A TGF- -CTCF regulated pathway suppresses stem cell associated tumor progression
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE69752 | GEO | 2016/04/30
SECONDARY ACCESSION(S): PRJNA286657
REPOSITORIES: GEO
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Project description:A TGF- -CTCF regulated pathway suppresses stem cell associated tumor progression
| PRJNA286657 | ENA
Project description:Beckwith-Wiedemann syndrome (BWS) is a human stem cell disorder, and individuals with this disease have a substantially increased risk (~800-fold) of developing tumors. Epigenetic silencing of ?2-spectrin (?2SP, encoded by SPTBN1), a SMAD adaptor for TGF-? signaling, is causally associated with BWS; however, a role of TGF-? deficiency in BWS-associated neoplastic transformation is unexplored. Here, we have reported that double-heterozygous Sptbn1+/- Smad3+/- mice, which have defective TGF-? signaling, develop multiple tumors that are phenotypically similar to those of BWS patients. Moreover, tumorigenesis-associated genes IGF2 and telomerase reverse transcriptase (TERT) were overexpressed in fibroblasts from BWS patients and TGF-?-defective mice. We further determined that chromatin insulator CCCTC-binding factor (CTCF) is TGF-? inducible and facilitates TGF-?-mediated repression of TERT transcription via interactions with ?2SP and SMAD3. This regulation was abrogated in TGF-?-defective mice and BWS, resulting in TERT overexpression. Imprinting of the IGF2/H19 locus and the CDKN1C/KCNQ1 locus on chromosome 11p15.5 is mediated by CTCF, and this regulation is lost in BWS, leading to aberrant overexpression of growth-promoting genes. Therefore, we propose that loss of CTCF-dependent imprinting of tumor-promoting genes, such as IGF2 and TERT, results from a defective TGF-? pathway and is responsible at least in part for BWS-associated tumorigenesis as well as sporadic human cancers that are frequently associated with SPTBN1 and SMAD3 mutations.
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Project description:A TGF-β-CTCF regulated pathway suppresses stem cell associated tumor progression
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Project description:Background:Renal fibrosis is a frequent pathway leading to end-stage kidney dysfunction. In addition, renal fibrosis is the ultimate manifestation of chronic kidney diseases (CKD). Long noncoding RNAs (lncRNAs) are known to be involved in occurrence of renal fibrosis, and lncRNA plasmacytoma variant translocation 1 (PVT1) has been reported to act as a key biomarker in renal diseases. However, the role of PVT1 in renal fibrosis remains unclear. Materials and Methods:HK-2 cells were treated with TGF-?1 to mimic renal fibrosis in vitro. Gene and protein expressions in HK-2 cells were measured by qRT-PCR and Western-blot, respectively. ELISA was used to test the level of creatinine (CR) and blood urea nitrogen (BUN) in serum of mice. Additionally, unilateral ureteral obstruction (UUO)-induced renal fibrosis mice model was established to investigate the effect of PVT1 on renal fibrosis in vivo. Results:PVT1 was upregulated in TGF-?1-treated HK-2 cells. In addition, TGF-?1-induced upregulation of ?-SMA and fibronectin in HK-2 cells was significantly reversed by PVT1 knockdown. Meanwhile, PVT1 bound to miR-181a-5p in HK-2 cells. Moreover, miR-181a-5p directly targeted TGF-?R1. Furthermore, miR-181a-5p antagonist could significantly reverse the anti-fibrotic effect of PVT1 knockdown. Besides, knockdown of PVT1 notably attenuated the symptom of renal fibrosis in vivo. Conclusion:Knockdown of PVT1 significantly inhibited the progression of renal fibrosis in vitro and in vivo. Thus, PVT1 may serve as a potential target for the treatment of renal fibrosis.
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Project description:Adipose-derived stem cell (ADSC) transplantation has become a prospective way to treat cardiovascular diseases and skin traumas. Propofol, a short-acting intravenous anesthetic agent, plays an important role in the induction and maintenance of general anesthesia. In this study, we investigated the effects of propofol on ADSCs. The flow cytometry results showed that ADSCs were positive for CD29, CD44, and CD90 and negative for CD31, CD34, and CD45. The results of MTT and BrdU assays demonstrated that propofol impeded the proliferation of ADSCs. The cell scratch test showed that propofol had an inhibitory effect on the migration of ADSCs. Transwell assay showed that invasive ASDC counts decreased significantly after propofol treatment. Propofol also promoted ADSC apoptosis and arrested ADSCs in the G0/G1 phase. All these effects showed in a dose-dependent manner that the higher the concentration, the stronger the effect. Western blot analysis revealed decreased levels of FAK, PI3K, AKT, and GSK3β phosphorylation, while the phosphorylation of β-catenin increased after 48 h of treatment with propofol. The findings above indicated that the PI3K/AKT-Wnt pathways mediated propofol-inhibited ADSC proliferation, providing new insights into the propofol application in ADSCs.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies and the therapeutic outcomes remain undesirable. Increasing evidence shows that aryl hydrocarbon receptor nuclear translocator like 2 (ARNTL2) plays crucial roles in tumorigenesis of multiple tumors. However, the expression status and functions of ARNTL2 in PDAC remain elusive. Here we showed that ARNTL2 expression was markedly upregulated in PDAC tissues and cell lines. elevated expression of ARNTL2 was positively related to unfavorable prognosis. Knockdown of ARNTL2 could suppress motility and invasive ability of PDAC cells in vitro, as well as tumor development in vivo. In addition, microRNA-26a-5p (miR-26a-5p) was identified as the crucial specific arbitrator for ARNTL2 expression and the expression of miR-26a-5p was inversely correlated with ARNTL2 expression in PDAC tissues. Functionally, elevated expression of miR-26a-5p was found to inhibit the proliferation, migration, and invasion of PDAC cells in vitro, while ARNTL2 increased expression could partially abolish the suppressive effect of miR-26a-5p. Mechanism study indicated that elevated expression of miR-26a-5p suppressed TGF/BETA signaling pathway by targeting ARNTL2 in PDAC cells. In conclusion, our data suggested that ARNTL2 acted as an oncogene to regulate PDAC growth. MiR-26a-5p/ARNTL2 axis may be a novel therapeutic candidate target in PDAC treatment.
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