Induction of Bcl-2 expression by hepatitis B virus pre-S2 mutant large surface protein resistance to 5-fluorouracil treatment in Huh-7 cells.
Induction of Bcl-2 expression by hepatitis B virus pre-S2 mutant large surface protein resistance to 5-fluorouracil treatment in Huh-7 cells.
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DOI：
10.1371/journal.pone.0028977
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Wang LH
中科院分区：
文献类型：
--
作者：
Hung JH;Teng YN;Wang LH;Su IJ;Wang CC;Huang W;Lee KH;Lu KY;Wang LH
肝细胞癌是世界范围内最常见的恶性肿瘤之一，由于对常规化疗耐药和放疗疗效有限，预后较差。我们以前的研究表明，乙肝病毒前S2大突变型表面抗原(HBVPre-S2Δ)的表达与肝癌的发生密切相关。然而，HBVPre-S2Δ蛋白与化疗药物耐药的关系尚不清楚。在这里，我们发现HBVPre-S2Δ突变表面蛋白在Huh-7细胞中的表达显著促进了细胞的生长和集落形成。此外，HBVPre-S2Δ蛋白使HUH-7细胞中Bcl2的基因表达水平(2.7±0.5倍，p = 0.0 5)和蛋白水平(3.2±0.3倍，p = 0.0 1)均升高。HBVPre-S2Δ蛋白还可增强Huh-7细胞Bcl2家族、Bclxl和Mcl-1的表达。同时，在表达HBVPre-S2的κ和表达HBVPre-S的细胞中，可以观察到NF-ΔBp65、ERK和Akt的磷酸化以及未折叠的蛋白应答伴侣蛋白GRP78的表达。HBVPre-S2Δ蛋白诱导Bcl2表达，在克隆形成、半胱氨酸天冬氨酸氨基转移酶3检测和细胞凋亡方面对5-氟尿嘧啶产生抵抗，并与Bcl2抑制剂共同孵育可促进细胞死亡。同样，在体内表达HBVPre-S2Δ大表面蛋白的转基因小鼠在肝组织中表现出更高的Bcl2表达。我们的结果表明，HBVPre-S2Δ增加了Bcl2的表达，这在抵抗5-FU诱导的细胞死亡中起着重要作用。因此，这些数据为HBVPre-S2Δ相关肿瘤的治疗提供了重要的化疗策略。
Hepatocellular 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. Here, 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. Our 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.
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影响因子：
13.5
作者：
Fan, YF;Lu, CC;Su, IJ
通讯作者：
Su, IJ
DOI：
10.1046/j.1440-1746.2000.02187.x
发表时间：
2000-05-01
影响因子：
4.1
作者：
Fan, YF;Lu, CC;Su, IJ
通讯作者：
Su, IJ
影响因子：
2
作者：
Kaneko, M;Takahashi, T;Nomura, Y
通讯作者：
Nomura, Y
影响因子：
2
作者：
Kaneko, M;Niinuma, Y;Nomura, Y
通讯作者：
Nomura, Y
影响因子：
64.5
作者：
CHISARI, FV;KLOPCHIN, K;PALMITER, RD
通讯作者：
PALMITER, RD