Division of Molecular and Cellular Biology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow G116NU, UK.
Mol Cancer. 2010 Jul 9;9:184. doi: 10.1186/1476-4598-9-184.
The latent membrane protein-1 (LMP1) encoded by Epstein-Barr virus (EBV) is an oncoprotein which acts by constitutive activation of various signalling pathways, including NF-kappaB. In so doing it leads to deregulated cell growth intrinsic to the cancer cell as well as having extrinsic affects upon the tumour microenvironment. These properties and that it is a foreign antigen, lead to the proposition that LMP1 may be a good therapeutic target in the treatment of EBV associated disease. LMP1 is expressed in several EBV-associated malignancies, notably in Hodgkin's lymphoma and nasopharyngeal carcinoma (NPC). However, the viral protein is only detected in approximately 30%-50% of NPC samples, as such its role in carcinogenesis and tumour maintenance can be questioned and thus its relevance as a therapeutic target.
In order to explore if LMP1 has a continuous function in established tumours, its activity was inhibited through expression of a dominant negative LMP1 mutant in tumour cell lines derived from transgenic mice. LMP1 is the tumour predisposing oncogene in two different series of transgenic mice which separately give rise to either B-cell lymphomas or carcinomas. Inhibition of LMP1 activity in the carcinoma cell lines lead to a reduction in clonagenicity and clone viability in all of the cell lines tested, even those with low or below detection levels of LMP1. Inhibition of LMP1 activity in the transgenic B-cell lines was incompatible with growth and survival of the cells and no clones expressing the dominant negative LMP1 mutant could be established.
LMP1 continues to provide a tumour cell growth function in cell lines established from LMP1 transgenic mouse tumours, of both B-cell and epithelial cell origin. LMP1 can perform this function, even when expressed at such low levels as to be undetectable, whereby evidence of its expression can only be inferred by its inhibition being detrimental to the growth of the cell. This raises the possibility that LMP1 still performs a pro-oncogenic function in the 50% to 70% of NPC tumours wherein LMP1 protein expression cannot be detected. This reinforces the basis for pursuing LMP1 as a therapeutic target in EBV associated LMP1-expressing malignancies.
Epstein-Barr 病毒 (EBV) 编码的潜伏膜蛋白-1 (LMP1) 是一种癌蛋白，通过固有激活各种信号通路，包括 NF-kappaB，发挥作用。这样做会导致癌细胞的生长失控，以及对肿瘤微环境的外在影响。这些特性以及它是一种外来抗原，导致人们提出 LMP1 可能是治疗 EBV 相关疾病的一个很好的治疗靶点。LMP1 在几种 EBV 相关恶性肿瘤中表达，特别是在霍奇金淋巴瘤和鼻咽癌 (NPC) 中。然而，该病毒蛋白仅在大约 30%-50%的 NPC 样本中检测到，因此其在癌变和肿瘤维持中的作用受到质疑，因此其作为治疗靶点的相关性受到质疑。
为了探索 LMP1 在已建立的肿瘤中是否具有连续功能，通过在源自转基因小鼠的肿瘤细胞系中表达显性负 LMP1 突变体来抑制其活性。LMP1 是两种不同系列转基因小鼠中的肿瘤易感致癌基因，它们分别导致 B 细胞淋巴瘤或癌。在所有测试的细胞系中，抑制 LMP1 活性会导致癌细胞系的克隆形成能力和克隆活力降低，即使在 LMP1 表达水平低或低于检测水平的细胞系中也是如此。在转基因 B 细胞系中抑制 LMP1 活性与细胞的生长和存活不兼容，并且无法建立表达显性负 LMP1 突变体的克隆。
LMP1 继续为源自 LMP1 转基因小鼠肿瘤的细胞系提供肿瘤细胞生长功能，这些细胞系起源于 B 细胞和上皮细胞。即使 LMP1 表达水平低至无法检测，LMP1 也可以发挥此功能，只有通过抑制其表达对细胞生长有害，才能推断出其表达的证据。这增加了这样一种可能性，即 LMP1 仍在 50%-70%的 NPC 肿瘤中发挥致癌作用，在这些肿瘤中无法检测到 LMP1 蛋白表达。这为在 EBV 相关 LMP1 表达恶性肿瘤中追求 LMP1 作为治疗靶点提供了依据。
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