Identifying colorectal cancer-specific vulnerabilities in the Wnt-driven long-noncoding transcriptome [GRO-seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE206582 | GEO | 2023/07/01
REPOSITORIES: GEO
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Project description:<p>Hepatoblastoma (HB) is the most common pediatric liver tumor, affecting mostly children under 3 years of age. This rare tumor represents 1% of all pediatric cancers. Genetic studies have shown that HB is characterized by high frequency mutations of the CTNNB1 gene encoding beta-catenin (around 75%) and relative genomic stability. Here we have analyzed the transcriptional profile of 21 HBs compared to matched non-tumor livers by Cap Analysis of Gene Expression (CAGE), which provides accurate and quantitative profiling of all transcripts. CAGE analysis revealed strong upregulation of known Wnt target coding genes in most tumors analyzed, consistent with previous transcriptomic studies. To better define the Wnt-dependent transcriptional landscape of HB, we integrated CAGE data with TCF4 ChIP-seq data from a CTNNB1-mutated cancer cell line and with the FANTOM5 genomic coordinates of TCF/LEF binding motifs. Both TCF/LEF binding motifs and ChIP-seq peaks were strongly enriched in the immediate upstream region, not only for protein-coding genes, but also for non-coding transcripts. Among the selected 112 top Wnt target genes at FDR<1.0E-6 and fold change>8, we found clear over-representation (66%) of distant transcription start sites (TSSs) representing lncRNAs and enhancer RNAs, which raises the question of their role in HB pathogenesis. Analysis of the 112 promoters using CAGEd-oPOSSUM confirmed the predominant involvement of Tcf/Lef transcription factors, together with HNF4G, GATA2, Sox3 and Ets-related genes. Finally, the 112 Wnt target signature defined 3 tumor subclasses, T1, T2 and T3, characterized by progressive alteration of the non-coding part of the transcriptome and significant differences in clinical behavior.</p>
| phs001433 | dbGaP
Project description:The transactivation of TCF target genes induced by Wnt pathway mutations constitutes the primary transforming event in colorectal cancer (CRC). We show that disruption of beta-catenin/TCF-4 activity in CRC cells induces a rapid G1 arrest and blocks a genetic program that is physiologically active in the proliferative compartment of colon crypts. Coincidently, an intestinal differentiation program is induced. The TCF-4 target gene c-MYC plays a central role in this switch by direct repression of the p21(CIP1/WAF1) promoter. Following disruption of beta-catenin/TCF-4 activity, the decreased expression of c-MYC releases p21(CIP1/WAF1) transcription, which in turn mediates G1 arrest and differentiation. Thus, the beta-catenin/TCF-4 complex constitutes the master switch that controls proliferation versus differentiation in healthy and malignant intestinal epithelial cells.
2005-09-02 | E-SMDB-1723 | biostudies-arrayexpress
Project description:The transactivation of TCF target genes induced by Wnt pathway mutations constitutes the primary transforming event in colorectal cancer (CRC). We show that disruption of beta-catenin/TCF-4 activity in CRC cells induces a rapid G1 arrest and blocks a genetic program that is physiologically active in the proliferative compartment of colon crypts. Coincidently, an intestinal differentiation program is induced. The TCF-4 target gene c-MYC plays a central role in this switch by direct repression of the p21(CIP1/WAF1) promoter. Following disruption of beta-catenin/TCF-4 activity, the decreased expression of c-MYC releases p21(CIP1/WAF1) transcription, which in turn mediates G1 arrest and differentiation. Thus, the beta-catenin/TCF-4 complex constitutes the master switch that controls proliferation versus differentiation in healthy and malignant intestinal epithelial cells. Groups of assays that are related as part of a time series. Computed
2005-09-10 | E-GEOD-3282 | biostudies-arrayexpress
