Inhibition of Breast Cancer Cell Invasion by Ras Suppressor-1 (RSU-1) Silencing Is Reversed by Growth Differentiation Factor-15 (GDF-15)
Inhibition of Breast Cancer Cell Invasion by Ras Suppressor-1 (RSU-1) Silencing Is Reversed by Growth Differentiation Factor-15 (GDF-15)
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DOI：
10.3390/ijms20010163
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发表时间：
2019-01-01
影响因子：
5.6
通讯作者：
Stylianopoulos, Triantafyllos
中科院分区：
文献类型：
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作者：
Gkretsi, Vasiliki;Louca, Maria;Stylianopoulos, Triantafyllos
细胞外基质（ECM）相关的粘附蛋白在转移中是重要的。Ras抑制子-1（RSU-1）是Ras转化的抑制子，定位于细胞-ECM粘附，在那里它与特别有趣的新的富含半胱氨酸-组氨酸的蛋白（PINCH-1）相互作用，PINCH-1连接到整合素连接激酶（ILK）和α-parvin（PARVA），α-parvin是一种直接肌动蛋白结合蛋白。RSU-1在转移性乳腺癌（BC）样本中也被发现上调，最近被证明具有促进转移的特性。在本研究中，我们在BC细胞、MCF-7和MDA-MB-231中瞬时沉默RSU-1。我们发现RSU-1沉默导致生长分化因子-15（GDF-15）下调，GDF-15与肌动蛋白细胞骨架重组和转移相关。RSU-1沉默还降低了PINCH-1和细胞分裂控制蛋白-42（Cdc 42）的mRNA表达，同时增加了ILK和Rac的mRNA表达，而与GDF-15的存在无关。然而，肌动蛋白调节基因PARVA，RhoA，Rho相关激酶-1（ROCK-1），和Fascin-1的下调后，RSU-1耗尽完全逆转GDF-15处理在两个细胞系。此外，通过GDF-15处理实现了RSU-1沉默对细胞侵袭的抑制作用的完全拯救，这也与基质金属蛋白酶-2表达相关。最后，使用图聚类方法，我们证实了我们的研究结果。这是第一项提供RSU-1和GDF-15在癌细胞侵袭方面功能相关的证据的研究。
Extracellular matrix (ECM)-related adhesion proteins are important in metastasis. Ras suppressor-1 (RSU-1), a suppressor of Ras-transformation, is localized to cell-ECM adhesions where it interacts with the Particularly Interesting New Cysteine-Histidine rich protein (PINCH-1), being connected to Integrin Linked Kinase (ILK) and alpha-parvin (PARVA), a direct actin-binding protein. RSU-1 was also found upregulated in metastatic breast cancer (BC) samples and was recently demonstrated to have metastasis-promoting properties. In the present study, we transiently silenced RSU-1 in BC cells, MCF-7 and MDA-MB-231. We found that RSU-1 silencing leads to downregulation of Growth Differentiation Factor-15 (GDF-15), which has been associated with both actin cytoskeleton reorganization and metastasis. RSU-1 silencing also reduced the mRNA expression of PINCH-1 and cell division control protein-42 (Cdc42), while increasing that of ILK and Rac regardless of the presence of GDF-15. However, the downregulation of actin-modulating genes PARVA, RhoA, Rho associated kinase-1 (ROCK-1), and Fascin-1 following RSU-1 depletion was completely reversed by GDF-15 treatment in both cell lines. Moreover, complete rescue of the inhibitory effect of RSU-1 silencing on cell invasion was achieved by GDF-15 treatment, which also correlated with matrix metalloproteinase-2 expression. Finally, using a graph clustering approach, we corroborated our findings. This is the first study providing evidence of a functional association between RSU-1 and GDF-15 with regard to cancer cell invasion.