TUNICAMYCIN-INDUCED ENDOPLASMIC RETICULUM STRESS UP-REGULATES TUMOUR-PROMOTING CYTOKINES IN ORAL SQUAMOUS CELL CARCINOMA

Abstract

Objectives Signal transducer and activator of transcription (STAT)-3 lies at the convergence point of key pathways involved in many malignancies including oral squamous cell carcinoma (OSCC). Endoplasmic reticulum stress (ERS) and the unfolded protein response promote either survival or apoptosis in different cancers. We investigated the expression of STAT3 pathway-related genes and proteins under ERS in OSCC. Three normal oral keratinocyte (NOK) and three OSCC cell lines were subjected to tunicamycin to induce ERS for 24 hours or to the vehicle medium as control. A pathway-focussed array was used to analyse the modulation of STAT3 pathway gene expression under ERS using qPCR. The expression of key regulated proteins was investigated in the cell lines using immunocytochemistry and in 76 OSCC and 9 normal oral mucosa (NOM) tissue samples using tissue microarray technology and immunohistochemistry. Findings ERS resulted in up-regulation of interleukin-6 receptor (IL6R) gene in NOK cell lines (p = 0.001) and IL5 (p = 0.005) and IL22 (p = 0.024) in OSCC cell lines. Greater STAT3 (p = 0.019) and leukaemia inhibitory factor receptor (p = 0.042) protein expression was observed in treated than untreated NOK cell lines. Conclusions The gene and protein regulation patterns show that ERS plays a role in modifying the tumour microenvironment in OSCC by up-regulating tumour-promoting cytokines.