RMP promotes venous metastases of hepatocellular carcinoma through promoting IL-6 transcription
RMP promotes venous metastases of hepatocellular carcinoma through promoting IL-6 transcription
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RMP通过促进IL-6转录促进肝细胞癌静脉转移
DOI：
10.1038/onc.2014.84
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发表时间：
2015-03-19
期刊：
影响因子：
8
通讯作者：
Wang, H-Y
中科院分区：
文献类型：
--
作者：
Zhang, J.;Pan, Y-F;Wang, H-Y
肝细胞癌(HCC)被认为是由肿瘤起始细胞(T-IC)引起的，T-IC与肿瘤复发和转移有关。门静脉癌栓(PVTT)起源于肝细胞癌，与预后不良密切相关。然而，PVTT形成的机制在很大程度上是未知的。在此，我们提供了RNA聚合酶II亚单位5(RPB5)-中介蛋白(RMP)在PVTT中逐渐上调的证据，并且过表达的RMP似乎促进了T-ICs的自我更新。此外，RMP在体内外均能促进PVTT细胞和肝癌细胞的转移。RMP抑制肝癌和PVTT细胞中T-ICs的自我更新和逆转上皮-间充质转化(EMT)。中和实验表明，IL-6在RMP调节肝癌细胞转移和自我更新过程中起着不可或缺的作用。此外，还证实RMP通过与p65和RPB5相互作用来调控IL-6的转录，从而促进T-IC/肿瘤干细胞群的扩大，以及诱导EMT。提示RMP可能通过促进IL-6转录促进PVTT的形成。因此，RMP是导致门静脉血栓形成的一个重要因素，也是肝细胞癌患者的一个有希望的治疗靶点。
Hepatocellular carcinoma (HCC) is believed to arise from tumor-initiating cells (T-ICs), which are responsible for tumor relapse and metastases. Portal vein tumor thrombus (PVTT) is raised from HCC and strongly correlated to a poor prognosis. However, the mechanism underling the formation of PVTT is largely unknown. Herein, we provide evidence that RNA polymerase II subunit 5 (RPB5)-mediating protein (RMP) was progressively upregulated in PVTT and overexpressed RMP appeared to increase T-ICs self-renewal. Moreover, RMP promoted metastases of PVTT cells and HCC cells in vitro and in vivo. Knockdown of RMP attenuated T-ICs self-renewal and reversed epithelial–mesenchymal transition (EMT) in HCC and PVTT cells. The neutralizing assays suggested that interleukin-6 (IL-6) had an indispensable role in RMP regulating metastases and self-renewal of HCC cells. Furthermore, the transcription of IL-6 was verified to be modulated by RMP via interaction with p65 and RPB5, through which expanding the T-IC/cancer stem cell populations, as well as inducing EMT was promoted. These results suggested that RMP may promote PVTT formation by promoting IL-6 transcription. Thus, RMP serves as a potent factor contributed to develop PVTT and a promising therapeutic target for HCC patients.