| 郭燕1 候玉2 马骥1 王倩荣1 刘文超1△.NDRG2 在热应激抗肝癌细胞侵袭中的作用和分子机制研究*[J].现代生物医学进展英文版,2014,14(15):2801-2807. |
| NDRG2 在热应激抗肝癌细胞侵袭中的作用和分子机制研究* |
| Function and Mechanismof NDRG2 in Heat stress Retards Invasion ofHepatocellular Carcainoma Cells* |
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| DOI： |
| 中文关键词: 热应激 NDRG2 肝癌 侵袭 分子机制 |
| 英文关键词: Hyperthermia NDRG2 Hepatocellular carcainoma Invasion Mechanism |
| 基金项目:国家自然科学基金项目（30973437） |
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| 中文摘要: |
| 摘要目的：探讨NDRG2 在热疗诱导的热应激抗肝癌细胞侵袭中所发挥的作用和机制研究。方法：构建NDRG2 过表达和干涉表
达的HepG-2 细胞稳转细胞株，通过Transwell 和Western-blot 方法检测了和细胞侵袭力和细胞内NDRG2、MMP-2 和MMP-9 的
表达量变化；构建荷瘤鼠模型，通过HE染色及免疫组化方法检测并对比了热对肿瘤细胞向周围肌肉组织的侵袭抑制作用。结果：
给予NDRG2 过表达的HepG-2 细胞45 ℃、30min 热处理后，细胞内NDRG2的表达明显增高，同时伴随细胞侵袭力、MMP-2 和
MMP-9 的表达明显降低(P<0.05)。与对照组相比，45 ℃的局部热作用能有效抑制肿瘤细胞对周围肌肉组织的侵袭，而干涉细胞内
NDRG2的表达则降低了热对肿瘤细胞侵袭的抑制。对其机制的研究中发现，给予对照和NDRG2 过表达的HepG-2 细胞45 ℃，
30min 热刺激后，HSP70 在热后6h 表达量开始升高，而在两个组之间没有显著差异；对照组的HepG-2 细胞在给予热处理后
ERK1/2 的磷酸化水平降低；NDRG2 的过表达不仅降低了细胞中ERK1/2 的本底水平，还降低了热作用早期对ERK1/2的诱导；
进一步分别应用ERK1/2，p38MAPK 和JNK 三个激酶的抑制剂作用于NDRG2 被敲除的HepG-2 细胞，经过热处理后ERK1/2 抑
制剂组可以明显抑制HepG-2细胞的侵袭。结论: 热应激所诱导NDRG2 的表达量与肝癌细胞的侵袭力呈现一种负相关性；在热
应激抗肝癌细胞侵袭的作用中，是通过影响NDRG2-ERK1/2通路而实现的。 |
| 英文摘要: |
| ABSTRACT Objective:To investigate the function and mechanism of NDRG2 in hyperthermia (HT) induced heat stress retards
invasion of hepatocellular carcainoma cells.Methods: We established the stable cell lines with NDRG2 overexpression or NDRG2
knockdown. Matrigel invasion assay and Western-blot were performed to evaluate the effect of heat stress on invasion of cells. We further
established mouse xenograft model. H&E and immunohistochemical staining examined the anti-invasion potential.Results: In NDRG2
over expressing cells, HT at 45 ℃ reduced the invasive potential significantly, compared with HepG-2 cells treated by HT alone. We next
detected the expression of MMP-2 and MMP-9. Western-blot revealed that expression of MMP-2 and MMP-9 decreased in NDRG2
overexpressing HepG-2 cells and even lower after the cells were treated by HT. Malignant tumors slightly invaded into nearby tissues in
HT treated mouse model. In contrast，suppression of NDRG2 facilitate invasion of tumor nodules and reversed anti-invasive effect of HT
in HepG-2 cells with significant destruction of the muscle layer as well as alleviated the repression of MMP-2 and MMP-9 expression by
HT. To elucidate the molecular mechanismof NDRG2 mediated the anti-invasion effect of HT. We examined the expression of HSPs and
MAPKs in HepG2 cells of control and overexpression of NDRG2 at different time points after cells were subjected to HT at 45 ℃ for 30
min. HSP70 expression was induced at 6h and kept at high levels after HT. However, the expression pattern of HSP70 was the same
between these two groups. The phosphorylation of ERK1/2 declined after heat treatment. Moreover, overexpression of NDRG2 abrogated
the intrinsic and HT induced activation of ERK1/2 pathway. The ERK1/2 inhibitor (PD98059) treatment could significantly enhance the
anti-invasive effect of HT. Conclusion:The expression of NDRG2 and cell invasion ability are negative correlation. In addition, NDRG2
mediates the anti-invasion effect of hyperthermia via inhibition of the ERK1/2 signaling pathway. |
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