Abstract
SMYD3 (SET and MYND domain-containing protein 3) is involved in histone modification, which initiates oncogenesis by activating transcription of multiple downstream genes. To investigate associations of variable numbers of tandem repeats (VNTR) variants in the SMYD3 gene promoter, SMYD3 serum levels and SMYD3 mRNA expression in hepatitis B virus (HBV) infection and clinical progression of related liver disease. SMYD3 VNTRs were genotyped in 756 HBV patients and 297 healthy controls. SMYD3 serum levels were measured in 293 patients and SMYD3 mRNA expression was quantified in 48 pairs of hepatocellular tumor and adjacent non-tumor liver tissues. Genotype SYMD3 VNTR 3/3 was more frequent among HCC patients than in controls (Padjusted = 0.037). SMYD3 serum levels increased according to clinical progression of liver diseases (P = 0.01); HCC patients had higher levels than non-HCC patients (P = 0.04). Among patients with SMYD3 VNTR 3/3, HCC patients had higher SMYD3 levels than others (P < 0.05). SMYD3 mRNA expression was up-regulated in HCC tumor tissues compared to other tissues (P = 0.008). In conclusion, upregulation of SMYD3 correlates with the occurrence of HCC and SMYD3 VNTR 3/3 appears to increase the risk of HCC through increasing SMYD3 levels. SMYD3 may be an indicator for HCC development in HBV patients.
Highlights
Effective hepatitis B virus (HBV) vaccines are in use worldwide, HBV-related liver diseases are still a major health concern with approximately 257 million chronic infections and 887,000 deaths in 20151
The present study aimed to investigate the association of variable number of tandem repeat (VNTR) polymorphisms in the SMYD3 promoter and SET and MYND domain containing proteins (SMYDs) expression with HBV infection and clinical progression of HBV-related liver diseases, in particular progression to hepatocellular carcinoma (HCC)
SMYD3, a histone H3-K4 specific methyltransferase, is an example of histone modification which is considered a crucial epigenetic factor contributing to the development of various human cancers, including liver cancer[12,15]
Summary
Effective hepatitis B virus (HBV) vaccines are in use worldwide, HBV-related liver diseases are still a major health concern with approximately 257 million chronic infections and 887,000 deaths in 20151. SMYD3 is the most important member, as several findings have demonstrated its role in tumor cell growth and its increased expression in various cancers. In vitro interaction of SMYD3 with HBV has been demonstrated, showing that SMYD3 expression was upregulated by hepatitis B x protein (HBx) in HepG2 cells, promoting HCC development and clinical progression[17]. It has been suggested that, compared to the genotype containing two copies, the genotype involving three copies of the CCGCC motif might enhance the binding affinity to E2F-1 and, as a result, promote cancer progression by activating transcription of multiple oncogenes such as myc gene (myc), signal transducer and activator of transcription 3 (STAT3) and β-catenin (β-cat)[14,20,21]. The present study aimed to investigate the association of VNTR polymorphisms in the SMYD3 promoter and SMYD expression with HBV infection and clinical progression of HBV-related liver diseases, in particular progression to HCC
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