A definitive role of RhoC in metastasis of orthotopic lung cancer in mice
A definitive role of RhoC in metastasis of orthotopic lung cancer in mice
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DOI：
10.1158/1078-0432.ccr-03-0275
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发表时间：
2004-02-01
影响因子：
11.5
通讯作者：
Kosai, K
中科院分区：
文献类型：
--
作者：
Ikoma, T;Takahashi, T;Kosai, K
目的：肺癌是癌症死亡的主要原因，其发病率在世界范围内呈上升趋势。传统治疗方法对肺癌转移的疗效仍较差，导致这种疾病的预后较差。本研究采用临床方法探讨RhoC在肺癌转移中的病理作用。肺癌小鼠模型的建立。实验设计：将RhoA、RhoC、显性阴性Rho （dnRho）或绿色荧光蛋白基因逆转录到小鼠肺癌细胞中。在体内研究中，将这些转导细胞接种于同基因小鼠肺内，随后分析其生长和转移情况。通过体外趋化室实验进一步研究其迁移和侵袭活性。采用逆转录pcr和明胶酶谱法研究了部分基质金属蛋白酶（MMPs）的表达水平和活性。结果：过表达RhoC或dnRho可显著增强或抑制动物模型中肺癌的转移、体外迁移和侵袭，但不影响原发肿瘤的生长。过表达RhoC或dnRho分别显著增强或抑制某些MMPs的表达水平和MMP-2的活性。结论：RhoC在肺癌转移过程中起重要作用。RhoC不影响肿瘤生长，但通过刺激细胞运动和上调某些MMPs来增强肺癌的转移性。降低RhoC活性可能是开发治疗肺癌转移新策略的潜在靶点。
Purpose: Lung cancer is a major cause of cancer death, and its incidence is increasing in the world. Conventional therapies remain less effective for metastases of lung cancer, leading to poor prognosis of this disorder. The present study investigates pathological roles of RhoC in metastasis of lung cancer using a clinically. relevant mouse model of lung cancer.Experimental Design: RhoA, RhoC, dominant-negative Rho (dnRho) or green fluorescent protein gene was retrovirally transduced to murine lung cancer cells. For in vivo study, these transduced cells were intrapulmonary inoculated in syngeneic mice, and subsequently, growth and metastasis were analyzed. Migration and invasion activities were further investigated by in vitro chemotaxic chamber assays. Expression levels and activities of certain matrix metalloproteinases (MMPs) were explored by reverse transcription-PCR and gelatin zymography.Results: Metastasis of lung cancer in the animal model, as well as in vitro migration and invasion, were significantly enhanced or inhibited by overexpression of RhoC or dnRho, respectively, without affecting the growth of primary tumors. Expression levels of certain MMPs and the activity of MMP-2 were significantly enhanced or suppressed by overexpression of RhoC or dnRho, respectively.Conclusion: RhoC plays a crucial role in metastasis of lung cancer. RhoC does not affect tumor growth but enhances the metastatic nature of lung cancer by not only stimulating cell motility but also up-regulating certain MMPs. Attenuation of RhoC activity may be a potential target in the development of a novel strategy for treating metastasis of lung cancer.