Epstein-Barr virus-encoded LMP2A induces an epithelial-mesenchymal transition and increases the number of side population stem-like cancer cells in nasopharyngeal carcinoma.
Epstein-Barr virus-encoded LMP2A induces an epithelial-mesenchymal transition and increases the number of side population stem-like cancer cells in nasopharyngeal carcinoma.
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DOI：
10.1371/journal.ppat.1000940
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发表时间：
2010-06-03
期刊：
影响因子：
6.7
通讯作者：
Zeng MS
中科院分区：
文献类型：
--
作者：
Kong QL;Hu LJ;Cao JY;Huang YJ;Xu LH;Liang Y;Xiong D;Guan S;Guo BH;Mai HQ;Chen QY;Zhang X;Li MZ;Shao JY;Qian CN;Xia YF;Song LB;Zeng YX;Zeng MS
近年来有报道称，鼻咽癌中存在一个具有干细胞样癌细胞特征的侧群。然而，这种干细胞样细胞群在NPC中的调节的分子机制仍不清楚。Epstein-Barr病毒是第一个发现的与各种恶性肿瘤相关的人类肿瘤病毒，最显著的是NPC。LMP 2A是Epstein-Barr病毒编码的潜伏蛋白，已被报道在致癌过程中发挥作用。通过免疫组织化学染色，我们发现LMP 2A在57.6%的鼻咽癌组织中过表达，主要分布在肿瘤浸润前沿。我们还发现，在NPC细胞中，外源性表达LMP 2A大大增加了它们的侵袭/迁移能力，诱导上皮-间质转化（EMT）样细胞标志物改变，并刺激干细胞侧群和干细胞标志物的表达。此外，LMP 2A在集落形成和软琼脂测定中增强癌细胞的转化能力，以及在球形培养测定中增强干细胞样癌细胞的自我更新能力。此外，LMP 2A在异种移植肿瘤形成测定中增加癌症起始细胞的数量。更重要的是，在NPC样品中LMP 2A的内源性表达与ABCG 2的表达正相关。最后，我们证明了Akt抑制剂（V）大大降低了表达LMP 2A的细胞中干细胞侧群的大小。综上所述，我们的数据表明，LMP 2A诱导EMT和干细胞样细胞的自我更新在NPC，提出了一种新的机制，EB病毒诱导的启动，转移和复发的NPC。EB病毒（EBV）感染了全世界约90%的人，并作为潜伏感染持续存在。然而，EBV与不同类型的人类癌症有关。鼻咽癌（NPC）是最常见的EBV相关癌症，表达一组明确的潜伏病毒基因，包括LMP 2A，已在大多数NPC样本中检测到。一些研究表明，这种潜伏的病毒蛋白驱动细胞侵袭和转移。对于该研究，产生了表达增强的LMP 2A的NPC细胞系。我们在这里表明，LMP 2A诱导上皮-间充质转化并增加NPC中的干细胞样癌细胞。我们的研究结果表明，LMP 2A支持肿瘤的启动和复发的受感染的鼻咽上皮细胞。我们首次报道了一种病毒蛋白，它通过诱导癌症干细胞样细胞在癌症的发生和发展中发挥作用。这些发现允许更详细地了解病毒的功能和致病作用，并为NPC治疗提供了新的治疗靶点。
It has been recently reported that a side population of cells in nasopharyngeal carcinoma (NPC) displayed characteristics of stem-like cancer cells. However, the molecular mechanisms underlying the modulation of such stem-like cell populations in NPC remain unclear. Epstein-Barr virus was the first identified human tumor virus to be associated with various malignancies, most notably NPC. LMP2A, the Epstein-Barr virus encoded latent protein, has been reported to play roles in oncogenic processes. We report by immunostaining in our current study that LMP2A is overexpressed in 57.6% of the nasopharyngeal carcinoma tumors sampled and is mainly localized at the tumor invasive front. We found also in NPC cells that the exogenous expression of LMP2A greatly increases their invasive/migratory ability, induces epithelial–mesenchymal transition (EMT)-like cellular marker alterations, and stimulates stem cell side populations and the expression of stem cell markers. In addition, LMP2A enhances the transforming ability of cancer cells in both colony formation and soft agar assays, as well as the self-renewal ability of stem-like cancer cells in a spherical culture assay. Additionally, LMP2A increases the number of cancer initiating cells in a xenograft tumor formation assay. More importantly, the endogenous expression of LMP2A positively correlates with the expression of ABCG2 in NPC samples. Finally, we demonstrate that Akt inhibitor (V) greatly decreases the size of the stem cell side populations in LMP2A-expressing cells. Taken together, our data indicate that LMP2A induces EMT and stem-like cell self-renewal in NPC, suggesting a novel mechanism by which Epstein-Barr virus induces the initiation, metastasis and recurrence of NPC. Epstein-Barr virus (EBV) infects about 90% of people worldwide and persists benignly as a latent infection. However, EBV is associated with different types of human cancer. Nasopharyngeal carcinoma (NPC) is the most commonly known EBV associated cancer and expresses a well defined set of latent viral genes, including LMP2A, which has been detected in the majority of NPC samples. Several studies indicated this latent viral protein drove cellular invasion and metastasis. For this study, enforced LMP2A expressing NPC cell lines were generated. We show here that LMP2A induces an Epithelial–Mesenchymal Transition and increases the Stem-like Cancer Cells in NPC. Our results suggest that LMP2A supports tumor initiation and recurrence of the infected nasopharyngeal epithelial cells. For the first time we report a virus protein that functions in the initiation and progression of cancer by inducing the cancer stem-like cells. These findings permit a more detailed understanding of function and contribution to viral pathogenesis and provide a novel therapeutic target for NPC therapy.
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