The Molecular Diagnosis of Hepatitis B Virus-Associated Hepatocellular Carcinoma

Abstract

Hepatitis B virus (HBV) infection is the major cause of hepatocellular carcinoma (HCC) worldwide. The pathogenesis of HBV-associated HCC has been studied extensively, and molecular changes during malignant transformation have been identified. It has been proposed that the insertion of HBV DNA into the human genome results in chromosomal instability and inactivation of tumor suppressor genes. Transactivation of oncogenes, inactivation of tumor suppressor genes, and alteration of the cell cycle by HBV proteins are also involved in the progression of hepatocellular carcinogenesis. Traditional clinical examinations of HCC, such as biopsy, computer tomography, ultrasonic imaging, and detection of such biomarkers as a-fetoprotein, are currently the "gold standard" in diagnosis. These tests diagnose HCC only in the late stages of disease. This limitation has greatly reduced the chance of survival of HCC patients. To resolve this problem, new biomarkers that can diagnose HCC in earlier stages are necessary. Based on recent molecular studies of the effects of HBV on cellular transformation, differentially expressed biomarkers of HBV infection have been elucidated. With the analyses of the HBV replication profile, the viral load (HBV DNA levels) of patients, and the viral protein expression, the severity of hepatitis in the preneoplastic stages can be assessed. In the future, with the molecular profiles identified by genomic and proteomic approaches, stage-specific biomarkers should be identified to monitor the progression and prognosis of HCC.

Molecular Pathogenesis of Hepatitis-B-virus-associated Hepatocellular Carcinoma

“…4,25,26 Many of these chromosomal segments contain known tumor suppressor genes such as p53, retinoblastoma protein (Rb), cyclin D1, and p16. 4 Several HBV genes have been found in infected tissues, including hepatitis B X gene, truncated pre-S2/S, and a novel spliced transcript of HBV referred to as hepatitis B spliced protein (HBSP).…”

“…Thus, HBx stimulates signal transduction pathways such as the MAPK/ERK pathway in the cytoplasm, and also behaves as a transcriptional transactivator that up-regulates the expression of proto-oncogenes such as c-Myc and c-Jun, transcriptional factors such as NF-kB, AP-1, AP-2, the RPB5 subunit of RNA polymerase II, TATA-binding protein, and ATF/cAMP-response element-binding protein (CREB), as well as other viral genes such as HBV enhancers in the nucleus. [26][27][28]44,45 More target proteins that directly interact with HBx are being identified, including Smad4 and nuclear-factor-activated T cells in tumor necrosis factor (TNF)-α signaling, COX-2, 46 and retinoid X receptor in phosphoenolpyruvate carboxykinase expression. 28 Moreover, several host genes are also reportedly indirectly affected by HBx, such as the up-regulation of interleukin (IL)-6 and IL-8, the induction of nitric oxide synthetase, and Fas ligand.…”

“…Moreover, the infected hepatocytes modulate signal transduction pathways leading to growth, inflammation, or cell death in order to maximize the symbiotic survival of both the virus and the cell, in a process that often progresses to cirrhosis and HCC. 26,27,44,45 The focus of this review is on the roles that signal transduction pathways play in liver cells undergoing pathological changes during an HBV infection. Several studies have investigated the effects of HBx on signaling pathways such as those involving MAPK/ERK, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), PKC, SAPK/JNK, Janus kinase (JAK) signal transducer, and activator of transcription factor (STAT) (Fig.…”

“…These pathways can overlap or interact with one another to generate unique constitutive or prolonged activations that increase cell proliferation and survival. 26 HBx has been shown to up-regulate the MAPK signaling cascade. HBx activation of the Ras/Raf/MAPK pathway also accelerates the entry of cells into the S phase, and is causally associated with transformation.…”

“…Telomeres are shorter in tumors than in normal tissue, suggesting that telomeres are involved in HCC development. 26 Activation of telomerase is considered to be a major mechanism underlying the development of HCC. There is recent evidence that telomere dysfunction leading to telomere-based chromosomal instability is present during the early stages of hepatocarcinogenesis, while telomerase activation occurs during HCC progression.…”