Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-κB signal transduction pathway
Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-κB signal transduction pathway
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DOI：
10.1038/sj.onc.1209706
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发表时间：
2006-11-09
期刊：
影响因子：
8
通讯作者：
Hsieh, C-Y
中科院分区：
文献类型：
--
作者：
Cheng, J. C-H;Chou, C. H.;Hsieh, C-Y
本研究旨在探讨放射增强肝细胞癌（HCC）细胞侵袭力的分子机制，其与临床患者接受放射治疗并随后发生转移相关。用不同剂量的γ射线照射三种肝癌细胞系（HepG 2、Hep 3B和Huh 7）和正常肝细胞系（CL-48）。使用Boyden小室测定法测定辐射对细胞侵袭力的影响。放射增强的侵袭能力在HCC细胞中是明显的，但在正常肝细胞中不是。在明胶涂层膜中观察到侵袭，但在纤连蛋白涂层膜或I型胶原涂层膜中未观察到侵袭。辐射可上调基质金属蛋白酶-9（MMP-9）mRNA水平、MMP-9蛋白水平和MMP-9活性。MMP-9反义寡核苷酸抑制辐射诱导的MMP-9表达，从而显著抑制辐射诱导的HCC侵袭。此外，磷脂酰肌醇3-激酶（PI 3 K）/Akt化学抑制剂LY 294002和渥曼青霉素抑制辐射诱导的MMP-9 mRNA的表达。瞬时转染显性失活Akt质粒也表明PI 3 K/Akt信号通路参与了辐射诱导的MMP-9表达。此外，核因子-κ B（NF-κ B）诱骗寡核苷酸完全抑制辐射增强MMP-9启动子活性。PI 3 K/Akt化学抑制剂抑制辐射诱导的NF-κ B驱动的荧光素酶启动子活性。以上结果提示，亚致死剂量的辐射可通过PI 3 K/Akt/NF-κ B信号转导途径，通过MMP-9的表达增强肝癌细胞的侵袭力。
This study is to investigate the molecular mechanism of radiation-enhanced cell invasiveness of hepatocellular carcinoma (HCC) correlating with clinical patients undergoing radiotherapy and subsequently developing metastasis. Three HCC cell lines (HepG2, Hep3B and Huh7) and normal hepatocyte cell line (CL-48) were irradiated with different doses. The effect of radiation on cell invasiveness was determined using the Boyden chamber assay. Radiation-enhanced invasion capability was evident in HCC cells but not in normal hepatocytes. Invasion was observed in gelatin-coated but not fibronectin-coated or type I collagen-coated membranes. Radiation upregulated matrix metalloproteinase-9 (MMP-9) mRNA level, MMP-9 protein level and MMP-9 activity. MMP-9 antisense oligonucleotides inhibited radiation-induced MMP-9 expression and thereby significantly inhibited radiation-induced HCC invasion. Furthermore, phosphatidylinositol 3-kinase (PI3K)/Akt chemical inhibitors LY294002 and wortmannin suppressed radiation-induced MMP-9 mRNA expression. Transient transfection with dominant-negative Akt plasmid also showed that the PI3K/Akt-signaling pathway was involved in this radiation-induced MMP-9 expression. Moreover, nuclear factor-kappa B (NF-kappa B) decoy oligodeoxynucleotide suppressed radiation enhanced MMP-9 promoter activity completely. PI3K/Akt chemical inhibitors inhibited radiation-induced NF-kappa B-driven luciferase promoter activity. Taken together, our results indicated that sublethal dose of radiation could enhance HCC cell invasiveness by MMP-9 expression through the PI3K/Akt/NF-kappa B signal transduction pathway.