TGFβ-induced long non-coding RNA LINC00313 activates Wnt signaling and promotes cholangiocarcinoma
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ABSTRACT:
SUBMITTER: Dr. Panagiotis Papoutsoglou
PROVIDER: S-SCDT-10_1038-S44319-024-00075-Z | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:Cholangiocarcinoma is a devastating liver cancer characterized by high aggressiveness and therapy resistance, resulting in poor prognosis. Long non-coding RNAs and signals imposed by oncogenic pathways, such as transforming growth factor β (TGFβ), frequently contribute to cholangiocarcinogenesis. Here, we explore novel effectors of TGFβ signalling in cholangiocarcinoma. LINC00313 is identified as a novel TGFβ target gene. Gene expression and genome-wide chromatin accessibility profiling reveal that nuclear LINC00313 transcriptionally regulates genes involved in Wnt signalling, such as the transcriptional activator TCF7. LINC00313 gain-of-function enhances TCF/LEF-dependent transcription, promotes colony formation in vitro and accelerates tumour growth in vivo. Genes affected by LINC00313 over-expression in CCA tumours are associated with KRAS and TP53 mutations and reduce overall patient survival. Mechanistically, ACTL6A and BRG1, subunits of the SWI/SNF chromatin remodelling complex, interact with LINC00313 and affect TCF7 and SULF2 transcription. We propose a model whereby TGFβ induces LINC00313 in order to regulate the expression of hallmark Wnt pathway genes, in co-operation with SWI/SNF. By modulating key genes of the Wnt pathway, LINC00313 fine-tunes Wnt/TCF/LEF-dependent transcriptional responses and promotes cholangiocarcinogenesis.
| S-EPMC10933437 | biostudies-literature
Project description:Cholangiocarcinoma (CCA) is a devastating liver cancer characterized by high aggressiveness and resistance to therapy, which results to poor prognosis. Signals imposed by oncogenic pathways, such as transforming growth factor β (TGFβ) frequently contribute to CCA development. In this study, we explored novel effectors of the TGFβ pathway in CCA by gene expression profiling. We identified the long non-coding RNA LINC00313 as a novel target gene of TGFβ signalling in CCA cells. TGFβ induced LINC00313 expression in a TβRI/Smad-dependent manner. Subcellular fractionation showed that LINC00313 is a predominantly nuclear lncRNA. By integrating RNA-seq and ATAC-seq data from LINC00313 over-expressing cells, we observed that LINC00313 regulates the expression of several genes involved in the Wnt signalling pathway. As a proof of concept, we focused on the gene encoding transcription factor 7 (TCF7), a major effector that drives transcription of Wnt-target genes. LINC00313 gain of function resulted in increased TCF7 expression, while its loss of function diminished basal or TGFβ-induced TCF7 expression levels. Interestingly, LINC00313 enhanced basal or chemically induced TCF/LEF-dependent transcriptional responses, promoted colony-forming capacities of CCA cells in vitro and accelerated tumor growth in vivo. We also report that genes associated with LINC00313 over-expression recapitulate poor prognosis human CCA associated with a reduced overall survival and KRAS mutations. To decipher the underlying molecular functions of LINC00313, we identified its interacting proteins by performing an unbiased RNA pull-down assay followed by mass spectrometry. We demonstrated that actin-like 6A (ACTL6A), a subunit of the SWI/SNF chromatin remodelling complex specifically binds to LINC00313 and impacts TCF7 expression and TCF/LEF signalling output. Thus, we propose a model whereby TGFβ induces LINC00313, in order to regulate the expression of a subset of target genes, such as TCF7 possibly in co-operation with the SWI/SNF chromatin remodelling complex, via establishing direct interaction with ACTL6A. By regulating key genes of the Wnt pathway, LINC00313 fine-tunes Wnt/TCF/LEF-dependent transcriptional responses and boosts cholangiocarcinogenesis.
2024-02-05 | E-MTAB-12879 | biostudies-arrayexpress
Project description:Cholangiocarcinoma (CCA) is a devastating liver cancer characterized by high aggressiveness and resistance to therapy, which results to poor prognosis. Signals imposed by oncogenic pathways, such as transforming growth factor β (TGFβ) frequently contribute to CCA development. In this study, we explored novel effectors of the TGFβ pathway in CCA by gene expression profiling. We identified the long non-coding RNA LINC00313 as a novel target gene of TGFβ signalling in CCA cells. TGFβ induced LINC00313 expression in a TβRI/Smad-dependent manner. Subcellular fractionation showed that LINC00313 is a predominantly nuclear lncRNA. By integrating RNA-seq and ATAC-seq data from LINC00313 over-expressing cells, we observed that LINC00313 regulates the expression of several genes involved in the Wnt signalling pathway. As a proof of concept, we focused on the gene encoding transcription factor 7 (TCF7), a major effector that drives transcription of Wnt-target genes. LINC00313 gain of function resulted in increased TCF7 expression, while its loss of function diminished basal or TGFβ-induced TCF7 expression levels. Interestingly, LINC00313 enhanced basal or chemically induced TCF/LEF-dependent transcriptional responses, promoted colony-forming capacities of CCA cells in vitro and accelerated tumor growth in vivo. We also report that genes associated with LINC00313 over-expression recapitulate poor prognosis human CCA associated with a reduced overall survival and KRAS mutations. To decipher the underlying molecular functions of LINC00313, we identified its interacting proteins by performing an unbiased RNA pull-down assay followed by mass spectrometry. We demonstrated that actin-like 6A (ACTL6A), a subunit of the SWI/SNF chromatin remodelling complex specifically binds to LINC00313 and impacts TCF7 expression and TCF/LEF signalling output. Thus, we propose a model whereby TGFβ induces LINC00313, in order to regulate the expression of a subset of target genes, such as TCF7 possibly in co-operation with the SWI/SNF chromatin remodelling complex, via establishing direct interaction with ACTL6A. By regulating key genes of the Wnt pathway, LINC00313 fine-tunes Wnt/TCF/LEF-dependent transcriptional responses and boosts cholangiocarcinogenesis.
