Overexpression of β-Adrenergic Receptors and the Suppressive Effect of β2-Adrenergic Receptor Blockade in Oral Squamous Cell Carcinoma

Purpose: The purpose of this project was to investigate the expression of β-adrenergic receptors in oral squamous cell carcinoma (OSCC) and the tumor suppressive activity of β₂-adrenergic receptor (β₂-AR) blockade.

Materials and methods: Samples of 15 normal oral mucosal epithelial tissues, 60 surgically resected OSCC tissues, and 60 adjacent para-carcinoma tissues were collected. The expression of β₁-adrenergic receptor and β₂-AR was detected by real-time quantitative polymerase chain reaction and the Western blot test. SCC9 and Cal27 cell lines and primary OSCC cells also were included and treated with ICI-118,551 (MedChemExpress, Monmouth Junction, NJ), a selective β₂-AR blocker. In addition, the Cal27 cell line was treated with propranolol (a nonselective β-adrenergic receptor blocker) to verify the suppressive effect of β₂-AR blockade. For in vivo assays, Cal27 cells were subcutaneously injected in the tongue flank of nude mice. ICI-118,551 was orally administered to the mice in the treatment group daily. High-throughput sequencing was used to screen for changes in gene expression.

Results: Real-time quantitative polymerase chain reaction and the Western blot test both showed that β₁-adrenergic receptor and β₂-AR were overexpressed in OSCC tissues and cells. A relationship was found between β₂-AR and a more advanced clinical stage, as well as preoperative lymphatic metastasis. After treatment with ICI-118,551 or propranolol, the capacities for proliferation, invasion, and metastasis of OSCC cells were significantly inhibited. Tumor size was significantly different between the ICI-118,551 and control groups. The survival time in the ICI-118,551 group also was prolonged significantly. Moreover, high-throughput sequencing identified 19 affected signaling pathways, including mitogen-activated protein kinase and PI3K-Akt. We confirmed a significant change to the expression of several genes closely related to the progression of Cancer.

Conclusion: This study showed that β₂-AR is related to a more advanced clinical stage and preoperative lymphatic metastasis. Additionally, a β₂-AR blocker has a significant suppressive effect in OSCC.