MicroRNA-431 promotes metastasis of pancreatic neuroendocrine tumors by targeting DAB2IP, a RasGAP tumor suppressor
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE139119 | GEO | 2019/11/21
REPOSITORIES: GEO
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Project description:MicroRNA-431 promotes metastasis of pancreatic neuroendocrine tumors by targeting DAB2IP, a RasGAP tumor suppressor
| PRJNA578481 | ENA
Project description:The incidence of pancreatic neuroendocrine tumor (PNET) is increasing, and it presents with various clinical manifestations and an unfavorable survival rate. A better understanding of the drivers of PNET tumorigenesis is urgently needed. Distinct miRNA signatures have been identified for different stages of tumorigenesis in both human and mouse PNETs. The functions of these miRNAs are poorly understood. miR-431 is the most up-regulated miRNA in the metastatic signature. However, it is unknown whether miR-431 contributes to metastasis of PNETs. Herein, we show that miR-431 overexpression activates Ras/extracellular signal-regulated kinase (Erk) signaling and promotes epithelial-mesenchymal transition, migration/invasion in vitro, and metastasis in both xenograft and spontaneous mouse models of PNET. Treatment of PNET cells with Erk inhibitor or locked nucleic acids sequestering miR-431 inhibits invasion. Four target prediction modules and dual-luciferase reporter assays were used to identify potential mRNA targets of miR-431. A Ras GTPase activating protein tumor suppressor (RasGAP), DAB2 interacting protein (DAB2IP), was discovered as an miR-431 target. Overexpression of DAB2IP's rat homolog, but not its mutant defective in Ras GTPase activating protein activity, reverses miR-431's effect on promoting invasion, Erk phosphorylation, and epithelial-mesenchymal transition of PNETs. Taken together, miR-431 silences DAB2IP to active Ras/Erk and promote metastasis of PNETs. miR-431 may be targeted to manage metastatic PNETs.
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Project description:Analysis of molecular mechanisms by which RHAMMB promote metastasis of pancreatic neuroendocrine tumor.
2024-04-16 | GSE200497 | GEO
Project description:Gene expression profiling of midgut carcinoid (neuroendocrine) primary tumors and metastasis
2008-10-30 | E-TABM-389 | biostudies-arrayexpress
Project description:The tumorigenesis of small intestinal neuroendocrine tumors (NETs) is poorly understood. Recent studies have associated alternative polyadenylation with proliferation, cell transformation and cancer. Polyadenylation is the process in which the pre-mRNA is cleaved at a polyA site and a polyA tail is added. Genes with two or more polyA sites can undergo alternative polyadenylation. This produces two or more distinct mRNA isoforms with different 3M-bM-^@M-^Y untranslated regions. Additionally, alternative polyadenylation can also produce mRNAs containing different 3M-bM-^@M-^Y-terminal coding regions. Therefore, alternative polyadenylation alters both the repertoire and the expression level of proteins. Here we used high-throughput sequencing data to map polyA sites and characterize polyadenylation genome-wide in three small intestinal neuroendocrine tumors and a reference sample. In the tumors sixteen genes showed significant changes of alternative polyadenylation pattern, which lead to either the 3M-bM-^@M-^Y truncation of mRNA coding regions or 3M-bM-^@M-^Y untranslated regions. Among these, 11 genes had been previously associated with cancer, with 4 genes being known tumor suppressors: DCC, PDZD2, MAGI1 and DACT2. We validated the alternative polyadenylation in 3 out of 3 cases with Q-RT-PCR. Our findings suggest that changes of alternative polyadenylation pattern in these 16 genes could be involved in the tumorigenesis of small intestinal neuroendocrine tumors. Furthermore, they also point to alternative polyadenylation as a new target for both diagnostic and treatment of small intestinal neuroendocrine tumors. The identified genes with alternative polyadenylation specific to the small intestinal neuroendocrine tumors could be further tested as diagnostic markers and drug targets for disease prevention and treatment. PolyA-seq profiling of 3 human neuroendocrine tumors compared and pituitary using Direct RNA Sequencing from Helicos Biosciences Technology
2014-04-10 | E-GEOD-56657 | biostudies-arrayexpress
Project description:The molecular mechanisms underlying the development of pancreatic neuroendocrine tumors (PanNETs) have not been well defined. We report here that the genomic region of the PHLDA3 gene undergoes loss of heterozygosity (LOH) at a remarkably high frequency in human PanNETs, and this genetic change is correlated with disease progression and poor prognosis. We also show that the PHLDA3 locus undergoes methylation in addition to LOH, suggesting that a two-hit inactivation of the PHLDA3 gene is required for PanNET development. We demonstrate that PHLDA3 represses Akt activity and Akt-regulated biological processes in pancreatic endocrine tissues, and that PHLDA3-deficient mice develop islet hyperplasia. In addition, we show that the tumor-suppressing pathway mediated by MEN1, a well-known tumor suppressor of PanNETs, is dependent on the pathway mediated by PHLDA3, and inactivation of PHLDA3 and MEN1 cooperatively contribute to PanNET development. Collectively, these results indicate the existence of a novel PHLDA3-mediated pathway of tumor suppression that is important in the development of PanNETs.
