Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
School of Biological Sciences, The University of Hong Kong, Hong Kong, China.
Cancer Lett. 2017 Dec 28;411:150-161. doi: 10.1016/j.canlet.2017.09.047. Epub 2017 Oct 6.
Presence of Met receptor tyrosine kinase in the nucleus of cells has been reported. However, the functions of Met which expresses in the nucleus (nMet) remain elusive. In this study, we found that nMet was increased in 89% of HCC tumorous tissues when compared with the corresponding non-tumorous liver tissues. nMet expression increased progressively along HCC development and significantly correlated with cirrhosis, poorer cellular differentiation, venous invasion, late stage HCC and poorer overall survival. Western blot analysis revealed that nMet is a 48-kDa protein comprising the carboxyl terminal of Met receptor. Induced expression of nMet promoted HCC cell growth, migration and invasiveness in vitro and tumorigenesis and pulmonary metastasis in vivo. Luciferase assay showed that nMet activated NF-κB pathway. Indeed, p-IKKα/β and nuclear p-p65 were higher in nMet stable cells than in the control cells. Perturbation of TAK1/NF-κB axis abrogated the aggressiveness of HCC cells, both in vitro and in vivo. In conclusion, nMet was overexpressed and as a potential prognostic biomarker of HCC. Functionally, nMet accelerated HCC tumorigenesis and metastasis via the activation of TAK1/NF-κB pathway.
已经有报道称，Met 受体酪氨酸激酶存在于细胞核中。然而，表达在细胞核中的 Met（nMet）的功能仍然难以捉摸。在这项研究中，我们发现与相应的非肿瘤性肝组织相比，nMet 在 89%的 HCC 肿瘤组织中增加。nMet 的表达随着 HCC 的发展而逐渐增加，并且与肝硬化、较差的细胞分化、静脉侵犯、晚期 HCC 和较差的总体生存率显著相关。Western blot 分析显示，nMet 是一种 48kDa 的蛋白质，包含 Met 受体的羧基末端。nMet 的诱导表达促进了 HCC 细胞在体外的生长、迁移和侵袭，以及体内的肿瘤发生和肺转移。荧光素酶测定显示，nMet 激活了 NF-κB 通路。事实上，nMet 稳定细胞中的 p-IKKα/β 和核内 p-p65 高于对照细胞。干扰 TAK1/NF-κB 轴可消除 HCC 细胞的侵袭性，无论是在体外还是体内。总之，nMet 在 HCC 中过表达，并作为 HCC 的一个潜在预后生物标志物。在功能上，nMet 通过激活 TAK1/NF-κB 通路加速了 HCC 的肿瘤发生和转移。
