The impact ofERP29on the progression of pharyngeal squamous cell carcinoma

Abstract

Objectives: We investigated ERP29 gene role on pharynx squamous cell carcinoma (PSCC) progression in cisplatin (CDDP)-sensitive (FaDu and LAU-2063), CDDP-treated (FaDu-CDDP), and CDDP-resistant (FaDu-R) cells. Materials and Methods: Cells, modified to induce ERP29 overexpression or silencing, were mainly submitted to cell proliferation, necrosis, and migration assay. E-cadherin immunoexpression was assessed in three-dimensional spheroids. WNT, MAPK, and PI3K/AKT pathways genes' expression were identified by PCR array and validated by qPCR. The influence of microRNA miR-4421 inhibitor on ERP29 expression, and its target genes, were quantified by qPCR. Results: ERP29 silencing especially decreased necrotic cell death and increased migration in CDDP-sensitive, treated, and resistant cells, and decreased E-cadherin immunoexpression in CDDP-sensitive three-dimensional-spheroids. During CDDP treatment, ERP29 silencing increased cell proliferation. In CDDP-sensitive cells, ERP29 silencing increased the expression of several genes involved in WNT, MAPK, and PI3K/AKT pathways and decreased CASP9 expression. During CDDP treatment, ERP29 silencing decreased MDM2 and CASP9 expression. In CDDP-resistant cells, ERP29 silencing increased SOS1, MAPK1, AKT1, ITGAV, and CCNE1; and decreased KRAS, JUN, MDM2, and CASP9 expression. In addition, miR-4421 inhibition increased ERP29 expression and decreased MAPK1, AKT1, and JUN expression in CDDP-sensitive cells; and SOS1, MAPK1, AKT1, and ITGAV in CDDP-resistant cells, suggesting a potential therapeutic use for miR-4421 inhibitor. Conclusions: ERP29 silencing seems to decrease necrosis and increase migration of PSCC cells by modulating genes enrolled in WNT, MAPK, and PI3K/AKT pathways. Once validated, our data may enable target therapy development based on ensuring ERP29 expression that could benefit patients with CDDP-sensitive and resistant tumors.