| S-EPMC4060701 | biostudies-literature
Project description:Despite being infrequent tumors, the incidence and prevalence of pancreatic neuroendocrine tumors (P-NETs) has been rising over the past few decades. In recent years, rigorous phase III clinical trials have been conducted, allowing the approval of several drugs that have become the standard of care in these patients. Although various treatments are used in clinical practice, including somatostatin analogues (SSAs), biological therapies like sunitinib or everolimus, peptide receptor radionuclide therapy (PRRT) or even chemotherapy, a consensus regarding the optimal sequence of treatment has not yet been reached. Notwithstanding, sunitinib is largely used in these patients after the promising results shown in SUN111 phase III clinical trial. However, both prompt progression as well as tumor recurrence after initial response have been reported, suggesting the existence of primary and acquired resistances to this antiangiogenic drug. In this review, we aim to summarize the most relevant mechanisms of angiogenesis resistance that are key contributors of tumor progression and dissemination. Furthermore, several targeted molecules acting selectively against these pathways have shown promising results in preclinical models, and preliminary results from ongoing clinical trials are awaited.
| S-EPMC6801829 | biostudies-literature
Project description:Pancreatic Neuroendocrine tumors are challenging to diagnose and often detected at advanced stages due to lack of specific and sensitive biomarkers. This study utilized proteomics as a valuable approach for cancer biomarker discovery, therefore, mass spectrometry-based proteomic profiling was conducted on plasma samples from 12 subjects (3 controls; 9 PanNET patients) to identify potential proteins capable of effectively distinguish PanNET from healthy controls. 13.2% of proteins were uniquely identified in PanNET, while 60% were commonly expressed in PanNET and controls. 17 proteins exhibiting significant differential expression between PanNET and controls were identified with downstream analysis.
2024-01-26 | PXD045045 | Pride
Project description:The tumorigenesis of small intestinal neuroendocrine tumors (NETs) is poorly understood. Recent studies have associated alternative polyadenylation with proliferation, cell transformation and cancer. Polyadenylation is the process in which the pre-mRNA is cleaved at a polyA site and a polyA tail is added. Genes with two or more polyA sites can undergo alternative polyadenylation. This produces two or more distinct mRNA isoforms with different 3’ untranslated regions. Additionally, alternative polyadenylation can also produce mRNAs containing different 3’-terminal coding regions. Therefore, alternative polyadenylation alters both the repertoire and the expression level of proteins. Here we used high-throughput sequencing data to map polyA sites and characterize polyadenylation genome-wide in three small intestinal neuroendocrine tumors and a reference sample. In the tumors sixteen genes showed significant changes of alternative polyadenylation pattern, which lead to either the 3’ truncation of mRNA coding regions or 3’ untranslated regions. Among these, 11 genes had been previously associated with cancer, with 4 genes being known tumor suppressors: DCC, PDZD2, MAGI1 and DACT2. We validated the alternative polyadenylation in 3 out of 3 cases with Q-RT-PCR. Our findings suggest that changes of alternative polyadenylation pattern in these 16 genes could be involved in the tumorigenesis of small intestinal neuroendocrine tumors. Furthermore, they also point to alternative polyadenylation as a new target for both diagnostic and treatment of small intestinal neuroendocrine tumors. The identified genes with alternative polyadenylation specific to the small intestinal neuroendocrine tumors could be further tested as diagnostic markers and drug targets for disease prevention and treatment.
2014-04-10 | GSE56657 | GEO
Project description:RHAMMB promotes metastasis of pancreatic neuroendocrine tumor
| PRJNA824826 | ENA