FBXO32 drives pancreatic cancer progression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE260802 | GEO | 2024/05/06
REPOSITORIES: GEO
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Project description:FBXO32 drives pancreatic cancer progression
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Project description:FBXO32 is upregulated in multiple human cancers, including hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA), and correlated to poor prognosis. Moreover, we demonstrated the tumor-promoting function in these cancers. Here, to explore the associated molecular mechanism of FBXO32 in tumor development, the RNA-seq of FBXO32-knockout Huh7 cells was investigated and analyzed
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Project description:The epithelial-mesenchymal transition (EMT) is a process by which cells lose their cell contacts and gain migratory and invasive properties. EMT is essential for numerous developmental processes including neural tube formation, in wound healing, organ fibrosis and cancer metastasis. Despite progress, the repertoire of factors involved in global transcriptional reprogramming underlying EMT remains unknown. Here we show that FBXO32, a member of the F-box protein family, is essential for phenotypic changes hallmark of EMT. Such dependency results from FBXO32-driven transcriptional reprogramming of critical EMT genes and involved changes in their chromatin state. Furthermore, we found that CTBP1, an established regulator of EMT, requires FBXO32 ubiquitination at Lysine 63 for its nuclear retention and gene regulatory function. FBXO32 is also highly amplified in a large panel of metastatic cancers and its knockdown severely impaired metastatic properties of cancer cells in vitro and in vivo. In addition, FBXO32 is also induced during neurogenesis and is essential for neuronal migration in vivo. Together, these findings uncover FBXO32-dependent gene regulatory circuitry that underlies EMT during development and disease.
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Project description:We compared gene expression profiles in Panc-1, AsPC1 and MDA-Panc28 pancreatic cancer cell lines stably expressing shControl or shTAK1 by microarray analysis in order to identify groups of genes associated with a specific signaling pathway or biological process
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Project description:To explore malignant phenotype related genes in Panc-1-CTC, we performed gene expression array analysis with Panc-1-CTC and Panc-1-Parent (Panc-1-P). As a result, TGFBI upregulation emerged as highly malignant feature for pancreatic ductal adenocarcinoma. Identification of malignant phenotype related genes in pancreatic ductal adenocarcinoma
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Project description:Pancreatic cancer is one of the uncurable cancers and 5-year survival rate is still under 10 %. Therefore, it is urgent to identify a new molecular target for cure. In this study, the mouse serial transplantations by pancreatic orthotopic inoculation model were utilized for screening of new targets. The gene expression of highly malignant cancer cell lines, established in our previous study, showed increased expression of neurotensin receptor-1 (NTSR1). Re-analysis of clinical databases revealed that its expression was higher in pancreatic cancer dependent upon its stage. Overexpression of NTSR1 in SUIT-2 and Panc-1 cells accelerated tumorigenic and metastatic ability in vivo. RNA-sequence analysis revealed that MAPK and NF-kB signaling pathway were activated with neurotensin (NTS) stimulation in highly malignant cancer cell lines from Panc-1 cells. Moreover, NTS induced not only MMP-9, but also CTGF and other pro-inflammatory cytokines and chemokines. Administration of SR48692, a selective antagonist for NTSR1, suppressed tumorigenicity in vivo. These data suggested that NTSR1 can be a diagnostic marker and a new molecular target for pancreatic cancer treatment.
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Project description:To the best of our knowledge, this is the first study presenting detailed evidences for the underlying role of LINC00261 in pancreatic cancer both in vitro and in vivo. Also, we thoroughly explored the clinical value of LINC00261 in multicenter cohorts and developed an individualized predictive model of survival. To investigate the potential downstream pathway of LINC00261, we performed RNA-seq using two PANC-1 cell groups: LINC00261 knockdown and control.
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Project description:Gemcitabine resistance is currently the main problem of chemotherapy for advanced pancreatic cancer patients. The resistance is thought to be caused by altered drug metabolism or reduced apoptosis of cancer cells. However, the underlying mechanism of Gemcitabine resistance in pancreatic cancer remains unclear. In this study, we established Gemcitabine resistant PANC-1 (PANC-1-GR) cell lines and compared the circular RNAs (circRNAs) profiles between PANC-1 cells and PANC-1-GR cells by RNA sequencing.
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Project description:GISTs are the most common mesenchymal tumors and they display neuromuscular features. Gain-of-function mutations in KIT or PDGFRA are the initiating event in most of the cases and KIT oncogenic signaling is essential throughout all the disease. Interestingly, KIT oncogenic signaling is driven by PI3K/mTOR and RAS/MAPK pathways regardless of KIT primary or secondary mutations. Hence, dissection of KIT-downstream pathways may result in the identification of novel KIT critical effectors and a new opportunity to overcome disease heterogeneity of resistance mechanisms in GIST. Using human clinically representative GIST cell models, we undertook pharmacological and functional screenings such as Cell titer glo, kinase activation, apoptosis induction and proliferation to identify key signaling nodes within PI3K/mTOR and RAS/MAPK pathways. In vitro and in vivo validations were undertaken to model novel therapeutic strategies. Transcriptomic analysis (RNAseq) found essential genes co-regulated by both pathways. Functional studies, such as immunofluorescence, kinase activation, flow cytometry and proliferation were performed on a viral gene overexpression and knock-down models to elucidate their regulation and potential role in GIST biology. PI3K/mTOR and MEK1/2 are the most essential KIT-downstream mediators. Single node inhibition did not yield sustained antiproliferative and apoptotic effect, but simultaneous intermittent ablation was synergistic in vitro and in vivo, supporting the critical role of these two pathways.Transcriptomic analyses underscored FBXO32 (a SCF E3 ubiquitin-ligase and the main effector of muscular atrophy) as the most differentially expressed gene co-regulated by PI3K/mTOR and RAS/MAPK pathways. Functional studies demonstrated that FBXO32 is transcriptionally activated by FOXO3a which, in turn, is regulated by PI3K/mTOR and RAS/MAPK pathways. Notoriously, FBXO32 proved to have a pro-survival role in GIST cells. Microarray studies hinted a participation of FBXO32 in cell cycle arrest, which has been previously described as an adaptive pro-survival mechanism in GIST cells. This mechanism was further confirmed by functional studies. Remarkably, FBXO32 was expressed upon KIT inhibition in a panel of GIST cell lines, regardless the mutational status of KIT, and in a gene set database from GIST patients treated with first-line treatment, imatinib. PI3K/mTOR and MEK1/2 are the critical mediators of KIT oncogenic signaling in GIST, and their intermittent co-inhibition is an effective and well-tolerated therapeutic strategy to treat GIST tumors, independently of their KIT mutational status. FBXO32 emerges as a common mediator of KIT-downstream PI3K/mTOR and RAS/MAPK pathways with a critical pro-survival role in GIST participating in cell cycle arrest as pro-survival mechanism.
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