ABSTRACT
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most important sanitary problems for its prevalence and poor prognosis. To date, no information is available on the prognostic value of the ov-serpin SERPINB3, detected in primary liver cancer but not in normal liver. The aim of the study was to analyse SERPINB3 expression in liver cancer in relation with molecular signatures of poor prognosis and with clinical outcome. METHODS: Liver tumours of 97 patients were analysed in parallel for SERPINB3, TGF-ß and ß-catenin. In a subgroup of 67 patients with adequate clinical follow-up, the correlation of molecular findings with clinical outcome was also carried out. RESULTS: High SERPINB3 levels were detectable in 22% of the patients. A significant correlation of this serpin with TGF-ß at transcription and protein level was observed, whereas for ß-catenin a strong correlation was found only at post-transcription level. These findings were in agreement with transcriptome data meta-analysis, showing accumulation of SERPINB3 in the poor-prognosis subclass (S1). High levels of this serpin were significantly associated with early tumour recurrence and high SERPINB3 was the only variable significantly associated with time to recurrence at multivariate analysis. CONCLUSIONS: SERPINB3 is overexpressed in the subset of the most aggressive HCCs.
Subject(s)
Antigens, Neoplasm/metabolism , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/metabolism , Neoplasm Recurrence, Local/metabolism , Serpins/metabolism , Transforming Growth Factor beta1/metabolism , beta Catenin/metabolism , Adult , Aged , Aged, 80 and over , Antigens, Neoplasm/genetics , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/surgery , Disease-Free Survival , Female , Gene Expression , Gene Expression Profiling , Hep G2 Cells , Humans , Kaplan-Meier Estimate , Liver/metabolism , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Liver Neoplasms/surgery , Male , MicroRNAs/genetics , MicroRNAs/metabolism , Middle Aged , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/prevention & control , Prognosis , Proportional Hazards Models , RNA, Messenger/genetics , RNA, Messenger/metabolism , Serpins/genetics , Transforming Growth Factor beta1/genetics , beta Catenin/geneticsABSTRACT
Epidermal growth factor receptor (EGFR) is a trans-membrane tyrosine kinase taking part in cell transformation and tumor progression. One of the downstream pathways controlled by EGFR involves the mammalian target of rapamycin (mTOR), a proto-oncogene activated in several cell functions. Recent evidence seems to confirm that both EGFR and mTOR regulate angiogenesis. The aim of this study was to investigate the expression of EGFR and mTOR in laryngeal squamous cell carcinoma (LSCC) cells in a retrospective clinical setting and their correlation with tumor neo-angiogenesis, judged on the grounds of CD105-assessed microvascular density (MVD), and prognosis. We considered 76 consecutive patients with LSCC treated with surgery alone. Immunohistochemical expressions of EGFR, mTOR, and CD105 were measured using image analysis and findings underwent statistical analysis using univariate and multivariate models. We found that nodal status correlated significantly with patient prognosis in terms of disease-free survival (DFS) (p = 0.01). There was a strong direct correlation between mTOR and EGFR expression (p = 0.0003), and between mTOR and CD105-assessed MVD (p = 0.0025). Patients with a CD105-assessed MVD >5.28 % had a significantly higher recurrence rate (RR) (p = 0.026), and a significantly shorter DFS (p = 0.025). On multivariate analysis, only N stage [hazard ratio (HR) 3.54, p = 0.009] and CD105-assessed MVD (HR 2.87, p = 0.027) maintained their independent prognostic significance in terms of DFS. Judging from our promising findings, the EGFR-mTOR pathway should be investigated further to understand its role in LSCC neo-angiogenesis.
Subject(s)
Antigens, CD/metabolism , Carcinoma, Squamous Cell/metabolism , ErbB Receptors/metabolism , Head and Neck Neoplasms/metabolism , Laryngeal Neoplasms/metabolism , Neovascularization, Pathologic/metabolism , Receptors, Cell Surface/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/surgery , Cohort Studies , Disease-Free Survival , Endoglin , Female , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/surgery , Humans , Immunohistochemistry , Laryngeal Neoplasms/pathology , Laryngeal Neoplasms/surgery , Male , Middle Aged , Neovascularization, Pathologic/pathology , Prognosis , Proto-Oncogene Mas , Retrospective Studies , Squamous Cell Carcinoma of Head and NeckABSTRACT
BACKGROUND: The serpin squamous cell carcinoma antigen (SCCA, SERPINB3) has been found over-expressed in primary liver cancer and at lower extent in cirrhosis and chronic hepatitis. A novel SCCA-1 variant (SCCA-PD), presenting a single mutation in the reactive centre (Gly351Ala), has been recently identified (rs3180227). AIM: To explore SCCA-1 polymorphism in patients with HCV infection as single etiologic factor and different extent of liver disease. METHODS: One hundred and fourty-eight patients with chronic HCV infection (45 chronic hepatitis, 53 cirrhosis, 50 HCC) and 50 controls were evaluated. SCCA-1 polymorphism was studied by restriction fragment length polymorphism and confirmed randomly by direct sequencing. Circulating SCCA-IgM complex was determined by ELISA. RESULTS: SCCA-PD was detected with higher frequency in cirrhotic patients (45.3%, odds ratio=2.62; 95%CI 1.13-6.10, p=0.038) than in patients with chronic hepatitis or in controls (24.4% and 24%, respectively). Intermediate figures were found in hepatocarcinoma (36.0%). SCCA-IgM in serum was lower in patients carrying SCCA-PD than in wild type patients and the difference was statistically significant in cirrhotic patients (mean+/-S.D.=117.45+/-54.45 U/ml vs. 268.52+/-341.27 U/ml, p=0.026). CONCLUSIONS: The newly identified SCCA-PD variant was more frequently found in liver cirrhosis, suggesting that patients carrying this polymorphism are more prone to develop progressive liver fibrosis.
