Carboxyl-terminal truncated HBx contributes to invasion and metastasis via deregulating metastasis suppressors in hepatocellular carcinoma.
Carboxyl-terminal truncated HBx contributes to invasion and metastasis via deregulating metastasis suppressors in hepatocellular carcinoma.
复制标题
DOI：
10.18632/oncotarget.10399
复制
发表时间：
2016-08-23
期刊：
影响因子：
--
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Li W;Li M;Liao D;Lu X;Gu X;Zhang Q;Zhang Z;Li H
B型肝炎病毒（HBV）X蛋白（HBx）是一种反式调节因子，在肝细胞癌（HCC）中以截短型表达，但其作用机制尚不清楚。在这份报告中，我们调查了这种天然HBx突变体在HCC中的频率及其功能意义。在102例HBV感染的HCC患者中，与全长HBx相比，HBx的C端截短在肿瘤中（70.6%）比在邻近非肿瘤组织中（29.4%）更普遍（p = 0.0032）。此外，在肿瘤中鉴定了两种天然存在的HBx变体（HBxΔ31），其在C端缺失了31个氨基酸（密码子123-125/124-126），并且发现HBxΔ31的存在与肝内转移显著相关。我们还发现，与全长HBx相比，HBxΔ31的过表达增强了肝癌细胞的体外侵袭和体内转移。有趣的是，HBxΔ31通过下调Maspin、RhoGDIα和CAPZB（HCC中一组假定的转移抑制因子）发挥这一功能，部分是通过增强转录抑制因子myc相关锌指蛋白（MAZ）与启动子的结合（通过与MAZ的物理缔合）。值得注意的是，这些HBxΔ31抑制蛋白在具有C-末端HBx截短的HCC组织亚组中的表达也显著低于邻近的非肿瘤组织，突出了这种新型HBxΔ31驱动的转移性分子级联的临床意义。我们的数据表明，HBx的C-末端截短，特别是在124 aa的断点，发挥了作用，在增强肝癌细胞的侵袭和转移，通过解除调节一组转移抑制部分通过MAZ，从而揭示了一个新的机制，HBV相关的肝癌发生的进展。
Hepatitis B virus (HBV) X protein (HBx), a trans-regulator, is frequently expressed in truncated form without carboxyl-terminus in hepatocellular carcinoma (HCC), but its functional mechanisms are not fully defined. In this report, we investigated frequency of this natural HBx mutant in HCCs and its functional significance. In 102 HBV-infected patients with HCC, C-terminal truncation of HBx, in contrast to full-length HBx, were more prevalent in tumors (70.6%) rather than adjacent non-tumorous tissues (29.4%) (p = 0.0032). Furthermore, two naturally-occurring HBx variants (HBxΔ31), which have 31 amino acids (aa) deleted (codons 123-125/124-126) at C-terminus were identified in tumors and found that the presence of HBxΔ31 significantly correlated with intrahepatic metastasis. We also show that over-expression of HBxΔ31 enhanced hepatoma cell invasion in vitro and metastasis in vivo compared to full-length HBx. Interestingly, HBxΔ31 exerts this function via down-regulating Maspin, RhoGDIα and CAPZB, a set of putative metastasis-suppressors in HCC, in part, by enhancing the binding of transcriptional repressor, myc-associated zinc finger protein (MAZ) to the promoters through physical association with MAZ. Notably, these HBxΔ31-repressed proteins were also significantly lower expression in a subset of HCC tissues with C-terminal HBx truncation than the adjacent non-tumorous tissues, highlighting the clinical significance of this novel HBxΔ31-driven metastatic molecular cascade. Our data suggest that C-terminal truncation of HBx, particularly breakpoints at 124aa, plays a role in enhancing hepatoma cell invasion and metastasis by deregulating a set of metastasis-suppressors partially through MAZ, thus uncovering a novel mechanism for the progression of HBV-associated hepatocarcinogenesis.