1. Anti-lipolysis-stimulated lipoprotein receptor monoclonal antibody as a novel therapeutic agent for endometrial cancer.
- Author
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Nagase Y, Hiramatsu K, Funauchi M, Shiomi M, Masuda T, Kakuda M, Nakagawa S, Miyoshi A, Matsuzaki S, Kobayashi E, Kimura T, Serada S, Ueda Y, Naka T, and Kimura T
- Subjects
- Animals, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal therapeutic use, Cell Line, Tumor, Cell Movement genetics, Female, Humans, Matrix Metalloproteinase 14, Matrix Metalloproteinase 2 metabolism, Mice, Neoplasm Invasiveness, Neoplasm Recurrence, Local, Endometrial Neoplasms genetics, Receptors, Lipoprotein genetics, Receptors, Lipoprotein metabolism
- Abstract
Background: Endometrial cancer (EC) is a common gynecologic malignancy and patients with advanced and recurrent EC have a poor prognosis. Although chemotherapy is administered for those patients, the efficacy of current chemotherapy is limited. Therefore, it is necessary to develop novel therapeutic agents for EC. In this study, we focused on lipolysis-stimulated lipoprotein receptor (LSR), a membrane protein highly expressed in EC cells, and developed a chimeric chicken-mouse anti-LSR monoclonal antibody (mAb). This study investigated the antitumor effect of an anti-LSR mAb and the function of LSR in EC., Methods: We examined the expression of LSR in 228 patients with EC using immunohistochemistry and divided them into two groups: high-LSR (n = 153) and low-LSR groups (n = 75). We developed a novel anti-LSR mAb and assessed its antitumor activity in an EC cell xenograft mouse model. Pathway enrichment analysis was performed using protein expression data of EC samples. LSR-knockdown EC cell lines (HEC1 and HEC116) were generated by transfected with small interfering RNA and used for assays in vitro., Results: High expression of LSR was associated with poor overall survival (hazard ratio: 3.53, 95% confidence interval: 1.35-9.24, p = 0.01), advanced stage disease (p = 0.045), deep myometrial invasion (p = 0.045), and distant metastasis (p < 0.01). In EC with deep myometrial invasion, matrix metalloproteinase (MMP) 2 was highly expressed along with LSR. Anti-LSR mAb significantly inhibited the tumor growth in EC cell xenograft mouse model (tumor volume, 407.1 mm
3 versus 726.3 mm3 , p = 0.019). Pathway enrichment analysis identified the mitogen-activated protein kinase (MAPK) pathway as a signaling pathway associated with LSR expression. Anti-LSR mAb suppressed the activity of MAPK in vivo. In vitro assays using EC cell lines demonstrated that LSR regulated cell proliferation, invasion, and migration through MAPK signaling, particularly MEK/ERK signaling and membrane-type 1 MMP (MT1-MMP) and MMP2. Moreover, ERK1/2-knockdown suppressed cell proliferation, invasion, migration, and the expression of MT1-MMP and MMP2., Conclusions: Our results suggest that LSR contributes to tumor growth, invasion, metastasis, and poor prognosis of EC through MAPK signaling. Anti-LSR mAb is a potential therapeutic agent for EC., (© 2022. The Author(s).)- Published
- 2022
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