Overexpression of squamous cell carcinoma antigen variants in hepatocellular carcinoma

Abstract

Pathogenetic mechanisms of hepatocellular carcinoma (HCC) are still unclear and new tools for diagnostic and therapeutic purposes are ongoing. We have assessed whether squamous cell carcinoma antigen (SCCA), a serpin overexpressed in neoplastic cells of epithelial origin, is also expressed in liver cancer. Squamous cell carcinoma antigen was evaluated by immunohistochemistry in 65 HCCs of different aetiology and in 20 normal livers. Proliferative activity was assessed using MIB-1 antibody. In 18 surgical samples, tumour and nontumour liver tissue was available for SCCA cDNA amplification and sequencing. Squamous cell carcinoma antigen was detected in 55 out of 65 (85%) tumour specimens, but in none of the 20 controls. In the majority of the cases, the positive signal was found in the cytoplasm of more than 50% of the hepatocytes. Low or undetectable SCCA (scorep1) was associated to lower MIB-1 labelling index, compared to cases with SCCA score X2 (mean7s.d.: 2%72.4 vs 7.5%710.3, Po0.05). Squamous cell carcinoma antigen mRNA could be directly sequenced in 14 out of 18 liver tumours but in none of the corresponding nontumour samples. From sequence alignment, a novel SCCA1 variant (G 351 to A) was identified in five cases, while SCCA1 was revealed in six cases and SCCA2 in three cases. In conclusion, SCCA variants are overexpressed in HCC, independently of tumour aetiology. A novel SCCA1 variant has been identified in one third of liver tumours. Hepatocellular carcinoma (HCC) is one of the most important sanitary problems over the world for its high prevalence and for its poor prognosis. More than 250 000 new cases per year are diagnosed and mean 5-year survival is lower than 5% (El-Serag and Mason, 1999). Several factors have been involved in the development of liver cancer, some of them differing in various geographic areas and explaining, at least in part, distinct geographical incidence (Bruix et al, 2001). The most powerful risk factor is the presence of liver cirrhosis. Among cirrhotic Caucasian patients, chronic viral infection by HBV and HCV are the most biologically relevant causes leading to this clinical condition (Benvegnù et al, 1994). However, pathogenetic mechanisms of neoplastic transformation are still unclear; several growth factors and tumour suppressor genes (Collier et al, 1993; Naka et al, 1998; Abou-Shady et al, 1999) have been involved but insufficient data have been generated to date. cDNA microarray analyses for gene expression profiling and potential identification of target genes for diagnostic or therapeutic purposes are ongoing (Shirota et al, 2001;Takeo et al, 2001;Xu et al, 2001).Squamous cell carcinoma antigen is a serine protease inhibitor physiologically found in the spinous and granular layers of normal squamous epithelium, but typically expressed by neoplastic cells of epithelial origin (Kato, 1996). Recent studies indicate that both SCCA1 and SCCA2, the two isoforms so far identified (Schneider et al, 1995), protect neoplastic cells from apoptotic death induced by several k...

Squamous cell carcinoma antigen 1 and 2 mRNA and a new variant expressed in hepatocellular carcinoma

“…Recently it was reported that expression of SCCA-PD, a variant presenting G351A mutation, detected in one third of HCCs [17]. However, only 2 of 31 SCCA positive HCCs were found SCCA-PD-expressing in the present study, and the 2 specimens express the T357A mutation at the same time.…”

“…Moreover mutation of G351A, termed SCCA-PD, has a higher proteinase inhibitory activity than wild type SCCA1, while the mutation of F352G causes a decrease inhibitory activity [25]. As for SCCA-PD, it was detected in 2.2% of HCC patients in our study, whereas an Italian study shown that 35.7% of HCCs was SCCA-PD positive [17]. The discrepancies in findings maybe caused by variations ethnic background.…”

“…The genotypic frequencies were AA 40.7% (11/27), AG 29.6% (8/27) and GG 29.6% (8/27); the G allelic frequency was 0.44. In addition, the new variant was observed in all SCCA1-positive PNT (n=7) and normal liver (n= 1) specimens.Recently it was reported that expression of SCCA-PD, a variant presenting G351A mutation, detected in one third of HCCs [17]. However, only 2 of 31 SCCA positive HCCs were found SCCA-PD-expressing in the present study, and the 2 specimens express the T357A mutation at the same time.…”

“…Recently Pontisso et al [17] detected SCCA expression in HCC by immunohistochemistry for the first time but the expression pattern of SCCA1 and SCCA2 in cancer pathogenesis is not fully defined. Biasiolo et al [18] quantified IgM-linked SCCA1, 2 isoforms in serum of patients with chronic liver diseases, however, their result could not represent the expression of SCCA isoforms in HCC since no correlation was found between serum and tissue levels of SCCA antigen [19].…”

SCCA antigen combined with alpha‐fetoprotein as serologic markers of HCC

“…8 It has been reported that the squamous cell carcinoma antigen (SCCA) is overexpressed in HCC tissues. 9 SCCA is a component of the high molecular weight serine protease inhibitors named serpins. 10 A different expression of SCCA in HCC and peritumoral tissue has recently been documented, together with a higher concentration of this antigen in the serum of HCC patients than cirrhotic patients.…”