Involvement of large tenascin-C splice variants in breast cancer progression
Involvement of large tenascin-C splice variants in breast cancer progression
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DOI：
10.1016/s0002-9440(10)64320-9
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发表时间：
2003-06-01
影响因子：
6
通讯作者：
Yoshida, T
中科院分区：
文献类型：
--
作者：
Tsunoda, T;Inada, H;Yoshida, T
纤维连接蛋白样M型(FNIII)重复的TN-C(TN-C)的选择性剪接产生了许多剪接变体。本文采用免疫印迹和免疫组织化学方法，利用抗FNIII B结构域的单抗(命名为4C8MS)，研究了在肿瘤间质重塑过程中上调的临时细胞外基质的典型成分--大变异体在人类乳腺癌中的分布。TN-C在正常乳腺组织中的表达水平较低，但在导管内癌的侵袭部位和浸润性导管癌的间质中高表达，尤其是在浸润性导管癌的侵袭前沿。大TN-C变异体的表达与Ki-67免疫标记法测定的细胞增殖率呈正相关。在转基因CHO-K1细胞表达的TN-C重组片段中，只有mFNIII FL能促进TN-C缺失小鼠乳腺癌细胞的体外迁移和有丝分裂活性。加入4C8MS可阻断mFNIII FL的功能。这些发现提供了强有力的证据，表明FNIII选择性剪接区在乳腺癌的肿瘤进展中具有重要作用。
Alternative splicing of fibronectin-like type M (FNIII) repeats of tenascin-C (Tn-C) generates a number of splice variants. The distribution of large variants, typical components of provisional extracellular matrices that are up-regulated during tumor stroma remodeling, was here studied by immunoblotting and immunohistochemistry using a monoclonal antibody against the FNIII B domain (named 4C8MS) in a series of human breast cancers. Large Tn-C variants were found at only low levels in normal breast tissues, but were highly expressed at invading sites of intraductal cancers and in the stroma of invasive ductal cancers, especially at invasion fronts. There was a positive correlation between the expression of large Tn-C variants and the cell proliferation rate determined by Immunolabeling of the Ki-67 antigen. Of the Tn-C recombinant fragments (all FNIII repeats or mFNIII FL, the conserved FNIII domain only, the epidermal growth factor-like domain, and the fibrinogen-like domain) which were expressed by CHO-K1 cells transfected with mouse Tn-C cDNAs, only the mFNIII FL enhanced in vitro migration and mitotic activity of mammary cancer cells derived from a Tn-C-null mouse. Addition of 4C8MS blocked the function of mFNIII FL. These findings provide strong evidence that the FNIII alternatively spliced region has important roles in tumor progression of breast cancer.