A novel tripeptide, tyroserleutide, inhibits irradiation-induced invasiveness and metastasis of hepatocellular carcinoma in nude mice
A novel tripeptide, tyroserleutide, inhibits irradiation-induced invasiveness and metastasis of hepatocellular carcinoma in nude mice
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DOI：
10.1007/s10637-010-9435-1
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发表时间：
2011-10-01
影响因子：
3.4
通讯作者：
Tang, Zhao-You
中科院分区：
文献类型：
--
作者：
Jia, Jin-Bin;Wang, Wen-Quan;Tang, Zhao-You
先前的研究表明，酪丝亮肽 (YSL) 可抑制肝细胞癌 (HCC) 动物模型中的肿瘤生长。然而，其对 HCC 转移的影响仍不完全清楚。为了检验 YSL 作为预防 HCC 转移的新型药物，使用了 MHCC97L 的转移性人 HCC 原位裸鼠模型。 YSL 的抗肿瘤和抗转移作用也与放射结合进行了评估。研究了缺氧和上皮间质转化（EMT）相关分子。 YSL 在体外有或没有辐射的情况下抑制 MHCC97L 细胞侵袭。 YSL 没有显着抑制肿瘤生长，但减少了肺转移并延长了寿命超过 40 天，这与基质金属蛋白酶-2 的下调相关。放射治疗抑制早期肿瘤生长并促进肿瘤缺氧。放疗组再植肿瘤体积与对照组无显着差异，放疗后肺转移发生率增加（6/6 vs 3/6，P = 0.046）；然而，YSL抑制了放疗后重新植入的肿瘤的生长。此外，160或320μg/kg/天的YSL几乎完全抑制由辐射诱导的肺转移（两种剂量的1/6对6/6，P = 0.002）。 YSL 下调缺氧诱导因子 1 α (HIF-1 α) 和跨膜蛋白酶丝氨酸 4 (TMPRSS4)，并抑制 EMT 与 YSL 的抗转移能力相关。我们的数据表明，YSL 通过下调 HIF-1 α 和 TMPRSS4 以及抑制 EMT 来抑制辐射诱导的 HCC 增强的侵袭性和转移潜力。 YSL 可能具有作为放射治疗的新型抗转移剂的潜力。
Previous studies have demonstrated that tyroserleutide (YSL) inhibits tumor growth in an animal model of hepatocellular carcinoma (HCC). However, its effects on HCC metastasis are still not fully understood. To examine YSL as a novel agent to prevent HCC metastasis, a metastatic human HCC orthotopic nude mouse model of MHCC97L was used. The antitumor and antimetastasis effects of YSL were also evaluated in combination with radiation. Hypoxia and epithelial-mesenchymal transition (EMT)-related molecules were studied. YSL inhibited MHCC97L cell invasion in vitro with or without irradiation. YSL did not significantly inhibit tumor growth but decreased pulmonary metastasis and prolonged life-span for more than 40 days, which correlated with down-regulation of matrix metalloproteinase-2. Radiotherapy inhibited early-stage tumor growth and promoted tumor hypoxia. The re-implanted tumor volume in the radiotherapy group was not significantly different from the control, in which the incidence of lung metastasis increased after radiotherapy (6/6 versus 3/6, P = 0.046); however, YSL inhibited the growth of re-implanted tumor after radiotherapy. Furthermore, YSL at 160 or 320 mu g/kg/day almost completely inhibited lung metastasis induced by irradiation (1/6 versus 6/6, P = 0.002 for both dosages). YSL down-regulated hypoxia-inducible factor 1 alpha (HIF-1 alpha) and transmembrane protease serine 4 (TMPRSS4), and inhibited EMT was associated with the antimetastasis capability of YSL. Our data suggest that YSL inhibits the enhanced invasiveness and metastatic potential of HCC induced by irradiation through down-regulation of HIF-1 alpha and TMPRSS4 and inhibition of EMT. YSL may have potential as a new antimetastasis agent for radiotherapy.