Epigenetic alterations of the SERPINE1 gene in oral squamous cell carcinomas and normal oral mucosa

TY - JOUR

T1 - Epigenetic alterations of the SERPINE1 gene in oral squamous cell carcinomas and normal oral mucosa

AU - Gao, Shan

AU - Nielsen, Boye Schnack

AU - Krogdahl, Annelise

AU - Sørensen, Jens Ahm

AU - Tagesen, Jan

AU - Dabelsteen, Sally

AU - Dabelsteen, Erik

AU - Andreasen, Peter

N1 - (c) 2010 Wiley-Liss, Inc.

PY - 2010/6/1

Y1 - 2010/6/1

N2 - A high level of plasminogen activator inhibitor-1 (PAI-1 or SERPINE1) in tumor extracts is a marker of a poor prognosis in human cancers, including oral carcinomas. However, the mechanisms responsible for the upregulation of PAI-1 in cancers remain unclear. Investigating specific PAI-1 expressing cells in oral carcinomas by immunohistochemistry, we found that PAI-1 was expressed in 18 of the 20 patients, mainly by cancer cells. Two showed PAI-1 positive stromal cells surrounding the tumor areas and five showed PAI-1 positive cells in tumor-adjacent normal epithelium. By real-time RT-PCR analysis, 17 of 20 patients with oral carcinoma were found to have between 2.5- and 50-fold increased tumor PAI-1 mRNA level, as compared with the matched tumor-adjacent normal tissues. The PAI-1 mRNA level in connective tissues from 15 healthy volunteers was similar to the level in tumor-adjacent normal tissues, but the level in epithelium was 5- to 10-fold lower. Analyzing DNA methylation of 25 CpG sites within 960 bp around the transcription initiation site of the SERPINE1 gene by bisulfite sequencing, we did the surprising observation that both tumors and tumor-adjacent normal tissue had a significant level of methylation, whereas there was very little methylation in tissue from healthy volunteers, suggesting that tumor-adjacent normal tissue already contains transformation-associated epigenetic changes. However, there was no general inverse correlation between PAI-1 mRNA levels and SERPINE1 gene methylation in all tissues, showing that CpG methylation is not the main determinant of the PAI-1 expression level in oral tissue.

AB - A high level of plasminogen activator inhibitor-1 (PAI-1 or SERPINE1) in tumor extracts is a marker of a poor prognosis in human cancers, including oral carcinomas. However, the mechanisms responsible for the upregulation of PAI-1 in cancers remain unclear. Investigating specific PAI-1 expressing cells in oral carcinomas by immunohistochemistry, we found that PAI-1 was expressed in 18 of the 20 patients, mainly by cancer cells. Two showed PAI-1 positive stromal cells surrounding the tumor areas and five showed PAI-1 positive cells in tumor-adjacent normal epithelium. By real-time RT-PCR analysis, 17 of 20 patients with oral carcinoma were found to have between 2.5- and 50-fold increased tumor PAI-1 mRNA level, as compared with the matched tumor-adjacent normal tissues. The PAI-1 mRNA level in connective tissues from 15 healthy volunteers was similar to the level in tumor-adjacent normal tissues, but the level in epithelium was 5- to 10-fold lower. Analyzing DNA methylation of 25 CpG sites within 960 bp around the transcription initiation site of the SERPINE1 gene by bisulfite sequencing, we did the surprising observation that both tumors and tumor-adjacent normal tissue had a significant level of methylation, whereas there was very little methylation in tissue from healthy volunteers, suggesting that tumor-adjacent normal tissue already contains transformation-associated epigenetic changes. However, there was no general inverse correlation between PAI-1 mRNA levels and SERPINE1 gene methylation in all tissues, showing that CpG methylation is not the main determinant of the PAI-1 expression level in oral tissue.

KW - Aged

KW - Aged, 80 and over

KW - Carcinoma, Squamous Cell

KW - Case-Control Studies

KW - Chi-Square Distribution

KW - DNA Methylation

KW - Epigenesis, Genetic

KW - Female

KW - Gene Expression Profiling

KW - Humans

KW - Immunohistochemistry

KW - Male

KW - Middle Aged

KW - Mouth Mucosa

KW - Mouth Neoplasms

KW - Plasminogen Activator Inhibitor 1

KW - Polymorphism, Genetic

KW - Promoter Regions, Genetic

KW - Reverse Transcriptase Polymerase Chain Reaction

U2 - 10.1002/gcc.20762

DO - 10.1002/gcc.20762

M3 - Journal article

C2 - 20222049

SN - 1045-2257

VL - 49

SP - 526

EP - 538

JO - Genes, Chromosomes & Cancer

JF - Genes, Chromosomes & Cancer

IS - 6

ER -