Zheng Qiao, Safina Alfiya, Bakin Andrei V
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Int J Cancer. 2008 Jan 1;122(1):78-90. doi: 10.1002/ijc.23025.
Transforming growth factor beta1 (TGF-beta1) suppresses tumor development at early stages of cancer, but enhances tumor invasion and formation of metastasis. TGF-beta1-mediated tumor invasion is associated with epithelial to mesenchymal transition (EMT) and matrix proteolysis. The mechanisms of these TGF-beta1 responses in normal and tumor cells are not well understood. Recently, we have reported that TGF-beta1 increases expression of high-molecular weight tropomyosins (HMW-tropomyosins) and formation of actin stress fibers in normal epithelial cells. The present study investigated the role of tropomyosin in TGF-beta1-mediated cell motility and invasion. We found that TGF-beta1 restricts motility of normal epithelial cells although it promotes EMT and formation of actin stress fibers and focal adhesions. Cell motility was enhanced by siRNA-mediated suppression of HMW-tropomyosins. TGF-beta1 stimulated migration and matrix proteolysis in breast cancer MDA-MB-231 cells that express low levels of HMW-tropomyosins. Tet-Off-regulated expression of HMW-tropomyosin inhibited cell migration and matrix proteolysis without affecting expression of matrix metalloproteinases. Tropomyosin increased cell adhesion to matrix by enhancing actin fibers and focal adhesions. Finally, tropomyosin impaired the ability of tumor cells to form lung metastases in SCID mice. Thus, these results suggest that HMW-tropomyosins are important for TGF-beta-mediated control of cell motility and acquisition of the metastatic potential.
转化生长因子β1（TGF-β1）在癌症早期抑制肿瘤发展，但会增强肿瘤侵袭和转移形成。TGF-β1介导的肿瘤侵袭与上皮-间质转化（EMT）和基质蛋白水解有关。在正常细胞和肿瘤细胞中，这些TGF-β1反应的机制尚不清楚。最近，我们报道了TGF-β1增加正常上皮细胞中高分子量原肌球蛋白（HMW-原肌球蛋白）的表达以及肌动蛋白应力纤维的形成。本研究调查了原肌球蛋白在TGF-β1介导的细胞运动和侵袭中的作用。我们发现，尽管TGF-β1促进EMT以及肌动蛋白应力纤维和粘着斑的形成，但它会限制正常上皮细胞的运动。通过siRNA介导抑制HMW-原肌球蛋白可增强细胞运动。TGF-β1刺激表达低水平HMW-原肌球蛋白的乳腺癌MDA-MB-231细胞的迁移和基质蛋白水解。Tet-Off调控的HMW-原肌球蛋白表达抑制细胞迁移和基质蛋白水解，而不影响基质金属蛋白酶的表达。原肌球蛋白通过增强肌动蛋白纤维和粘着斑增加细胞与基质的粘附。最后，原肌球蛋白损害肿瘤细胞在SCID小鼠中形成肺转移的能力。因此，这些结果表明HMW-原肌球蛋白对于TGF-β介导的细胞运动控制和转移潜能的获得很重要。
