Riplinger Selina M, Wabnitz Guido H, Kirchgessner Henning, Jahraus Beate, Lasitschka Felix, Schulte Bianca, van der Pluijm Gabri, van der Horst Geertje, Hämmerling Günter J, Nakchbandi Inaam, Samstag Yvonne
Institute for Immunology, Ruprecht-Karls-University, Heidelberg, Germany.
Mol Cancer. 2014 Jan 18;13:10. doi: 10.1186/1476-4598-13-10.
Tumor cell migration and metastasis require dynamic rearrangements of the actin cytoskeleton. Interestingly, the F-actin cross-linking and stabilizing protein L-plastin, originally described as a leukocyte specific protein, is aberrantly expressed in several non-hematopoietic malignant tumors. Therefore, it has been discussed as a tumor marker. However, systematic in vivo analyses of the functional relevance of L-plastin for tumor cell metastasis were so far lacking.
We investigated the relevance of L-plastin expression and phosphorylation by ectopical expression of L-plastin in human melanoma cells (MV3) and knock-down of endogenous L-plastin in prostate cancer (PC3M). The growth and metastatic potential of tumor cells expressing no L-plastin, phosphorylatable or non-phosphorylatable L-plastin was analyzed in a preclinical mouse model after subcutaneous and intracardial injection of the tumor cells.
Knock-down of endogenous L-plastin in human prostate carcinoma cells led to reduced tumor cell growth and metastasis. Vice versa, and in line with these findings, ectopic expression of L-plastin in L-plastin negative melanoma cells significantly increased the number of metastases. Strikingly, the metastasis promoting effect of L-plastin was not observed if a non-phosphorylatable L-plastin mutant was expressed.
Our data provide the first in vivo evidence that expression of L-plastin promotes tumor metastasis and, importantly, that this effect depends on an additionally required phosphorylation of L-plastin. In conclusion, these findings imply that for determining the importance of tumor-associated proteins like L-plastin a characterization of posttranslational modifications is indispensable.
肿瘤细胞的迁移和转移需要肌动蛋白细胞骨架的动态重排。有趣的是，F-肌动蛋白交联和稳定蛋白L- plastin最初被描述为一种白细胞特异性蛋白，在几种非造血恶性肿瘤中异常表达。因此，它被作为一种肿瘤标志物进行讨论。然而，迄今为止，尚缺乏对L- plastin在肿瘤细胞转移中功能相关性的系统性体内分析。
我们通过在人黑色素瘤细胞（MV3）中异位表达L- plastin以及在前列腺癌（PC3M）中敲低内源性L- plastin，研究了L- plastin表达和磷酸化的相关性。在将肿瘤细胞皮下和心内注射到临床前小鼠模型后，分析了不表达L- plastin、可磷酸化或不可磷酸化L- plastin的肿瘤细胞的生长和转移潜能。
人前列腺癌细胞中内源性L- plastin的敲低导致肿瘤细胞生长和转移减少。反之，与这些发现一致，L- plastin阴性黑色素瘤细胞中L- plastin的异位表达显著增加了转移灶的数量。引人注目的是，如果表达不可磷酸化的L- plastin突变体，则未观察到L- plastin的促转移作用。
我们的数据提供了首个体内证据，表明L- plastin的表达促进肿瘤转移，重要的是，这种作用取决于L- plastin额外所需的磷酸化。总之，这些发现意味着，为了确定像L- plastin这样的肿瘤相关蛋白的重要性，翻译后修饰的表征是必不可少的。
