NF-κB p65 Subunit Is Modulated by Latent Transforming Growth Factor-β Binding Protein 2 (LTBP2) in Nasopharyngeal Carcinoma HONE1 and HK1 Cells.
NF-κB p65 Subunit Is Modulated by Latent Transforming Growth Factor-β Binding Protein 2 (LTBP2) in Nasopharyngeal Carcinoma HONE1 and HK1 Cells.
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DOI：
10.1371/journal.pone.0127239
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Lung ML
中科院分区：
文献类型：
--
作者：
Kan R;Shuen WH;Lung HL;Cheung AK;Dai W;Kwong DL;Ng WT;Lee AW;Yau CC;Ngan RK;Tung SY;Lung ML
NF-κB 是一种特征明确的转录因子，被广泛认为是肿瘤源性炎症和癌症发展中的关键角色。在此，我们介绍了典型 NF-κB p65 亚基在鼻咽癌 (NPC) 中的功能和分子相关性。利用功能丧失和获得方法来揭示p65在NPC细胞中增殖肿瘤生长、肿瘤相关血管生成和上皮间质转化中的功能特征。细胞外炎症刺激是触发 NF-κB p65 信号传导的关键因素；因此，我们研究了可能影响 p65 信号通路的肿瘤微环境的组成部分。这导致了一种细胞外基质（ECM）蛋白的鉴定，该蛋白先前被报道为鼻咽癌的候选肿瘤抑制因子。我们对潜在转化生长因子-β 结合蛋白 2 (LTBP2) 蛋白的研究提供了大量证据，证明它可以调节 p65 转录活性。 LTBP2 的重新表达会引发肿瘤抑制作用，这与 NPC 细胞中 p65 的失活类似。 LTBP2能够减少p65丝氨酸536位点的磷酸化，抑制活性磷酸化p65的核定位，并损害p65 DNA结合能力。这导致 p65 相关基因表达的相应下调。因此，数据表明p65表达的整体上调和这种候选ECM肿瘤抑制因子的丧失是促进NPC发展的里程碑事件。
NF-κB is a well-characterized transcription factor, widely known as a key player in tumor-derived inflammation and cancer development. Herein, we present the functional and molecular relevance of the canonical NF-κB p65 subunit in nasopharyngeal carcinoma (NPC). Loss- and gain-of-function approaches were utilized to reveal the functional characteristics of p65 in propagating tumor growth, tumor-associated angiogenesis, and epithelial-to-mesenchymal transition in NPC cells. Extracellular inflammatory stimuli are critical factors that trigger the NF-κB p65 signaling; hence, we investigated the components of the tumor microenvironment that might potentially influence the p65 signaling pathway. This led to the identification of an extracellular matrix (ECM) protein that was previously reported as a candidate tumor suppressor in NPC. Our studies on the Latent Transforming Growth Factor-β Binding Protein 2 (LTBP2) protein provides substantial evidence that it can modulate the p65 transcriptional activity. Re-expression of LTBP2 elicits tumor suppressive effects that parallel the inactivation of p65 in NPC cells. LTBP2 was able to reduce phosphorylation of p65 at Serine 536, inhibit nuclear localization of active phosphorylated p65, and impair the p65 DNA-binding ability. This results in a consequential down-regulation of p65-related gene expression. Therefore, the data suggest that the overall up-regulation of p65 expression and the loss of this candidate ECM tumor suppressor are milestone events contributing to NPC development.
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