Dataset Information

Linc00423 as a tumor suppressor in retroperitoneal liposarcoma via activing MAPK signaling pathway through destabilizing of NFATC3.

ABSTRACT: Unraveling the noncoding RNA expression networks governing cancer initiation and development is essential while remains largely uncompleted in retroperitoneal liposarcoma (RLS). Through RNA-seq technologies and computational biology, deregulated long noncoding RNAs (lncRNAs) are being identified and reveal that lncRNAs are implicated in serial steps of RLS development. High-throughput sequencing with computational methods for assembling the transcriptome of five paired RLS patient's tissues. We found that long intergenic noncoding RNA 423 (linc00423) was downregulated in RLS tissues. Gain-of-function assays revealed that overexpressed linc00423 obviously inhibited RLS cell growth in vitro and in vivo. Additionally, RNA sequence, RNA-pulldown and RIP assays evidenced that linc00423 involved in MAPK signaling pathway via destabilizing of nuclear factor of activated T-cells 3 (NFATC3). Summing up, our findings demonstrated that linc00423 acted as the tumor suppressor in RLS cells through regulating the protein level of NFATC3 at a post-transcriptional level and negatively regulated the MAPK signaling pathway at a transcriptional level. Linc00423 might serve as a candidate prognostic biomarker and a target for novel therapies of RLS patients.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC6546787 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Linc00423 as a tumor suppressor in retroperitoneal liposarcoma via activing MAPK signaling pathway through destabilizing of NFATC3.

Zhang Yong Y Tong Hanxing H He Junyi J Shao Yebo Y Guo Xi X Zhuang Rongyuan R Yang Jue J Liu Ju J Ding Yuqin Y Liu Wenshuai W Lu Weiqi W Zhou Yuhong Y

Cell death & disease 20190603 6

Unraveling the noncoding RNA expression networks governing cancer initiation and development is essential while remains largely uncompleted in retroperitoneal liposarcoma (RLS). Through RNA-seq technologies and computational biology, deregulated long noncoding RNAs (lncRNAs) are being identified and reveal that lncRNAs are implicated in serial steps of RLS development. High-throughput sequencing with computational methods for assembling the transcriptome of five paired RLS patient's tissues. We ...[more]

PMID: 31160581

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Project description:Background:Retroperitoneal liposarcoma (RLPS) is a rare tumor with high recurrence rate. Ribonucleotide reductase small subunit M2 (RRM2) protein is essential for DNA synthesis and replication. Our previous study has demonstrated that RRM2 downregulation inhibited the proliferation of RLPS cells, but further association between RRM2 and RLPS and relevant mechanisms remains to be explored. Methods:RRM2 expression was evaluated in RLPS tumor tissues and cell lines by using real-time PCR and immunohistochemical analysis. The effect of RRM2 downregulation on cell proliferation, apoptosis, cell cycle, cell migration and invasion was tested by lentivirus. The effect of RRM2 inhibition on tumor growth in vivo was assessed by using patient-derived tumor xenograft (PDX) of RLPS and RRM2 inhibitor. The underlying mechanisms of RRM2 in RLPS were explored by protein microarray and Western blotting. Results:The results showed that RRM2 mRNA expression was higher in RLPS tissues than in normal fatty tissues (P<0.001). RRM2 expression was higher in the dedifferentiated, myxoid/round cell, and pleomorphic subtypes (P=0.027), and it was also higher in the high-grade RLPS tissues compared to that in the low-grade RLPS tissues (P=0.004). There was no correlation between RRM2 expression and overall survival (OS) or disease-free survival (DFS) in this group of RLPS patients (P>0.05). RRM2 downregulation inhibited cell proliferation, promoted cell apoptosis, facilitated cell cycle from G1 phase to S phase and inhibited cell migration and invasion. Inhibition of RRM2 suppressed tumor growth in NOD/SCID mice. Protein microarray and Western blot verification showed that activity of Akt/mammalian target of rapamycin/eukaryotic translation initiation factor 4E binding protein 1 (Akt/mTOR/4EBP1) pathway was downregulated along with RRM2 downregulation. Conclusion:RRM2 was overexpressed in RLPS tissues, and downregulation of RRM2 could inhibit RLPS progression. In addition, suppression of RRM2 is expected to be a promising treatment for RLPS patients.