Project description:Unrestrained transcriptional activity of β-CATENIN and its binding partner TCF7L2 frequently underlies colorectal tumor initiation and is considered an obligatory oncogenic driver throughout intestinal carcinogenesis. Yet, the TCF7L2 gene carries inactivating mutations in about 10 % of colorectal tumors and is non-essential in colorectal cancer (CRC) cell lines. To determine whether CRC cells acquire TCF7L2-independence through cancer-specific compensation by other T-cell factor (TCF)/lymphoid enhancer‑binding factor (LEF) family members, or rather lose addiction to β-CATENIN/TCF7L2-driven gene expression altogether, we generated multiple CRC cell lines entirely negative for TCF/LEF or β-CATENIN expression. Viability of these cells demonstrates complete β‑CATENIN- and TCF/LEF-independence, albeit one β-CATENIN-deficient cell line eventually became senescent. Absence of TCF/LEF proteins and β-CATENIN consistently impaired CRC cell proliferation, reminiscent of mitogenic effects of WNT/β-CATENIN signaling in the healthy intestine. Despite this common phenotype, β-CATENIN-deficient cells exhibited highly cell-line-specific gene expression changes with little overlap between β-CATENIN- and TCF7L2-dependent transcriptomes. Apparently, β‑CATENIN and TCF7L2 control sizeable fractions of their target genes independently from each other. The observed divergence of β-CATENIN and TCF7L2 transcriptional programs, and the finding that neither β-CATENIN nor TCF/LEF activity is strictly required for CRC cell survival has important implications when evaluating these factors as potential drug targets.
2022-12-13 | GSE199835 | GEO
Project description:Human colorectal cancer (CRC) is the third most common cancer in the world.Recent studies have shown that long non-coding (lncRNA) plays critical roles in a myriad of biological processes and human diseases,Since the roles of lncRNA in CRC remain largely unknown,they were investigated in the study.Our findings indicate that the expression profiles of lncRNAs has changed in CRC as compared with adjacent non-tumor samples, and may provide novel insight into the molecular mechanism underlying the disease and potential novel diagnostic or therapeutic targets for CRC.
2016-11-26 | GSE90524 | GEO
Project description:The transactivation of TCF target genes induced by Wnt pathway mutations constitutes the primary transforming event in colorectal cancer (CRC). We show that disruption of beta-catenin/TCF-4 activity in CRC cells induces a rapid G1 arrest and blocks a genetic program that is physiologically active in the proliferative compartment of colon crypts. Coincidently, an intestinal differentiation program is induced. The TCF-4 target gene c-MYC plays a central role in this switch by direct repression of the p21(CIP1/WAF1) promoter. Following disruption of beta-catenin/TCF-4 activity, the decreased expression of c-MYC releases p21(CIP1/WAF1) transcription, which in turn mediates G1 arrest and differentiation. Thus, the beta-catenin/TCF-4 complex constitutes the master switch that controls proliferation versus differentiation in healthy and malignant intestinal epithelial cells. Groups of assays that are related as part of a time series. Keywords: time_series_design
2005-09-10 | GSE3282 | GEO
Project description:Background: circRNAs, a recently identified new member of non-coding RNAs, have been proved to play an essential role in the development and progression of various cancers. However, the functions and mechanisms of circRNAs in colorectal liver metastasis have not been fully elucidated. Methods: We performed circRNA microarray to screen differentially expressed novel circRNAs in the pathology of colorectal liver metastasis. Quantitative real-time PCR was used to detect the circ102049 expression in colorectal cancer (CRC) samples. Then CRC cells were transfected with a circ102049 over-expression vector or siRNAs, and the effects of circ102049 on biological functions in CRC cells were accessed in vitro. Mechanistically, the bioinformatics analysis, fluorescence in situ hybridization, RIP assay, RNA pull down assay and luciferase reporter assay were conducted to confirm the relationships among circ102049, miR-761, miR-192-3p and FRAS1. Moreover, the mechanism of circ102049 how to recruit and distribute DGCR8 protein in cytoplasm was elucidated. Results: The results showed that circ102049 was highly expressed in primary CRC tumors with liver metastasis and closely correlated with the CRC patients' prognosis. Circ102049 might act as a novel metastasis-related non-coding RNA, and significantly promote the adhesion, migration