The stress hormone norepinephrine promotes tumor progression through β2-adrenoreceptors in oral cancer

Highlights

• Chronic stress hormone NE can induce OSCC progression through activiating the β2-AR signaling pathway.

• ADBR2/ERK/CREB signaling pathway contributes to the NE-promoted OSCC invasion and proliferation.

• Some important stemness-associated genes are up-regulated through β2-AR signaling pathway, such as CD44, OCT4, SOX2 and ALDH1.

• β2-AR signaling is essential for the activation and maintenance of oral CSC stemness.

Abstract

Objective

Chronic stress hormone norepinephrine (NE) has been previously reported to play a role in the development of cancer, but the correlation between NE and oral squamous cell carcinoma (OSCC) progression is not well understood.

Method

To address this, the expression of adrenergic receptors (ARs) in human OSCC cell lines and clinic OSCC samples was detected, and the role of NEin vivo and in vitro was further investigated.

Results

It was found that β2-AR was the main AR of NE in OSCC. Stimulation of OSCC cells with NE significantly increased the OSCC proliferation and invasion, which was, however, blocked by β2-AR inhibitor. NE could induce the phosphorylation of extracellular regulated protein kinases (ERK) and cAMP-response element binding protein (CREB). Inhibition of ERK and CREB pathway abrogated NE-induced OSCC invasion and proliferation. NE could enhance cancer stem cells (CSCs)-like phenotype and up-regulate the expression of stemness marker. In tumor-bearing nude mice, it was found that consecutive administration of NE significantly promoted the tumor growth, while daily injection of β2-AR inhibitor blocked this phenomenon.

Conclusions

Those findings indicated a critical role of the chronic stress hormone NE in OSCC progression. Inhibition of β2-AR may serve as a potential therapeutic strategy for protecting OSCC patients from chronic stress related deleterious effect.