Radiation enhances long-term metastasis potential of residual hepatocellular carcinoma in nude mice through TMPRSS4-induced epithelial-mesenchymal transition
Radiation enhances long-term metastasis potential of residual hepatocellular carcinoma in nude mice through TMPRSS4-induced epithelial-mesenchymal transition
复制标题
放射通过TMPRSS4诱导的上皮间质转化增强裸鼠残留肝细胞癌的长期转移潜力
DOI：
10.1038/cgt.2011.29
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发表时间：
2011-09-01
影响因子：
6.4
通讯作者：
Tang, Z-Y
中科院分区：
文献类型：
--
作者：
Li, T.;Zeng, Z-C;Tang, Z-Y
肝细胞癌（HCC）放射治疗后经常发生复发和转移，放射诱导的基质金属蛋白酶（MMPs）和血管内皮生长因子（VEGF）表达上调与此有关，但其机制尚不清楚。在本研究中，通过使用MHCC 97 L，一个人肝癌细胞系的转移潜力，并在裸鼠异种移植瘤，我们发现，辐射诱导48- 72-h暂时增加MMP-2和VEGF的表达在体外和体内，但只有MHCC 97 L细胞的体外侵袭性增强，而在体内的肿瘤转移潜力被抑制。然而，辐射后30天，当MMP-2和VEGF的表达降低到未辐射的对照水平时，残留肿瘤的体内扩散和转移潜力刚刚开始随着TMPRSS 4的过表达而增加，TMPRSS 4通过诱导Smad相互作用蛋白1（SIP 1）（一种E-钙粘蛋白转录抑制物）而诱导E-钙粘蛋白的损失，并导致上皮-间充质转化（EMT）。该过程通过siRNA-TMPRSS 4的处理被阻断。总之，我们的研究揭示了放射对残留肝癌转移潜能的双相效应的新发现。TMPRSS 4的过表达通过促进EMT在放射诱导的残留HCC的长期播散和转移中起关键作用。这些发现可能为抑制放射性肝细胞癌的播散和转移，从而改善患者的预后提供新的线索。Cancer Gene Therapy（2011）18，617-626; doi：10.1038/cgt.2011.29; 2011年6月3日在线发表
Recurrence and metastasis are frequently observed after radiotherapy for hepatocellular carcinoma (HCC), although upregulation of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) induced by radiation has been claimed to be involved, the mechanism is not clarified yet. In the present study, by using MHCC97L, a human HCC cell line with metastatic potential, and its xenograft in nude mice, we found that radiation induced a 48- to 72-h temporary increase in the expression of MMP-2 and VEGF both in vitro and in vivo, but only the in vitro invasiveness of MHCC97L cells was enhanced, while the in vivo metastatic potential of tumors was suppressed. Whereas, 30 days after radiation, when the expression of MMP-2 and VEGF decreased to unirradiated control levels, the in vivo dissemination and metastatic potential of residual tumors have just begun to increase with overexpression of TMPRSS4, which induced loss of E-cadherin through induction of Smad-Interacting Protein 1 (SIP1), an E-cadherin transcriptional repressor, and led to epithelial-mesenchymal transition (EMT). This process was blocked by treatment of siRNA-TMPRSS4. In conclusion, our study revealed novel findings regarding the biphasic effect of radiation on the metastatic potential of residual HCC. Overexpression of TMPRSS4 has a critical role in radiation-induced long-term dissemination and metastasis of residual HCC by facilitating EMT. These findings may provide new clues to suppress the radiation-induced dissemination and metastasis, thereby improve the prognosis of HCC patients. Cancer Gene Therapy (2011) 18, 617-626; doi:10.1038/cgt.2011.29; published online 3 June 2011