Department of Neuroscience, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan.
Carcinogenesis. 2010 Jul;31(7):1185-93. doi: 10.1093/carcin/bgq065. Epub 2010 Mar 25.
Two members of the myocardin protein family, myocardin-related transcription factor (MRTF)-A and MRTF-B are co-activators of serum response factor (SRF). We recently reported that MRTF-A/B activates the transcription of several actin cytoskeletal/focal adhesion genes SRF dependently, thereby enhancing the formation of stress fibers and focal adhesions. Here, we showed that the levels of caldesmon and tropomyosin, both SRF/MRTF-regulated actin cytoskeletal proteins, were reduced in rat intestinal epithelial (RIE) cell lines that had been transformed with oncogenic ras (RIE-ras) or src (RIE-src) compared with their parental cell line. These cells exhibited morphological abnormalities associated with a disorganized actin cytoskeleton. The serum-stimulated nuclear translocation of MRTF-A/B was suppressed in the RIE-ras and RIE-src cells. However, the transient expression of constitutively active (CA) MRTF-A or MRTF-B reversed the reduced expression levels of caldesmon and tropomyosin and the associated morphological phenotypes. We isolated stable CA-MRTF-A-expressing cell lines from transfected RIE-ras and RIE-src cells and found that their levels of caldesmon and tropomyosin were close to those of untransformed RIE cells. Their morphologies were also normal, with a flattened cell shape and well-developed stress fibers. The CA-MRTF-A-expressing RIE-ras and RIE-src lines also showed lower invasiveness and anchorage-independent growth than their transformed parental cells, in vitro. In vivo, CA-MRTF-A expression suppressed tumor formation and reduced liver metastases. Therefore, we concluded that MRTF-A/B are potent repressors of cancer progression and metastasis and may be good targets for cancer therapy.
肌球蛋白相关转录因子（MRTF）-A 和 MRTF-B 是血清反应因子（SRF）的共激活因子。我们最近报道，MRTF-A/B 依赖性激活几个肌动蛋白细胞骨架/黏附基因的转录，从而增强应力纤维和黏附斑的形成。在这里，我们表明，在已被致癌 ras（RIE-ras）或 src（RIE-src）转化的大鼠肠上皮（RIE）细胞系中，肌球蛋白调节轻链（calponin）和原肌球蛋白这两种肌动蛋白细胞骨架蛋白的 SRF/MRTF 调节的水平均降低，与它们的亲本细胞系相比。这些细胞表现出与细胞骨架排列紊乱相关的形态异常。在 RIE-ras 和 RIE-src 细胞中，血清刺激的 MRTF-A/B 核易位受到抑制。然而，组成激活（CA）MRTF-A 或 MRTF-B 的瞬时表达逆转了 calponin 和原肌球蛋白的表达水平降低和相关的形态表型。我们从转染的 RIE-ras 和 RIE-src 细胞中分离出稳定表达 CA-MRTF-A 的细胞系，发现它们的 calponin 和原肌球蛋白水平接近未转化的 RIE 细胞。它们的形态也正常，具有扁平的细胞形状和发育良好的应力纤维。CA-MRTF-A 表达的 RIE-ras 和 RIE-src 系在体外也表现出比其转化的亲本细胞更低的侵袭性和锚定非依赖性生长。在体内，CA-MRTF-A 表达抑制肿瘤形成并减少肝转移。因此，我们得出结论，MRTF-A/B 是癌症进展和转移的有效抑制剂，可能是癌症治疗的良好靶点。
