Human tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 suppresses hepatocellular carcinoma metastasis through inhibiting Rac1.
Human tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 suppresses hepatocellular carcinoma metastasis through inhibiting Rac1.
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人肿瘤坏死因子（TNF）-α诱导蛋白8-like 2通过抑制Rac1抑制肝细胞癌转移
DOI：
10.1186/1476-4598-12-149
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发表时间：
2013-11-26
期刊：
影响因子：
37.3
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Cao X;Zhang L;Shi Y;Sun Y;Dai S;Guo C;Zhu F;Wang Q;Wang J;Wang X;Chen YH;Zhang L
研究背景肿瘤的侵袭和转移是导致肝细胞癌（HCC）患者死亡的主要原因。因此，寻找能够抑制肿瘤侵袭和转移的分子将为肝癌的治疗提供新的靶点。肿瘤坏死因子（TNF）-α诱导的蛋白8样2（Tumor Necrosis Factor-α-induced protein 8-like 2，TIPE 2）是一种新型的免疫负性分子，在小鼠中是致癌Ras的抑制剂，但其在人体中的功能尚不清楚。我们以前的研究表明，TIPE 2是下调在人类原发性肝癌与配对相邻的非肿瘤tissues.ResultsIn本研究中，我们提供的证据表明，TIPE 2有效地抑制人类肝细胞癌转移。TIPE 2在肝癌细胞系中的强制表达在体外显著抑制肿瘤细胞的生长、迁移和侵袭，在体内显著抑制肝癌的生长和转移。来自112名患者的队列的临床信息揭示，原发性HCC组织中TIPE 2表达的丧失或降低与肿瘤转移显著相关。TIPE 2通过靶向Rac 1抑制肝癌细胞的迁移和侵袭，进而抑制F-actin的聚合，抑制基质金属肽酶9（MMP 9）和尿激酶纤溶酶原激活物（uPA）的表达。结论TIPE 2是Rac 1的内源性抑制剂，通过抑制Rac 1的表达抑制肝癌细胞的侵袭和转移。提示TIPE 2可能成为肝癌治疗的新靶点。
BackgroundTumor invasion and metastasis are the major reasons for leading death of patients with hepatocellular carcinoma (HCC). Therefore, to identify molecules that can suppress invasion and metastasis of tumor will provide novel targets for HCC therapies. Tumor necrosis factor (TNF)-alpha-induced protein 8-like 2, TIPE2, is a novel immune negative molecule and an inhibitor of the oncogenic Ras in mice but its function in human is unclear. Our previous research has shown that TIPE2 is downregulated in human primary HCC compared with the paired adjacent non-tumor tissues.ResultsIn present study, we provide evidence that TIPE2 inhibits effectively human hepatocellular carcinoma metastasis. The forced expression of TIPE2 in HCC-derived cell lines markedly inhibits tumor cell growth, migration and invasionin vitroand suppresses growth and metastasis of HCCin vivo. Clinical information from a cohort of 112 patients reveals that loss or reduced expression of TIPE2 in primary HCC tissues is significantly associated with tumor metastasis. Mechanically, TIPE2 inhibits the migration and invasion through targeting Rac1 and then reduces F-actin polymerization and expression of matrix metallopeptidase 9 (MMP9) and urokinase plasminogen activator (uPA).ConclusionOur results indicate that human TIPE2 is endogenous inhibitor of Rac1 in HCC by which it attenuates invasion and metastasis of HCC. The data suggest that TIPE2 will be a new target for HCC therapy.
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