J Cancer 2020; 11(9):2518-2528. doi:10.7150/jca.40055

Research Paper

DRG Neurons Promote Perineural Invasion of Endometrial Cancer via GluR2

Ting Ni1*, Ting Huang1*, Sheng-Lan Gu1, Jing Wang1, Yao Liu1, Xiao Sun2✉, Yu-dong Wang1,3,4✉

1. Department of Gynecology, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, No. 910 Hengshan Road, Shanghai 200030, China.
2. Laboratory for Gynecologic Oncology, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, No. 910 Hengshan Road, Shanghai 200030, China.
3. Shanghai Key Laboratory of Embryo Original Disease, Shanghai, China
4. Shanghai Municipal Key Clinical Specialty, Shanghai, China
*The first two authors contributed equally to the study.

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Citation:
Ni T, Huang T, Gu SL, Wang J, Liu Y, Sun X, Wang Yd. DRG Neurons Promote Perineural Invasion of Endometrial Cancer via GluR2. J Cancer 2020; 11(9):2518-2528. doi:10.7150/jca.40055. Available from http://www.jcancer.org/v11p2518.htm

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Abstract

Background: Perineural invasion (PNI) is correlated with negative prognosis in multiple cancers, but its role in endometrial cancer (EC) is still largely unknown; thus, targeted treatment for nerve infiltration is lacking as well.

Methods: The interaction between nerve and EC cells were investigated by in vitro neural invasion assay and transwell coculture system. Then the nerve-related receptor gene glutamate ionotropic receptor AMPA type subunit 2 (GRIA2) was detected in EC tissues and cells using PCR array, western blotting, and immunohistochemistry. The role of GluR2 (gene name GRIA2) on EC proliferation, migration and invasion was evaluated by a GluR2 antagonist and shRNA. At the same time, the neurotransmitter effect on GluR2 (glutamate) from the cocultured conditional medium was measured using high-performance liquid chromatography (HPLC).

Results: EC cell line Ishikawa (ISK) showed the ability to migrate along neurites in vitro and the numbers of migrated/invaded EC cells in the DRG neuron coculture group were significantly increased. The expression of GluR2 in EC tissue was found to be higher than that in para-carcinoma tissue. After GluR2 antagonist and GluR2 shRNA treatment, the proliferation, migration and invasion of ISK cells was markedly inhibited. Moreover, the ability of DRG neurons to promote the migration and invasion of ISK cells could also be attenuated by downregulation of GluR2, and the concentration of the neurotransmitter glutamate was notably increased in the coculture conditional medium compared to that in the DRG neuron or ISK cells alone.

Conclusions: DRG neurons promote metastasis of EC cells via GluR2, which might be a risk factor for PNI in EC. Moreover, the perineural system may promote tumor invasion and metastasis under certain circumstances.

Keywords: endometrial cancer, GluR2, DRG neurons, perineural invasion, metastasis