Hyperthermia-induced NDRG2 upregulation inhibits the invasion of human hepatocellular carcinoma via suppressing ERK1/2 signaling pathway.
Hyperthermia-induced NDRG2 upregulation inhibits the invasion of human hepatocellular carcinoma via suppressing ERK1/2 signaling pathway.
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热疗诱导的 NDRG2 上调通过抑制 ERK1/2 信号通路抑制人肝细胞癌的侵袭
DOI：
10.1371/journal.pone.0061079
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Liu W
中科院分区：
文献类型：
--
作者：
Guo Y;Ma J;Wu L;Wang Q;Li X;Li X;Zhang Y;Zhang J;Yao L;Zhang J;Liu W
热疗（HT）已被证明能够改变癌细胞的侵袭能力。然而，HT抗肿瘤转移作用的具体机制尚未阐明。N-myc下游调控基因2 （NDRG2）作为NDRG家族的一员，已被认为对各种应激反应高度敏感，并与肿瘤抑制有关。本研究旨在探讨NDRG2在暴露于HT的人肝细胞癌（HCC）细胞侵袭中的生物学作用。我们发现在45°C高温下可以诱导NDRG2。此外，NDRG2过表达可抑制基质金属蛋白酶-2 （MMP-2）和MMP-9的表达，抑制HCC细胞的侵袭，而下调NDRG2可逆转HT在体内的抗侵袭作用。进一步的研究发现，在NDRG2过表达的细胞中，ERK1/2的磷酸化水平降低，而JNK和p38MAPK的磷酸化水平没有降低。此外，NDRG2表达的下调导致细胞侵袭增加，用ERK1/2抑制剂PD98059处理HepG2细胞可以挽救细胞侵袭，而用p38MAPK抑制剂SB203580或JNK抑制剂SP600125则不能。最后，43°C HT与NDRG2表达的协同合作有效降低了45°C HT的细胞毒性，促进了其抗侵袭作用。综上所述，这些数据表明，NDRG2可以被HT诱导，并通过抑制ERK1/2信号通路介导HT对HCC细胞侵袭的抑制。组成型NDRG2表达与HT联合应用可能产生最佳的治疗效果。
Hyperthermia (HT) has been proven to be able to alter the invasion capacity of cancer cells. However, the detailed mechanisms responsible for the anti-metastasis effects of HT have not been elucidated. N-myc downstream-regulated gene 2 (NDRG2), as a member of the NDRG family, has been suggested to be highly responsive to various stresses and is associated with tumor suppression. The present study aimed to investigate the biological role of NDRG2 in the invasion of human hepatocellular carcinoma (HCC) cells exposed to HT. We found that NDRG2 could be induced by HT at 45°C. In addition, NDRG2 overexpression inhibited the expression of matrix metallo proteinases-2 (MMP-2) and MMP-9 as well as the invasion of HCC cells, whereas knockingdown NDRG2 reversed the anti-invasion effect of HT in vivo. Further investigation revealed that the phosphorylation level of ERK1/2, but not that of JNK and p38MAPK, was reduced in NDRG2 overexpressing cells. Moreover, the knockdown of NDRG2 expression resulted in increased cell invasion, which was rescued by treating the HepG2 cells with the ERK1/2 inhibitor PD98059, but not with the p38MAPK inhibitor SB203580 or the JNK inhibitor SP600125. Finally, the synergistic cooperation of HT at 43°C and NDRG2 expression effectively reduced cytotoxicity and promoted the anti-invasion effect of HT at 45°C. Taken together, these data suggest that NDRG2 can be induced by HT and that it mediates the HT-caused inhibition of invasion in HCC cells by suppressing the ERK1/2 signaling pathway. The combined application of constitutive NDRG2 expression with HT may yield an optimized therapeutic benefit.
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DOI：
10.1073/pnas.1006646107
发表时间：
2010-11-23
影响因子：
11.1
作者：
Moon, Eui Jung;Sonveaux, Pierre;Dewhirst, Mark W.
通讯作者：
Dewhirst, Mark W.
影响因子：
5.5
作者：
Foletta, Victoria C.;Prior, Matthew J.;Walder, Ken R.
通讯作者：
Walder, Ken R.
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影响因子：
4.8
作者：
Liang, Xinhua;Zhou, Hao;Yang, Jing
通讯作者：
Yang, Jing
影响因子：
9.7
作者：
Deng, Haiyun;Ravikumar, T. S.;Yang, Weng-Lang
通讯作者：
Yang, Weng-Lang
DOI：
10.1054/ijom.2001.0176
发表时间：
2002-02-01
影响因子：
2.4
作者：
Nagashima, K;Takagi, R;Hoshina, H
通讯作者：
Hoshina, H