The differential regulation of Signal Transducer and Activator of Transcription-3 pathway under Endoplasmic Reticulum Stress in Oral Squamous Cell Carcinoma

Abstract

Background 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 (ER) stress and the unfolded protein response (UPR) promote either survival or apoptosis in different cancers. The aim of the study was to investigate the expression of STAT3 pathway-related genes and proteins under ER stress in OSCC. Methods Three normal oral keratinocyte (NOK) and three OSCC cell lines were subjected to tunicamycin (an agent known to induce ER stress) for 24 hours or to the vehicle medium as control. A focussed STAT3 Pathway Array was used to analyse the modulation of STAT3 pathway gene expression under ER stress using qPCR. The expression of key regulated proteins was investigated in the cell lines using immunocytochemistry (ICC) and in 76 OSCC and 9 normal oral mucosa (NOM) tissue using immunohistochemistry (IHC) using tissue microarray (TMA) technology. Results ER stress resulted in up-regulation of IL6 receptor (IL6R) gene in NOK cell lines (p=0.001) and IL5 (p=0.005) and IL22 (p=0.024) in OSCC cell lines. Leukaemia inhibitory factor receptor (LIFR) gene was up-regulated in OSCC cell lines (p=0.04). ICC showed a greater extent of STAT3 (p=0.019) and LIFR (p=0.042) protein expression in treated NOK than untreated NOK cell lines. IHC showed more STAT3 (p=0.046) and IL6R (p=0.027) protein expression in OSCC than in NOM tissue. Conclusion The gene and protein regulation patterns show that ER stress plays a role in immune-modulation in the tumour microenvironment in OSCC by up-regulating tumour-promoting cytokines.