IRF-1 and p65 mediate upregulation of constitutive HLA-A antigen expression by hepatocellular carcinoma cells.
Malignant transformation of hepatocytes is frequently associated with upregulation of HLA-A expression. Currently there is no information available regarding the mechanisms underlying this phenotypic change. We investigated HLA-A expression in 165 paraffin embedded tissues and 21 fresh tissues from liver cancer patients. Utilizing truncated HLA-A promoter-reporter constructs and gel-shift assay we had identified the regulatory elements and transcription factors required for HLA-A upregulation. 54% of the paraffin embedded tissues showed increased HLA-A expression in their cancerous part. 43% of the fresh liver cancer tissues had increased HLA-A complex expression with the HLA-A heavy chain gene demonstrating the highest level of upregulation (62%). Enhanced HLA-A expression in the liver cell lines QGY7701 and BEL7402 was found to be mediated by binding of interferon regulatory factor 1 (IRF-1) to interferon stimulated response element, and of nuclear transcription factor p65 binding to enhancer A element in the HLA-A promoter of these cell lines. The in vivo relevance of these findings was indicated by the association of the enhanced expression of IRF-1 and accumulation of nuclear p65 with HLA-A upregulation in 8 of the 21 liver cancer lesions investigated. Our results indicated that HLA-A upregulation in liver cancer was mediated by both increased nuclear aggregation of transcription factor p65 and upregulation of transcription factor IRF-1.
The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Department of Genetics and Developmental Biology, Southeast University Medical School, Nanjing, Jiangsu 210009, China.
Yuqing
Y
Shen
Mei
M
Xia
Jianqiong
J
Zhang
Lianhong
L
Xu
Jin
J
Yang
Aiqin
A
Chen
Fengqin
F
Miao
Soldano
S
Ferrone
Wei
W
Xie
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015234:HLA-A Antigens / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D020218:Response Elements / Q000235:genetics; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics*
D015234:HLA-A Antigens; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D051996:Transcription Factor RelA