206P - Unveiling the link: How metabolic syndrome drives endometrial cancer progression

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.