFN) expression is closely related to the progression of several human cancers, but the potential roles of SFN in hepatocellular carcinoma (HCC) remain largely unknown. In this study, we found that SFN was upregulated in HCC cell lines and tissues and was positively associated with tumor size, poor differentiation, Tumor Node Metastasis (TNM) stage, and vascular invasion. In addition, high expression levels of SFN were associated with poor overall survival and disease-free survival. Biologically, downregulation of SFN suppressed tumor cell proliferation, epithelial–mesenchymal transition (EMT), invasion, and migration in vitro and tumor growth in vivo. However, overexpression of SFN promoted cell proliferation, EMT, invasion, and migration in vitro and tumor growth in vivo. Mechanistically, overexpression of SFN activated the Wnt/β-catenin pathway by promoting Glycogen synthase kinase-3 beta (GSK-3β) phosphorylation, decreasing β-catenin phosphorylation, promoting β-catenin transport into the nucleus, and enhancing the expression of c-Myc, whereas depletion of SFN inhibited the Wnt/β-catenin pathway. In addition, TOPFlash/FOPFlash reporter assays showed that overexpression or downregulation of SFN obviously increased or decreased, respectively, the activity of the Wnt/β-catenin pathway. Our results indicated that SFN plays an important role in HCC, possibly providing a prognostic factor and therapeutic target for HCC.
| S-EPMC10427227 | biostudies-literature
Project description:Lung cancer poses severe threats to human health. It is indispensable to discover more druggable molecular targets. We identified a novel dysregulated long non-coding RNA (lncRNA), LINC00669, in lung adenocarcinoma (LUAD) by analyzing the TCGA and GEO databases. Pan-cancer analysis indicated significantly upregulated LINC00669 across 33 cancer types. GSEA revealed a tight association of LINC00669 with the cell cycle. We next attempted to improve the prognostic accuracy of this lncRNA by establishing a risk signature in reliance on cell cycle genes associated with LINC00669. The resulting risk score combined with LINC00669 and stage showed an AUC of 0.746. The risk score significantly stratified LUAD patients into low- and high-risk subgroups, independently predicting prognosis. Its performance was verified by nomogram (C-index = 0.736) and decision curve analysis. Gene set variation analysis disclosed the two groups' molecular characteristics. We also evaluated the tumor immune microenvironment by dissecting 28 infiltrated immune cells, 47 immune checkpoint gene expressions, and immunophenoscore within the two subgroups. Furthermore, the risk signature could predict sensitivity to immune checkpoint inhibitors and other anticancer therapies. Eventually, in vitro and in vivo experiments were conducted to validate LINC00669's function using qRT-PCR, CCK8, flow cytometry, western blot, and immunofluorescence staining. The gain- and loss-of-function study substantiated LINC00669's oncogenic effects, which stimulated non-small cell lung cancer cell proliferation but reduced apoptosis via activating the Wnt/β-catenin pathway. Its oncogenic potentials were validated in the xenograft mouse model. Overall, we identified a novel oncogenic large intergenic non-coding RNA (lincRNA), LINC00669. The resulting signature may facilitate predicting prognosis and therapy responses in LUAD.
| S-EPMC10134358 | biostudies-literature
Project description:BackgroundAccumulating evidence have highlighted the importance of long noncoding RNAs (lncRNAs) in multiple cancers development and progression. Cancer susceptibility candidate 9 (CASC9) is a novel long non-coding RNA and plays important regulatory role in diverse biological processes of cancers. However, the clinical significance and molecular mechanism of CASC9 in bladder cancer is still unknown.MethodsComprehensive lncRNAs profiling analysis were conducted to identify lncRNAs profile alterations and uncover valuable lncRNA candidates for bladder cancer. The expression level of CASC9 was determined in a total of 106 patients with bladder cancer. Loss-of-function experiments were performed to identify the functions of CASC9 in tumor growth and metastasis of bladder cancer in vitro and in vivo. Bioinformatics analysis and further experiments were performed to explore the molecular mechanisms underlying the functions of CASC9.ResultsThis study found that CASC9 expression was markedly upregulated in bladder cancer and related to histological grade, TNM stage and prognosis. Knockdown of CASC9 inhibited tumor growth and metastasis of bladder cancer in vitro and in vivo. Mechanistically, we found that CASC9 functions as a miRNA sponge to positively regulate FZD6 expression and subsequently activates Wnt/β-catenin signaling pathway, thus playing an oncogenic role in bladder cancer pathogenesis.ConclusionIn summary, lncRNA CASC9 plays a critical regulatory role in bladder cancer. The CASC9/miR-497-5p/ FZD6 axis provides insights for regulatory mechanism of bladder cancer, and new strategies for clinical practice.
| S-EPMC7364562 | biostudies-literature
Project description:BackgroundThe expression of forkhead box protein H1 (FOXH1) is frequently upregulated in various cancers. However, the molecular mechanisms underlying the association between FOXH1 expression and lung cancer progression still remain poorly understood. Thus, the main objective of this study is to explore the role of FOXH1 in lung cancer.MethodsThe Cancer Genome Atlas dataset was used to investigate FOXH1 expression in lung cancer tissues, and the Kaplan-Meier plotter dataset was used to determine the role of FOXH1 in patient prognosis. A549 and PC9 cells were transfected with short hairpin RNA targeting FOXH1 mRNA. The Cell Counting Kit-8, colony formation, soft agar, wound healing, transwell invasion and flow cytometry assays were performed to evaluate proliferation, migration and invasion of lung cancer cells. Tumorigenicity was examined in a BALB/c nude mice model. Western blot analysis was performed to assess the molecular mechanisms, and β-catenin activity was measured by a luciferase reporter system assay.ResultsHigher expression level of FOXH1 was observed in tumor tissue than in normal tissue, and this was associated with poor overall survival. Knockdown of FOXH1 significantly inhibited lung cancer cell proliferation, migration, invasion, and cycle. In addition, the mouse xenograft model showed that knockdown of FOXH1 suppressed tumor growth in vivo. Further experiments revealed that FOXH1 depletion inhibited the epithelial-mesenchymal transition of lung cancer cells by downregulating the expression of mesenchymal markers (Snail, Slug, matrix metalloproteinase-2, N-cadherin, and Vimentin) and upregulating the expression of an epithelial marker (E-cadherin). Moreover, knockdown of FOXH1 significantly downregulated the activity of β-catenin and its downstream targets, p-GSK-3β and cyclin D1.ConclusionFOXH1 exerts oncogenic functions in lung cancer through regulation of the Wnt/β-catenin signaling pathway. FOXH1 might be a potential therapeutic target for patients with certain types of lung cancer.
| S-EPMC8180118 | biostudies-literature