2024-02-05 | E-MTAB-12030 | biostudies-arrayexpress
Project description:Rationale: Steroid receptor activator (SRA), a long non-coding RNA, serves as a critical regulator of gynecologic cancer. The objective of this study was to determine biological function and clinical significance of SRA expression in endometrial cancer. Method: We investigated whether SRA was involved in the development of endometrial cancer via binding to eukaryotic translation initiation factor 4E-binding protein 1 (EIF4E-BP1) as a transcription factor to enhance Wnt/ ?-catenin signaling pathway. Results: Expression levels of SRA were upregulated in endometrial cancer tissues compared to those in adjacent control tissues. We also found high expression of SRA in EC cells. The relationship between SRA and EIF4E-BP1 was corroborated by transfection of a luciferase reporter plasmid. In addition, SRA knockdown inhibited the expression of EIF4E-BP1 known to play a critical role in the control of protein synthesis, cell growth, and cell survival, thus promoting tumourigenesis and epithelial-mesenchymal transition (EMT) important for cell motility and metastasis. Consistently, immunostaining and western blotting analysis showed that expression levels of ?-catenin and 4EBP1 in the nucleus were significantly decreased by SRA knockdown but increased by SRA over-expression. Conclusions: These results suggest that SRA is involved in proliferation, migration, and invasion of endometrial cancer cells by increasing the expression of EIF4E-BP1 and activity of Wnt/ ?-catenin signaling. These findings indicate that SRA might be a novel biomarker for predicting recurrence and prognosis. It might also serve as a promising therapeutic target in endometrial cancer.
| S-EPMC6930375 | 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:BackgroundLong non-coding RNAs (lncRNAs) are implicated in many pathophysiological processes, including cancers. In particular, lncRNA DANCR is regarded as a cancer-associated lncRNA exerting various regulatory mechanisms. However, the expressions, functions, and mechanisms of action of DANCR in cervical cancer are still unclear.MethodsThe expressions of DANCR in cervical cancer tissues and cell lines were evaluated using qRT-PCR. Correlations between DANCR expression and clinicopathological features and prognosis were analyzed. The roles of DANCR in cervical cancer growth were evaluated by in vitro CCK-8 and EdU assay, and in vivo xenograft assay. The regulatory effects of DANCR on Wnt/β-catenin signaling pathway were evaluated using nuclear proteins extraction, western blot, and qRT-PCR.ResultsDANCR is increased in cervical cancer tissues and cell lines. Increased expression of DANCR is associated with large tumor size, advanced FIGO stage, and poor overall survival of cervical cancer patients. Functional experiments showed that enhanced expression of DANCR promotes cervical cancer cell proliferation in vitro and xenograft growth in vivo. Conversely, DANCR knockdown inhibits cervical cancer cell proliferation in vitro and xenograft growth in vivo. Mechanistic investigation demonstrated that DANCR upregulates the expressions of FRAT1 and FRAT2 and activates the Wnt/β-catenin signaling pathway. Blocking the Wnt/β-catenin signaling pathway abolishes the pro-proliferative roles of DANCR overexpression and anti-proliferative roles of DANCR knockdown.ConclusionsOur findings suggest DANCR as an oncogenic lncRNA in cervical cancer through activating the Wnt/β-catenin signaling pathway, and imply that DANCR may be a promising prognostic biomarker and therapeutic target for cervical cancer.
| S-EPMC7036257 | biostudies-literature
Project description:BackgroundLncRNA can regulate gene at various levels such as apparent genetics, alternative splicing, and regulation of mRNA degradation. However, the molecular mechanism of LncRNA in cholangiocarcinoma is still unclear. This deserves further exploration.MethodsWe investigated the expression of AGAP2-AS1 in 32 CCA tissues and two CCA cell lines. We found a LncRNA AGAP2-AS1 which induced by SP1 has not been reported in CCA, and Knockdown and overexpression were used to investigate the biological role of AGAP2-AS1 in vitro. CHIP and RIP were performed to verify the putative targets of AGAP2-AS1.ResultsAGAP2-AS1 was significantly upregulated in CCA tumor tissues. SP1 induced AGAP2-AS1 plays an important role in tumorigenesis. AGAP2-AS1 knockdown significantly inhibited proliferation and caused apoptosis in CCA cells. In addition, we demonstrated that AGAP2-AS1 promotes the proliferation of CCA.ConclusionsWe conclude that the long non-coding RNA AGAP2-AS1 plays a role in promoting the proliferation of cholangiocarcinoma.
