Objectives Lipolysis-stimulated lipoprotein receptor (LSR) is a membrane protein that has been studied in various malignant tumors. We previously reported that high expression of LSR was associated with poor prognosis, advanced stage, deep myometrial invasion, and metastasis in endometrial cancer (EC). However, the mechanism by which LSR affects patient’s prognosis remains largely unclear. Here, we aimed to investigate the functions of LSR in EC.

Methods Cell proliferation and invasion were analyzed using LSR-knockdown cell lines (HEC1 and HEC116), and the activity of several signaling pathways were examined by Western blotting. To investigate the function of LSR in EC cells, the pathway enrichment and ontology analysis were performed using the publicly available proteomic data.

Results LSR-knockdown significantly suppressed cell proliferation in WST-8 assay. The pathway analysis demonstrated that MAPK signaling pathway was enriched in proteins correlated with high LSR expression. In ontology analysis, we found several biological processes, including ‘regulation of ERK1/2’ and ‘MAPK cascade.’ Following the results of pathway enrichment and ontology analysis, we confirmed that LSR-knockdown downregulated the phosphorylation of MEK/ERK pathway, including MEK1/2, ERK1/2, and p90RSK in western blotting. Cell invasion assay and western blot analysis demonstrated that LSR-knockdown suppressed MT1-MMP/MMP2 expression and cell invasion. Interestingly, ERK1/2-knockdown also suppressed MT1-MMP/MMP2 expression, suggesting that LSR activated MT1-MMP/MMP2 via ERK1/2 and promoted cell invasion.

Conclusions Our results of in vitro study and bioinformatic analysis showed that LSR regulated cell proliferation and invasion via MEK/ERK pathway, and contributed poor prognosis in EC. LSR may be a new therapeutic target of advanced EC.