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[Clinical significance of σ1 receptor over-expression in cervical cancer and the effect of its synthetic ligands on the growth of cervical cancer cells].

Objective: To explore the role of σ1 receptor (σ1R) in the clinical prognosis of cervical cancer,and provide a theoretical basis for σ1R targeted molecular therapy through observing the inhibition of synthetic σ1R-specific ligand compounds on the growth of cervical cancer cells. Methods: (1) Immunohistochemical or immunocytochemistry staining were respectively used to detect the expression and localization of σ1R protein. (2) The Cancer Genome Atlas (TCGA) data set was used to validate our results. (3) Two series of 4 novel σ1R ligand compounds were synthesized by altering the N-terminal substituents on the piperidine ring of the prezamicol analogue, named as 14a, 14e, 15c and 15f. Methyl thiazolyl-tetrazolium (MTT) assay was detect the anti-proliferative effect of the four compounds on HeLa and SiHa cells. Compound 14a with potent inhibitory activity and the highest specificity of σ1R was selected for further experiments. Scratch test was observed the migration effect of compound 14a on HeLa and SiHa cells. Flow cytometry was determined cell cycles and apoptosis. Results: (1) Immunostaining of σ1R protein was located in the cytoplasm and nucleus of cervical epithelium. The expression of cervical squamous cell carcinoma (SCC) was significantly higher than those of high-grade squamous intraepithelial lesion (HSIL) or normal cervical tissues. There was no significant difference in the expression of σ1R between HSIL and normal cervical tissues. σ1R expression in cervical adenocarcinoma (AC) was higher than that in SCC (P=0.020). The nuclear expression rate of σ1R in AC (10/18) was higher than that of SCC (27.1%, 19/70; P=0.024). The median overall survival (MOS) of σ1R-positive SCC patients was lower than that of σ1R-negative patients [(45.8±3.1) vs (51.7±2.9) months, P=0.045]. MOS of the patients with σ1R nuclear positive SCC was lower than that of non-nuclear staining [(38.9±3.8) vs (48.7±2.1) months, P=0.022]. MOS of the patients with σ1R nuclear positive AC was lower than that of non-nuclear staining [(35.0±6.3) vs (44.2±4.2) months, P=0.034]. (2) Analysis of TCGA data showed that σ1R expression of in SCC was correlated with age (P=0.005). σ1R expression in AC was significantly associated with advanced stage, lymphnode metastasis and vascular invasion (all P<0.05). MOS of AC patients with σ1R overexpression was significantly lower than that of the patients with low expression (P=0.034). There was no significant difference in the MOS of different expression of σ1R mRNA in SCC patients(P=0.930). (3) MTT assay showed that these four compounds could suppressed the growth of HeLa and SiHa cells in time- and dose-dependent manner. The growth inhibition rates of HeLa and SiHa cells at 48 hours treated by combination of different concentrations of nedaplatin (NDP) with compound 14a (6 μmol/L) were significantly higher than those treated by NDP alone. Compound 14a (30 μmol/L) significantly inhibited the migration (both P<0.01) and induced the apoptosis of HeLa or SiHa cells (both P<0.01). Conclusions: σ1R is over-expressed in cervical cancer and HSIL. σ1R nuclear expression is an important marker of AC. σ1R over-expression, especially σ1R nuclear expression is associated with the poor prognosis of cervical cancer. Our study is mostly consistent with cervical cancer data of TCGA. These results suggest that the novel synthetic prezamicol analogues 14a for σ1R could inhibit the growth of cervical cancer cells and cell migration through inducing apoptosis and arresting cell cycle in G(0)/G(1) period, enhance NDP-induced cytotoxicity.