Project description:BackgroundThe current study investigated the role of radiotherapy (RT) in patients with primary nonmetastatic retroperitoneal liposarcomas.MethodsA total of 607 patients with localized retroperitoneal well-differentiated liposarcomas (WDLPS) and dedifferentiated liposarcomas (DDLPS) underwent surgical resection with or without RT at 8 high-volume sarcoma centers (234 patients with WDLPS, 242 patients with grade 1 to 2 DDLPS, and 131 patients with grade 3 DDLPS; grading was performed according to the National Federation of Centers for the Fight Against Cancer [Federation Nationale des Centres de Lutte Contre le Cancer; FNCLCC]). RT was administered in 19.7%, 34.7%, and 35.1%, respectively, of these 3 cohorts. Overall survival (OS) was estimated using the Kaplan-Meier method, and the incidences of local recurrence and distant metastasis (DM) were estimated in a competing risk framework. To account for bias consistent with nonrandom RT assignment, propensity scores were estimated. Cox univariable analysis of the association between RT and oncological endpoints was performed by applying inverse probability of treatment weighting (IPTW) using propensity scores.ResultsAge, tumor size, and the administration of chemotherapy were found to be significantly imbalanced between patients who did and did not undergo RT in all cohorts. IPTW largely removed imbalances in key prognostic variables. Although the 8-year local recurrence incidences in patients treated with surgery plus RT versus surgery only were 11.8% and 39.2%, respectively, for patients with WDLPS (P = .011;); 29.0% and 56.7%, respectively, for patients with grade 1 to 2 DDLPS (P = .008); and 29.8% and 43.7%, respectively, for patients with grade 3 DDLPS (P = .025), this significant benefit was lost after IPTW analyses. There were no significant differences noted with regard to DM and OS between irradiated and unirradiated patients across all 3 cohorts.ConclusionsPerioperative RT was found to be associated with better local control in univariable unadjusted analysis in all 3 cohorts, but not after accounting for imbalances in prognostic variables. RT did not impact on DM or OS. The appropriate selection of RT in this disease remains challenging. The results of the European Organization for Research and Treatment of Cancer (EORTC)-Soft Tissue and Bone Sarcoma Group (STBSG) 62092-22092 prospective randomized trial are awaited.

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Project description:Rationale: Synovial inflammation is one of the main pathological features of rheumatoid arthritis (RA) and is a key factor leading to the progression of RA. Understanding the regulatory mechanism of synovial inflammation is crucial for the treatment of RA. Acid-sensing ion channel 1a (ASIC1a) is an H+-gated cation channel that promotes the progression of RA, but the role of ASIC1a in synovial inflammation is unclear. This study aimed to investigate whether ASIC1a is involved in the synovial inflammation and explore the underlying mechanisms in vitro and in vivo. Methods: The expression of ASIC1a and nuclear factor of activated T cells (NFATs) were analyzed by Western blotting, immunofluorescence, and immunohistochemistry both in vitro and in vivo. The Ca2+ influx mediated by ASIC1a was detected by calcium imaging and flow cytometry. The role of ASIC1a in inflammation was studied in rats with adjuvant-induced arthritis (AA). Inflammatory cytokine profile was analyzed by protein chip in RA synovial fibroblasts (RASF) and verified by a magnetic multi-cytokine assay and ELISA. The NFATc3-regulated RANTES (Regulated upon activation, normal T cell expressed and secreted) gene transcription was investigated by ChIP-qPCR and dual-luciferase reporter assay. Results: The expression of ASIC1a was significantly increased in human RA synovial tissues and primary human RASF as well as in ankle synovium of AA rats. Activated ASIC1a mediated Ca2+ influx to increase [Ca2+]i in RASF. The activation/overexpression of ASIC1a in RASF up-regulated the expression of inflammatory cytokines RANTES, sTNF RI, MIP-1a, IL-8, sTNF RII, and ICAM-1 among which RANTES was increased most remarkably. In vivo, ASIC1a promoted inflammation, synovial hyperplasia, articular cartilage, and bone destruction, leading to the progression of AA. Furthermore, activation of ASIC1a upregulated the nuclear translocation of NFATc3, which bound to RANTES promoter and directly regulated gene transcription to enhance RANTES expression. Conclusion: ASIC1a induces synovial inflammation, which leads to the progression of RA. Our study reveals a novel RA inflammation regulatory mechanism and indicates that ASIC1a might be a potential therapeutic target for RA.

Dataset Information

Linc00423 as a tumor suppressor in retroperitoneal liposarcoma via activing MAPK signaling pathway through destabilizing of NFATC3.

Publications

Linc00423 as a tumor suppressor in retroperitoneal liposarcoma via activing MAPK signaling pathway through destabilizing of NFATC3.

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