Chronic stress-related hormones modulate tumor pathogenesis at multiple levels; however, the molecular pathways involved in stress and cervical cancer progression are not well understood. We established a preclinical orthotopic mouse model of cervical cancer and used the model to show that daily restraint stress increased tumor growth and metastatic tumor burden. Exposure to norepinephrine significantly protected cervical cancer cells from anoikis. We demonstrated that YAP1 was dephosphorylated and translocated from the cytoplasm to the nucleus by norepinephrine, a process initiated by ADRB2/cAMP/protein kinase A activation. Furthermore, anoikis resistance and YAP1 activation induced by norepinephrine could be rescued by a broad β-adrenergic receptor antagonist, propranolol. Collectively, our results provide a pivotal molecular pathway for disrupting pro-tumor neuroendocrine signaling in cervical cancer.

慢性应激相关激素可在多个层面上调节肿瘤的发病机制。然而，有关压力和宫颈癌进展的分子途径尚不十分清楚。我们建立了宫颈癌的临床前原位小鼠模型，并使用该模型显示每日约束压力可增加肿瘤生长和转移性肿瘤负担。暴露于去甲肾上腺素可显着保护子宫颈癌细胞免于缺氧。我们证明YAP1被去甲肾上腺素去磷酸化并从细胞质转移到细胞核，这是由ADRB2 / cAMP /蛋白激酶A激活引发的过程。此外，去甲肾上腺素引起的厌食症抵抗和YAP1激活可以通过广泛的β-肾上腺素能受体拮抗剂普萘洛尔得以挽救。总的来说，