title: Elevated expression of SerpinA1 and SerpinA3 in HLA-positive cervical carcinoma.
abstract: In cervical cancer, an important mechanism by which tumour cells escape immune surveillance is loss of HLA class I, enabling tumours to evade recognition and lysis by cytotoxic T lymphocytes. Some tumours, however, escape from immune surveillance without accumulating defects in antigen presentation. We hypothesized that tumours with no or partial loss of HLA class I develop alternative mechanisms to prevent immune elimination. To investigate this hypothesis, genome-wide expression profiling using Illumina arrays was performed on cervical squamous cell carcinomas showing overall loss of HLA class I, partial, and normal HLA class I protein expression. Statistical analyses revealed no significant differences in gene expression between tumours with partial (n = 11) and normal HLA class I expression (n = 10). Comparison of tumours with normal/partial HLA class I expression (n = 21) with those with overall loss of HLA class I expression (n = 11) identified 150 differentially expressed genes. Most of these genes were involved in the defence response (n = 27) and, in particular, inflammatory and acute phase responses. Especially SerpinA1 and SerpinA3 were found to be up-regulated in HLA-positive tumours (3.6- and 8.2-fold, respectively), and this was confirmed by real-time PCR and immunohistochemistry. In a group of 117 tumours, high SerpinA1 and SerpinA3 expression in association with normal/partial HLA expression correlated significantly with poor overall survival (p = 0.035 and p = 0.05, respectively). Thus, HLA-positive tumours are characterized by higher expression of genes associated with an inflammatory profile. In addition, expression of the acute phase proteins SerpinA1 and SerpinA3 in HLA-positive tumours is associated with worse prognosis.
authors.affiliation: Department of Pathology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: J N
authors.initials: JN
authors.lastname: Kloth
authors.forename: A
authors.initials: A
authors.lastname: Gorter
authors.forename: G J
authors.initials: GJ
authors.lastname: Fleuren
authors.forename: J
authors.initials: J
authors.lastname: Oosting
authors.forename: S
authors.initials: S
authors.lastname: Uljee
authors.forename: N
authors.initials: N
authors.lastname: ter Haar
authors.forename: E J
authors.initials: EJ
authors.lastname: Dreef
authors.forename: G G
authors.initials: GG
authors.lastname: Kenter
authors.forename: E S
authors.initials: ES
authors.lastname: Jordanova
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000032:analysis / Q000235:genetics*; D019139:Tumor Escape; D002583:Uterine Cervical Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D000515:alpha 1-Antitrypsin / Q000032:analysis / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D015395:Histocompatibility Antigens Class I; C043392:SERPINA1 protein, human; C516148:SERPINA3 protein, human; D015843:Serpins; D000515:alpha 1-Antitrypsin