title: Tumor HLA-DR expression linked to early intrahepatic recurrence of hepatocellular carcinoma.
abstract: The outcome of patients with hepatocellular carcinoma (HCC) remains poor because of the high frequency of intrahepatic recurrence (IHR), particularly early IHR within 1 year of hepatectomy. To search for genes involved in early IHR, we performed DNA microarray analysis in a training set of 33 HCCs and selected 46 genes linked to early IHR from approximately 6,000 genes by means of a supervised learning method. Gene selection was validated by a false discovery rate of 0.37%. The 46 genes included many immune response-related genes, which were all downregulated in HCCs with early IHR. Four of these genes (HLA-DRA, HLA-DRB1, HLA-DG and HLA-DQA), encoding MHC class II antigens, were coordinately downregulated in HCCs with early IHR compared to levels in HCCs with nonrecurrence. A cluster analysis reproduced expression patterns of the 4 MHC class II genes in 27 blinded HCC samples. To localize the major site of production of HLA-DR protein in the tumor, we used 50 frozen specimens from 50 HCCs. Immunofluorescence staining showed that HLA-DR protein levels in tumor cells, but not in stromal cells, were associated with the transcription levels of HLA-DRA determined by both DNA microarray analysis and real-time quantitative reverse transcription-PCR. Univariate analysis showed that tumor HLA-DR protein expression, pTNM stage and venous invasion were associated with early IHR. Multivariate analysis showed that tumor HLA-DR protein expression was one of the independent risk factors for early IHR, suggesting HLA-DR protein potential as a biomarker and a molecular target for therapeutic intervention.
authors.affiliation: Department of Surgery II, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Matoba
authors.forename: Norio
authors.initials: N
authors.lastname: Iizuka
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Gondo
authors.forename: Tokuhiro
authors.initials: T
authors.lastname: Ishihara
authors.forename: Hisafumi
authors.initials: H
authors.lastname: Yamada-Okabe
authors.forename: Takao
authors.initials: T
authors.lastname: Tamesa
authors.forename: Norikazu
authors.initials: N
authors.lastname: Takemoto
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Takanobu
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Shunji
authors.initials: S
authors.lastname: Uchimura
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hamamoto
authors.forename: Masaaki
authors.initials: M
authors.lastname: Oka
mesh_terms: D000368:Aged; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006684:HLA-DR Antigens / Q000235:genetics* / Q000378:metabolism; D006499:Hepatic Artery / Q000473:pathology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000378:metabolism; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D014408:Biomarkers, Tumor; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; C045084:invariant chain