and invasion abilities of CRC cells. Mechanistically, we verified that circ102049 promoted the CRC development and progression via a miR-761/miR-192-3p-FRAS1-dependent mechanism. Notably, due to the distribution of DGCR8 protein, circ102049 might also reduce the mature products of miR-761 and miR-192-3p in cytoplasm indirectly. In addition, the role of circ102049 in promoting colorectal liver metastasis was also confirmed in vivo. Conclusions: Our findings provided new clues that circ102049 might be a potential prognostic factor in CRC, and the circ102049-miR-761/miR-192-3p-FRAS1 axis could be further explored as a therapeutic target for anti-metastatic therapy in CRC patients with liver metastases. Keywords: Hsa_circ_102049, miR-761, miR-192-3p, FRAS1, Colorectal liver metastasis
2021-02-08 | GSE147602 | GEO
Project description:The WNT-TCF signaling pathway participates in adult tissue homeostasis and repair, and is hyperactive in a number of human diseases including cancers of the colon. Whereas to date there are no antagonists approved for patient use, a potential problem for their sustained use is the blockade of WNT signaling in healthy tissues, thus provoking potentially serious co-lateral damage. Here we have screened a library of plant and microorganism small molecules for novel WNT signaling antagonists and describe withanolide F as a potent WNT-TCF response blocker. This steroidal lactone inhibits TCF-dependent colon cancer xenograft growth and mimics the effects of genetic blockade of TCF and of ivermectin, a previously reported WNT-TCF blocker. However, withanolide F is unique in that it imposes a long-lasting repression of tumor growth, WNT-TCF targets and cancer stem cell clonogenicity long after drug treatment
2017-02-22 | GSE87874 | GEO
Project description:Activation of Wnt/β-catenin signaling plays a central role in the development and progression of colorectal cancer (CRC). Previously, we demonstrated that the Wnt transcription factor, TCF7L2, was overexpressed in primary rectal cancers that were resistant to chemoradiotherapy (CRT), and that TCF7L2 functionally mediates resistance of CRC cells to CRT. However, it remained unclear whether the resistance was mediated by a TCF7L2 inherent mechanism or Wnt/β-catenin signaling in general. We now show that silencing of β-catenin resulted in sensitization of the CRC cell lines LS1034, SW480, and SW837 to CRT, demonstrating a relationship between Wnt/β-catenin signaling and CRT resistance. To investigate the potential role of Wnt/β-catenin signaling in controlling therapeutic responsiveness, non-tumorigenic RPE-1 cells were stimulated with Wnt-3a, a physiological ligand at the Frizzled receptor, which significantly increased resistance to CRT. This effect could be recapitulated by overexpression of mutated, undegradable β-catenin (S33Y). Again, this resulted in a significantly boosted resistance of RPE-1 cells to CRT, which was abrogated by siRNA-mediated silencing of β-catenin. Consistent with these findings, we observed higher expression levels of active (unphosphorylated) β-catenin as well as increased TCF/LEF reporter activity in SW1463 cells that evolved radiation-resistance due to repeated radiation-treatment. Global gene expression profiling identified several altered pathways associated with treatment response as a consequence of Wnt/β-catenin pathway activation, sheading new light on PPARD signaling as a possible mechanism of Wnt mediated resistance. Hence, synergistic pathway inhibition of either Wnt and/or one of the downstream-pathways may represent a promising strategy to increase therapeutic responsiveness to CRT.
2017-05-01 | GSE97543 | GEO
Project description:Dysregulation of Wnt/TCF signaling is closely associated with cancers arising from the gastrointestinal tract, inlcluding colon cancer and liver cancer. The goal of this study is to understand the transcriptional programs underlying Wnt/TCF activation in gastrointestinal cancers. We examined the transcriptional responses to TCF inhibition in cultured human colon cancer cells and liver cancer cells that are characteristic of Wnt pathway activation. Human liver cancer cell line HepG2 and colon cancer cell line LS174T with or without expression of a dominant negative form of TCF4
2013-08-01 | E-GEOD-46465 | biostudies-arrayexpress