Abstract 206P
Background
Endometrial cancer (EC) is most strongly associated with obesity compared to all other cancers. As the population with obesity and metabolic disorders rises globally, the incidence and mortality of EC increase remarkedly. Metabolic syndrome (MS) is not only related to the occurrence of EC, but in recent years, researchers have shown that MS also plays an important role in the progression and poor prognosis of EC. However, the mechanism is unclear.
Methods
Untargeted and targeted metabolomics, multiplex immune fluorescence staining, Raman spectroscopy, Co-IP, GST-pull down, surface plasmon resonance, thermal stability assay, cellular immunofluorescence, gene knockdown, gene overexpression, WB, CCK-8, wound healing, transwell, qPCR, half-life assay, in-situ and LNM xenograft mice model were used.
Results
We found that polyamine metabolites were significantly elevated in the serum of EC with MS (ECWMS). Hyperlipidemia is a key factor in promoting ECWMS, and oleic acid (OA), a very important monounsaturated fatty acid was screened out from 12 common fatty acids as a key factor in upregulating the Ornithine Decarboxylase 1 (ODC1), the rate-limiting enzyme in polyamine metabolism, and downstream polyamines in the EC cell lines. Mechanistically, OA directly binds to HOXB9 and stabilizes it by preventing its interaction with E3 ligases Praja2. HOXB9 further interacts with ODC1 and competes with the interaction between Antizyme 1 (OAZ1) and ODC1 for proteasomal degradation. Downstream accumulation of polyamine metabolites, especially putrescine, further in turn inhibits the degradation of HOXB9. Targeting feedback of the HOXB9-ODC1-polyamine axis decreases polyamines and inhibits tumor proliferation and metastasis in vitro and in vivo. Clinically, the combination of ODC1, HOXB9, and obesity could better differentiate the prognosis. Multiplex IHC and Ramen spectroscopy indicated that the lipid-HOXB9-ODC1 axis also exists in ECWMS.
Conclusions
This study links fatty acid levels to polyamine accumulation, ultimately promoting EC progression and unveiling the mechanism for MS promoting EC progression. Targeting HOXB9 or ODC1 is expected to be a potential therapeutic strategy to control patients with MS-related refractory or progressive EC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
National Science Foundation of China.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
826P - Efficacy of non-doxorubicin based regimens in severely G6PD deficient patients with DLBCL
Presenter: Shruti Prem Sudha
Session: Poster session 09
827P - Comparison of efficacy and safety between glofitamab and real-world regimens among Chinese patients with 3L+ relapsed/refractory diffuse large B-cell lymphoma: An external control study
Presenter: Keshu Zhou
Session: Poster session 09
828P - Translocation 11;14 is not associated with adverse prognosis in the era of novel anti-myeloma therapeutics
Presenter: Ioannis Ntanasis-Stathopoulos
Session: Poster session 09
829P - Flumatinib combined with chemotherapy for newly diagnosed adult with Ph-positive acute lymphoblastic leukemia: A single-center, retrospective observational study
Presenter: HAN SHUYU
Session: Poster session 09
830P - Prognostic model of pediatric AML patients with RUNX1-RUNX1T1 fusion gene
Presenter: Yang Xun
Session: Poster session 09
Resources:
Abstract
831P - Impact of chronic kidney disease on disease outcomes in hospitalized multiple myeloma patients: A National inpatient sample study from 2016 to 2020
Presenter: Marco Bermudez
Session: Poster session 09
Resources:
Abstract
832P - CLOMB: A validated scoring model to predict the relapse in the central nervous system of pediatric acute B-cell lymphoblastic leukemia
Presenter: Jiacheng Li
Session: Poster session 09
Resources:
Abstract
833P - Latest results of GVM±R regimen for the salvage therapy of patients with relapsed or refractory aggressive non-Hodgkin's lymphoma
Presenter: Wei Liu
Session: Poster session 09
834P - Treatment of DLBCL in HIV patient: Still a dilemma
Presenter: Devashish Desai
Session: Poster session 09
835P - Genetic, epigenetic, and clinical significance of Wilms’ tumor 1 (WT1) gene in acute myeloid leukemia
Presenter: Harsh Goel
Session: Poster session 09
Resources:
Abstract