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

Research output: ThesisDoctoral Thesis

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
Original languageEnglish
QualificationDoctor of Health Science
Awarding Institution
  • University of Otago
Supervisors/Advisors
  • Seo, Benedict, Advisor, External person
  • Rich, Alison, Advisor, External person
Award date13 Nov 2016
Publication statusPublished - 2016
Externally publishedYes

Fingerprint

STAT3 Transcription Factor
Endoplasmic Reticulum Stress
Squamous Cell Carcinoma
Keratinocytes
Cell Line
OSM-LIF Receptors
Immunohistochemistry
Interleukin-6 Receptors
Mouth Mucosa
Proteins
Unfolded Protein Response
Tunicamycin
Neoplasms
Tumor Microenvironment
Interleukin-5
Heat-Shock Proteins
Transducers
Genes
Up-Regulation
Apoptosis

Grant Number

  • NZDA RF8.21 2015
  • NZDA RF8.19 2016

Cite this

@phdthesis{7b7fe97fc5604a9397223e438224c52b,
title = "The differential regulation of Signal Transducer and Activator of Transcription-3 pathway under Endoplasmic Reticulum Stress in Oral Squamous Cell Carcinoma",
abstract = "BackgroundSignal 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.MethodsThree 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.ResultsER 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.ConclusionThe 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",
author = "Muhammed Yakin",
year = "2016",
language = "English",
school = "University of Otago",

}

TY - THES

T1 - The differential regulation of Signal Transducer and Activator of Transcription-3 pathway under Endoplasmic Reticulum Stress in Oral Squamous Cell Carcinoma

AU - Yakin, Muhammed

PY - 2016

Y1 - 2016

N2 - BackgroundSignal 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.MethodsThree 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.ResultsER 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.ConclusionThe 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

AB - BackgroundSignal 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.MethodsThree 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.ResultsER 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.ConclusionThe 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

UR - http://hdl.handle.net/10523/6927

M3 - Doctoral Thesis

ER -