Abstract
BackgroundHepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor prognosis due to resistance to conventional chemotherapy and limited efficacy of radiotherapy. Our previous studies have indicated that expression of Hepatitis B virus pre-S2 large mutant surface antigen (HBV pre-S2Δ) is associated with a significant risk of developing HCC. However, the relationship between HBV pre-S2Δ protein and the resistance of chemotherapeutic drug treatment is still unclear.Methodology/Principal FindingsHere, we show that the expression of HBV pre-S2Δ mutant surface protein in Huh-7 cell significantly promoted cell growth and colony formation. Furthermore, HBV pre-S2Δ protein increased both mRNA (2.7±0.5-fold vs. vehicle, p = 0.05) and protein (3.2±0.3-fold vs. vehicle, p = 0.01) levels of Bcl-2 in Huh-7 cells. HBV pre-S2Δ protein also enhances Bcl-2 family, Bcl-xL and Mcl-1, expression in Huh-7 cells. Meanwhile, induction of NF-κB p65, ERK, and Akt phosphorylation, and GRP78 expression, an unfolded protein response chaperone, were observed in HBV pre-S2Δ and HBV pre-S-expressing cells. Induction of Bcl-2 expression by HBV pre-S2Δ protein resulted in resistance to 5-fluorouracil treatment in colony formation, caspase-3 assay, and cell apoptosis, and can enhance cell death by co-incubation with Bcl-2 inhibitor. Similarly, transgenic mice showed higher expression of Bcl-2 in liver tissue expressing HBV pre-S2Δ large surface protein in vivo.Conclusion/SignificanceOur result demonstrates that HBV pre-S2Δ increased Bcl-2 expression which plays an important role in resistance to 5-fluorouracil-caused cell death. Therefore, these data provide an important chemotherapeutic strategy in HBV pre-S2Δ-associated tumor.
Highlights
Hepatocellular carcinoma (HCC) is a common malignancy affecting approximately one million people worldwide annually [1]
We show that HBV pre-S2D large surface protein enhances Bcl-2 gene expression and alters chemotherapeutic drug resistance by a mechanism involving Bcl-2 proto-oncogene expression in human hepatoma cancer cells
Expression of Bcl-2 was increased by pre-S2D proteins in human immortalized hepatocyte cells and pre-S2D transgenic mice liver tissue
Summary
Hepatocellular carcinoma (HCC) is a common malignancy affecting approximately one million people worldwide annually [1]. It is one of the most common causes of cancer morbidity and mortality in Asia and Africa. One of the major mutant types is the deletion of the pre-S2 region (pre-S2D) These pre-S2D mutants are becoming increasingly prevalent in serum and liver tissues of patients with chronic HBV infection and HCC [15,16,17]. Our previous studies have indicated that expression of Hepatitis B virus pre-S2 large mutant surface antigen (HBV pre-S2D) is associated with a significant risk of developing HCC. The relationship between HBV pre-S2D protein and the resistance of chemotherapeutic drug treatment is still unclear
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