Myoferlin depletion in breast cancer cells promotes mesenchymal to epithelial shape change and stalls invasion.
Myoferlin depletion in breast cancer cells promotes mesenchymal to epithelial shape change and stalls invasion.
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DOI：
10.1371/journal.pone.0039766
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kniss DA
中科院分区：
文献类型：
--
作者：
Li R;Ackerman WE 4th;Mihai C;Volakis LI;Ghadiali S;Kniss DA
Myoferlin(MYOF)是哺乳动物的一种Ferlin蛋白，与祖先Fer-1同源，Fer-1是一种线虫蛋白，调节精子膜融合，后者是精子变形体运动的基础。在肌肉和内皮细胞中的研究已经报道了肌铁蛋白在膜修复、内吞作用、成肌细胞融合以及各种质膜受体的正确表达中的作用。在这项研究中，利用体外培养的人乳腺癌细胞模型，我们证明了Myoferlin在浸润性乳腺肿瘤细胞中大量表达。用慢病毒驱动的shRNA表达耗尽MYOF显示，MDA-MB-231细胞恢复到上皮性形态，表明至少有一些间质向上皮性转变(MET)的特征。一些间充质细胞标记物(如纤维连接蛋白和波形蛋白)的下调和E-钙粘蛋白上皮标记物的上调证实了这些观察结果。Boyden小室的细胞侵袭实验表明，MYOF的缺失导致通过Matrigel或I型胶原的侵袭显著减少，而细胞的迁移没有受到影响。对shRNAMYOF转导的MDA-MB-231细胞的无血清培养上清液进行的PCR阵列和筛选表明，几种基质金属蛋白酶的稳态水平显著降低。综合考虑这些数据，提示MYOF在乳腺肿瘤细胞侵袭中的新作用，以及MYOF缺失后可能逆转为上皮表型的可能性。
Myoferlin (MYOF) is a mammalian ferlin protein with homology to ancestral Fer-1, a nematode protein that regulates spermatic membrane fusion, which underlies the amoeboid-like movements of its sperm. Studies in muscle and endothelial cells have reported on the role of myoferlin in membrane repair, endocytosis, myoblast fusion, and the proper expression of various plasma membrane receptors. In this study, using an in vitro human breast cancer cell model, we demonstrate that myoferlin is abundantly expressed in invasive breast tumor cells. Depletion of MYOF using lentiviral-driven shRNA expression revealed that MDA-MB-231 cells reverted to an epithelial morphology, suggesting at least some features of mesenchymal to epithelial transition (MET). These observations were confirmed by the down-regulation of some mesenchymal cell markers (e.g., fibronectin and vimentin) and coordinate up-regulation of the E-cadherin epithelial marker. Cell invasion assays using Boyden chambers showed that loss of MYOF led to a significant diminution in invasion through Matrigel or type I collagen, while cell migration was unaffected. PCR array and screening of serum-free culture supernatants from shRNAMYOF transduced MDA-MB-231 cells indicated a significant reduction in the steady-state levels of several matrix metalloproteinases. These data when considered in toto suggest a novel role of MYOF in breast tumor cell invasion and a potential reversion to an epithelial phenotype upon loss of MYOF.
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