Proteasome Subunit Alpha Type-7 Expression Suppresses Cutaneous Squamous Cell Carcinoma Progression by Inhibiting Cancer-associated Cytokines.

Abstract

Cutaneous squamous cell carcinoma (cSCC) is a common non-melanoma skin cancer, and its incidence is increasing. Proteasome subunit alpha type-7 (PSMA7) has been found to be aberrantly expressed in several cancers. However, whether it functions as a tumor suppressor or oncogene in the pathogenesis of cancers, particularly cSCC, remains controversial. Here, we aimed to investigate the functions of PSMA7 in cSCC pathogenesis. Clinicopathological characteristics were evaluated in 131 patients with cSCC using tissue sections. The expression of PSMA7, nucleotide-binding oligomerization domain-containing protein 1 (NOD1), and mitochondrial antiviral signaling protein (MAVS) was determined in cSCC tissue sections using immunohistochemical staining. The effect of PSMA7 expression on the biological behavior of cSCC cells was investigated in vitro. High immunoreactivity of PSMA7 (high-PSMA7) was detected in 53 (40.5%) patients with cSCC and was significantly associated with histologic grade (p=0.008) and favorable recurrence-free survival (p=0.018). The expression of PSMA7 and NOD1 (p=0.026) and MAVS (p=0.032) was negatively correlated in cSCC tissues. Contrary to the results of the cohort study, cell viability and invasiveness significantly decreased after PSMA7 down-regulation in cSCC cells in vitro. mRNA expression of tumor necrosis factor-alpha, interleukin-1 alpha (IL-1α), IL-6, and IL-8 were significantly increased after PSMA7 down-regulation in cSCC cells (all p=0.002). PSMA7-mediated degradation of NOD1 and MAVS as well as the subsequent reduction of the cancer-associated cytokine network may be a crucial mechanism of the antitumoral function of PSMA7 in patients with cSCC.