DLC1 suppresses distant dissemination of human hepatocellular carcinoma cells in nude mice through reduction of RhoA GTPase activity, actin cytoskeletal disruption and down-regulation of genes involved in metastasis.
DLC1 suppresses distant dissemination of human hepatocellular carcinoma cells in nude mice through reduction of RhoA GTPase activity, actin cytoskeletal disruption and down-regulation of genes involved in metastasis.
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DOI：
10.3892/ijo_32_6_1285
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发表时间：
1992-06
影响因子：
5.2
通讯作者：
Xiaoling Zhou;D. Zimonjic;Sang-won Park;Xuyu Yang;M. Durkin;N. Popescu
中科院分区：
文献类型：
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作者：
Xiaoling Zhou;D. Zimonjic;Sang-won Park;Xuyu Yang;M. Durkin;N. Popescu
细胞从原发肿瘤扩散到远处的过程是癌症进展过程中最有害的事件，也是癌症死亡的主要原因。我们以前已经证明，在DLC 1阴性Focus和7703 K人肝细胞癌（HCC）细胞系中恢复DLC 1肿瘤抑制基因表达诱导caspase-3介导的凋亡，降低体外细胞生长和体内致瘤性，并降低通过Matrigel迁移的能力，这是一种暗示体内转移潜力的特性。我们现在表明，皮下肿瘤接种Focus和7703 K细胞到裸鼠后，发展传播细胞到肝脏和肺，这一过程被DLC 1表达的恢复显着抑制。肿瘤细胞播散的抑制与RhoA活性水平降低、圆形细胞增加以及肌动蛋白应力纤维和粘着斑分子减少相关，这些在癌细胞侵袭和转移中至关重要。此外，DLC 1下调骨桥蛋白和基质金属蛋白酶-9的表达，这是高度上调，在大多数原发性肝癌与相关的转移。这些观察结果表明DLC 1基因抑制HCC细胞的传播，并确定了新的细胞和遗传改变，有助于预防转移，癌症进展中危及生命的事件。
The process of cell dissemination from the primary tumors to distant sites is the most harmful event during cancer progression, and the leading cause of cancer death. We have previously demonstrated that restoration of DLC1 tumor suppressor gene expression in the DLC1-negative Focus and 7703K human hepatocellular carcinoma (HCC) cell lines induced caspase-3 mediated apoptosis, reduced cell growth in vitro and tumorigenicity in vivo and diminished the ability to migrate through Matrigel, a property suggestive of metastatic potential in vivo. We now show that subcutaneous tumors developing after inoculation of Focus and 7703K cells into nude mice disseminate cells to liver and lung, and this process is markedly suppressed by restoration of DLC1 expression. Inhibition of tumor cell dissemination was associated with lower levels of RhoA activity, an increase in rounded cells and a reduction in actin stress fibers and focal adhesion molecules that are of critical importance in cancer cell invasion and metastasis. In addition, DLC1 down-regulated the expression of osteopontin and matrix metalloproteinase-9, which are highly up-regulated in most primary HCC with associated metastases. These observations implicate the DLC1 gene in suppression of HCC cell dissemination and identify novel cellular and genetic alterations that contribute to prevention of metastasis, a life-threatening event in cancer progression.