| S-EPMC7852216 | biostudies-literature
Project description:PurposeIntrahepatic cholangiocarcinoma (ICC) is one of the most common liver primary tumors but its treatments are limited. Bioinformatics showed that the expression level of long non-coding RNA cancer-associated susceptibility 15 gene (CASC15) is correlated with ICC progression, but its functional mechanism remains unclear.Materials and methodsTissues from ICC patients, tumor and adjacent tissue, were used for detection of the expression of CASC15. Clinical data were also collected for clinicopathologic and survival analysis. Short interfering RNA and lentiviral short hairpin RNA were used to knock down CASC15 and PRDX2 expression in ICC cell lines, for the analysis of changes of cell function and xenografts. RNA-pulldown and RNA immunoprecipitation assays were used to detect RNA-binding protein, PRDX2. Male nude mice were used for ICC xenografts, and livers were collected after 4 weeks for immunohistochemistry.ResultsCASC15 is highly expressed in ICC tissues and is related to higher TNM stage. Knockdown of CASC15 in ICC cells reduced cell proliferation, migration, invasiveness and increased apoptosis, and G1/S block. PRDX2 bound to CASC15. Knockdown of CASC15 decreased PRDX2 expression which was rescued by the inhibition of proteasome formation. Downregulation of PRDX2 resulted in G1/S block, reduced ICC cell invasion. Downregulation of CASC15 inhibited phosphoinositide 3-kinase (PI3K)/AKT/c-Myc pathway through downregulating of PRDX2 and overexpressed PRDX2 rescued the block. CASC15 knockout in ICC xenografts suppressed tumor development in vivo, decreased the expression of PRDX2 and Ki67 and inhibited PI3K/AKT pathway.ConclusionCASC15 promotes ICC possibly by targeting PRDX2 via the PI3K/AKT pathway, indicating poor prognosis and high degree of malignancy of ICC.
| S-EPMC7812017 | biostudies-literature
Project description:Long non-coding RNA colon cancer associated transcript 2 (CCAT2) is dysregulated in a number of different types of human cancer, and affects cancer progression via the Wnt/?-catenin signaling pathway. However, the roles of CCAT2 and the Wnt/?-catenin signaling pathway in prostate cancer (PCa) are not completely understood. The present study aimed to investigate the potential mechanism of CCAT2 in PCa. In the present study, the reverse transcription-quantitative PCR (RT-qPCR) results indicated that CCAT2 expression was significantly upregulated in PCa tissues, and DU145 and PC3 cell lines compared with normal prostate tissues and the epithelial RWPE-1 cell line, respectively. Functional assays indicated that CCAT2 downregulation inhibited DU145 and PC3 cell proliferation, cell cycle, migration and invasion. In addition, the luciferase reporter assay, RT-qPCR and western blotting results indicated that CCAT2 regulated transcription factor 7 like 2 (TCF7L2) expression by binding to microRNA-217. Further western blotting and TOPFlash assays indicated that CCAT2-knockdown inhibited the Wnt/?-catenin signaling pathway in DU145 and PC3 cell lines by inhibiting the expression of TCF7L2. However, CCAT2-knockdown-mediated effects were reversed by the Wnt/?-catenin signaling pathway activator lithium chloride (LiCl). Further cell experiments suggested that LiCl treatment reversed CCAT2-knockdown-mediated inhibition of PCa cell proliferation, cell cycle, epithelial-mesenchymal transition, migration and invasion. Overall, the results indicated that CCAT2 regulated PCa via the Wnt/?-catenin signaling pathway; therefore, CCAT2 may exhibit key role during the progression of PCa and may serve as a therapeutic target for the disease.
| S-EPMC7439128 | biostudies-literature
Project description:Cholangiocarcinoma (CCA) is the most common biliary tract malignancy, with a low survival rate and limited treatment options. Long non-coding RNAs (lncRNAs) have recently been verified to have significant regulatory functions in many kinds of human cancers. It was discovered in this study that the lncRNA PVT1, whose expression is significantly elevated in CCA, could be a molecular marker of CCA. Experiments indicated that PVT1 knockdown greatly inhibited cell migration and proliferation in vitro and in vivo. According to RNA sequencing (RNA-seq) analysis, PVT1 knockdown dramatically influenced target genes associated with cell angiogenesis, cell proliferation, and the apoptotic process. RNA immunoprecipitation (RIP) analysis demonstrated that, by binding to epigenetic modification complexes (PRC2), PVT1 could adjust the histone methylation of the promoter of ANGPTL4 (angiopoietin-like 4) and, thus, promote cell growth, migration, and apoptosis progression. The data verified the significant functions of PVT1 in CCA oncogenesis, and they suggested that PVT1 could be a target for CCA intervention.
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