The pleiotropic HBx protein of hepatitis B virus is linked functionally to the development of hepatocellular carcinoma (HCC) via effectors and signalling pathways of the host. To identify such effectors in a macrocarcinogenic environment, a PCR-based cDNA subtraction analysis was carried out in the X15-myc oncomouse model of HCC. Altogether, 19 categories of genes, mainly involved in protein biosynthesis and the electron-transport chain, were found to be upregulated in the liver of these mice. Ribosomal protein S27a (RPS27a), which is a natural fusion protein of N-terminal ubiquitin and C-terminal extension protein (CEP), topped the list of expressed genes, with .20-fold higher expression compared with its normal level. Sustained and elevated expression of RPS27a in the mouse liver and its moderate expression in cell culture in the presence of HBx suggested an indirect role of RPS27a in hepatocarcinogenesis. Nevertheless, a remarkable change in the intracellular distribution of ubiquitin from cytoplasm to late-endosomal lysosomes, and of CEP from nucleoli to the perinucleolar region/nuclear foci, was observed in the presence of HBx. RPS27a accelerated the progression of the cell cycle and cooperated with HBx in this process. Further, the knockdown of RPS27a expression by RNA interference in an HBx microenvironment led to retarded cell-cycle progression and reduced cell size. Thus, these results suggest strongly that RPS27a could be an effector of HBx-mediated hepatocarcinogenesis. INTRODUCTIONChronic infection by hepatitis B virus (HBV) is a major public-health threat worldwide because of its reported association with cirrhosis, and more ominously hepatocellular carcinoma (HCC) (McMahon, 2009;Yang & Roberts, 2010). The oncogenic mechanisms of HBV have now begun to be elucidated. Multiple direct and indirect processes are involved in establishing HBV-related HCC (Kremsdorf et al., 2006). Integration of the HBV genome may stimulate tumorigenesis through either the cisactivation of cellular genes, such as the myc family of genes in woodchucks (Fourel et al., 1990), or transactivation by the viral X protein or HBx (Caselmann, 1996). HBx has been studied extensively for its role in HCC. It is a pleiotropic trans-activator that can stimulate a wide range of viral and cellular promoters (reviewed by Benhenda et al., 2009;Kumar & Sarkar, 2004). The oncogenic potential of HBx is evident from its ability to modulate tumorigenic signalling pathways (reviewed by Benhenda et al., 2009;Bouchard & Schneider, 2004), upregulate the expression of cellular oncogenes such as c-myc and c-jun (Caselmann, 1996) and functionally inactivate the tumour-suppressor protein p53 (Ueda et al., 1995). Besides, HBx can transform immortalized cells in vitro (Höhne et al., 1990; Shirakata et al., 1989) and induce liver-specific tumours in transgenic mouse models (reviewed by Kumar, 2008). There is constitutive activation of selected signalling pathways that promote cell growth and survival (Chemin & Zoulim, 2009).Although HBx stimulates a number...
Butea monosperma (Lam.) (family: Fabaceae) popularly known as 'Palas' or 'fire of forest' has been used traditionally as a hepatoprotective agent. This study evaluated the hepatoprotective and antitumorigenic properties of the aqueous extract and butanol fractions of B. monosperma flowers in animal models. Dried flowers of B. monosperma were extracted with water and fractionated further using n-butanol. The hepatoprotective activity of the aqueous extract was initially confirmed in a carbon tetrachloride-induced liver damage model of rats. Oral administration of the aqueous extract produced a strong hepatoprotective effect similar to silymarin and normalized the serum levels of ALT, AST, bilirubin and triglyceride in rats. However, it did not affect the levels of glutathione and malondialdehyde which are oxidative stress markers in liver. Intraperitoneal administration of the aqueous extract in the X15-myc oncomice not only maintained liver architecture and nuclear morphometry but also down-regulated the serum VEGF levels. Immunohistochemical staining of liver sections with anti-Ribosomal protein S27a antibody showed post-treatment abolition of this proliferation marker from the tumor tissue. The butanol fractions, however, did not show antitumorigenic activity. Thus, the aqueous extract of B. monosperma flowers is not only hepatoprotective but also antitumorigenic by preserving the nuclear morphometry of the liver.
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