DLC1 negatively regulates angiogenesis in a paracrine fashion.
DLC1 negatively regulates angiogenesis in a paracrine fashion.
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DOI：
10.1158/0008-5472.can-10-1174
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发表时间：
2010-11-01
期刊：
影响因子：
11.2
通讯作者：
Lo SH
中科院分区：
文献类型：
--
作者：
Shih YP;Liao YC;Lin Y;Lo SH
The Rho GTPase activating protein DLC1 is a tumor suppressor that is often deleted in liver cancer and downregulated in other cancers. DLC1 regulates the actin cytoskeleton, cell shape, adhesion, migration, and proliferation through its RhoGAP activity and focal adhesion localization. In this study we silenced DLC1 in non-malignant prostate epithelial cells to explore its tumor suppression functions. shRNA-mediated silencing of DLC1 was insufficient to promote more aggressive phenotypes associated with tumor cell growth. In contrast, DLC1 silencing promoted pro-angiogenic responses through VEGF upregulation, accompanied by the accumulation of hypoxiainducible factor HIF1α and its nuclear localization. Notably, modulation of VEGF expression by DLC1 was dependent on EGFR-MEK-HIF1 signaling but on RhoA pathways. Clinically, VEGF upregulation is a highly significant event in prostate cancers where DLC1 is downregulated. Thus, our results strongly suggest that loss of DLC1 may serve as a “second hit” in promoting angiogenesis in a paracrine fashion during tumorigenesis.
