Introduction: Advanced endometrial cancer (EC) still has poor prognosis and requires the development of new therapeutic agents. In ovarian and gastric cancer, we revealed that high expression of lipolysis-stimulated lipoprotein receptor (LSR), a cell-surface membrane protein, was associated with poor prognosis and LSR could be a new therapeutic target. However, in EC, the clinical and cell biological role of LSR is still unclear. We aimed to investigate the functions of LSR in EC.

Methods: We evaluated LSR expression by immunohistochemistry and analyzed overall survival (OS) and clinicopathological factors in 228 EC patients. To investigate the mechanism by which LSR affects the prognosis of EC patients, the pathway enrichment analysis and gene ontology analysis were conducted using the publicly available proteogenomic dataset of EC. Cell proliferation was analyzed by WST-8 assay using two LSR-knockdown cell lines (HEC1 and HEC116) developed by transfection of LSR-siRNA, and the activity of several signaling pathways were examined by Western blotting.

Results: Patients were divided into two groups based on LSR expression; High (darkly stained cells in ≥25% of the area, n=153) and Low (darkly stained cells in <25% of the area, n=75) groups. 5-year OS rate in High group was significantly lower than Low group (hazard ratio: 3.53, 95% confidence interval: 1.35 - 9.24, p=0.01). Stage III-IV, deep myometrial invasion (≥75% of uterine myometrium), tumor involvement of adnexa or serosa, and distant metastasis were more frequently observed in High group than in Low group (p<0.05, respectively). The pathway analysis demonstrated that genes correlated with high LSR expression were enriched in MAPK signaling pathway. In gene ontology analysis, these genes were enriched in regulation of ERK1/2 and MAPK cascade. In vitro, LSR-knockdown suppressed cell proliferation (p<0.01) and phosphorylation of MEK1/2, ERK1/2, and p90RSK, suggesting that LSR promoted cell proliferation via MEK/ERK pathway. However, LSR did not regulate the other signaling pathways (SAPK/JNK, p38-MAPK, JAK/STAT3, and PI3K/AKT/mTOR pathway).

Conclusion: LSR regulated cell proliferation via MEK/ERK pathway, and contributed poor prognosis in EC. LSR may be a new therapeutic target of advanced EC.

Citation Format: Yoshikazu Nagase, Kosuke Hiramatsu, Satoshi Nakagawa, Shinya Matsuzaki, Toshihiro Kimura, Satoshi Serada, Yutaka Ueda, Tetsuji Naka, Tadashi Kimura. LSR is a novel prognostic factor by regulating cell proliferation via MEK/ERK pathway in endometrial cancer:Analysis of signal transduction, bioinformatics, and in vitro/in vivo study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1989.