title: SH2D4A is frequently downregulated in hepatocellular carcinoma and cirrhotic nodules.
abstract: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. The lack of effective therapeutic options for advanced stage HCCs combined with an increasing incidence rate calls for the identification of early stage HCC molecular markers. SH2 Domain Containing 4A (SH2D4A) gene maps to human chromosome 8p21.3 and encodes for SH(2)A. The chromosomal region containing SH2D4A is frequently lost in colorectal, lung and HCC cancers. Our study aimed to investigate SH2D4A involvement in HCC pathogenesis combining mRNA expression, protein and clinical data. Transcriptome analysis performed on 37 HCC needle biopsies (matched with their corresponding non-neoplastic parenchyma) and five normal liver donor samples revealed that SH2D4A is downregulated in HCC. Results were confirmed by quantitative real-time-polymerase chain reaction (qRT-PCR), 25 out of 37 (67.6%) fresh frozen samples showed SH2D4A downregulation (p = 0.026). Furthermore, combining qRT-PCR and immunohistochemistry data we demonstrated a direct correlation between SH2D4A mRNA and SH(2)A protein levels. The analysis of a tissue microarray (TMA) containing 336 specimens confirmed that SH(2)A is frequently reduced in HCC (56.8%) as well as in cirrhotic nodules (50.5%) compared to normal liver samples (31.1%). To conclude, our study revealed that SH2D4A is frequently downregulated in HCC samples thus corroborating its putative role as a tumour suppressor gene. In addition, we provide new evidence for SH2D4A involvement in HCC pathogenesis demonstrating for the first time its deregulation in cirrhotic nodules.
authors: Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
authors: Luca
authors: L
authors: Quagliata
authors: Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
authors: Mariacarla
authors: M
authors: Andreozzi
authors: Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
authors: Michal
authors: M
authors: Kovac
authors: Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
authors: Luigi
authors: L
authors: Tornillo
authors: Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland.
authors: Zuzanna
authors: Z
authors: Makowska
authors: Department of Biomedicine, Institute of Biochemistry and Genetics, University of Basel, Basel, Switzerland.
authors: Francesca
authors: F
authors: Moretti
authors: Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland.
authors: Markus H
authors: MH
authors: Heim
authors: Research Group Human Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland; Division of Medical Genetics, University Children's Hospital, Basel, Switzerland.
authors: Karl
authors: K
authors: Heinimann
authors: Institute of Pathology, University Hospital of Basel, Basel, Switzerland; Research Group Human Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland; Division of Medical Genetics, University Children's Hospital, Basel, Switzerland.
authors: Salvatore
authors: S
authors: Piscuoglio
authors: Institute of Pathology, University Hospital of Basel, Basel, Switzerland. Electronic address: lterracciano@uhbs.ch.
authors: Luigi Maria
authors: LM
authors: Terracciano
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000235:genetics*; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008103:Liver Cirrhosis / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D008113:Liver Neoplasms / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D046888:Tissue Array Analysis
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C474507:SH2D4A protein, human
keywords: Cirrhotic nodules; Hepatocellular carcinoma; SH2D4A; Tumour suppressor gene