Prognostic significance of CD44v5 expression in human thymic epithelial neoplasms

Division of Thoracic Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
The Annals of Thoracic Surgery (Impact Factor: 3.85). 08/2003; 76(1):213-8; discussion 218. DOI: 10.1016/S0003-4975(03)00319-9
Source: PubMed


Cell surface glycoproteins of the CD44 family play roles in cell-cell and cell-matrix interactions. Their aberrant expression has been implicated in tumor invasion and metastasis of a variety of neoplasms, but not, to date, of thymic epithelial tumors.
To investigate the expression of CD44 molecules, immunohistochemical staining using monoclonal antibodies against human CD44 standard form (CD44 s) and two common splicing variant (CD44v) isoforms, CD44v5 and CD44v6, was performed on 64 resected thymomas and 20 normal thymuses. These tumors were categorized histologically according to the World Health Organization (WHO) histologic classification, and the pathologic staging was classified according to the definitions of Masaoka.
The positive expression rates in these patients were as follows: CD44 s (normal thymuses, 10%; thymomas, 22%), CD44v5 (normal thymuses, 0%; thymomas, 67%), and CD44v6 (normal thymuses, 0%; thymomas, 26%). CD44 s and CD44v5 immunoreactivity showed a positive correlation with tumor stages (p = 0.034 and 0.027, respectively). The CD44v5 expression of neoplastic cells in tumor capsules has significant correlation with tumor stages (II, 5%; III, 70%; IVA, 100%; p < 0.001). On the basis of univariate survival analysis, the Masaoka staging system, WHO histologic classification, and CD44v5 expression showed a statistically significant positive relation to survival (p < 0.001, 0.002, 0.011, respectively). Using Cox's regression model, increasing CD44v5 expression, the Masaoka staging, and the WHO classification system were found to be significant independent prognostic factors.
CD44v5 expression is independently positively correlated with the aggressiveness of thymic epithelial tumors. The expression of CD44v5 may be a potential trigger of tumor invasion in thymomas.

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Available from: Horng-Jyh Harn, Dec 21, 2013
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    • "The CD44 gene contains 10 constitutive and variable exons that can be differentially assembled in the mature mRNA (52). Inclusion of several variable exons (v5, v6, v8 and v10) correlates with increased cell motility, invasion of neighboring tissues and malignancy and it has been correlated to poor prognosis in patients (50–53). Moreover, recent data have implicated a change in CD44 splicing isoforms as an adaptive response of some cancer cells to genotoxic stress (12). "
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    ABSTRACT: DNA-damaging agents cause a multifaceted cellular stress response. Cells set in motion either repair mechanisms or programmed cell death pathways, depending on the extent of the damage and on their ability to withstand it. The RNA-binding protein (RBP) Sam68, which is up-regulated in prostate carcinoma, promotes prostate cancer cell survival to genotoxic stress. Herein, we have investigated the function of Sam68 in this cellular response. Mitoxantrone (MTX), a topoisomerase II inhibitor, induced relocalization of Sam68 from the nucleoplasm to nuclear granules, together with several other RBPs involved in alternative splicing, such as TIA-1, hnRNP A1 and the SR proteins SC35 and ASF/SF2. Sam68 accumulation in nuclear stress granules was independent of signal transduction pathways activated by DNA damage. Using BrU labelling and immunofluorescence, we demonstrate that MTX-induced nuclear stress granules are transcriptionally active foci where Sam68 and the phosphorylated form of RNA polymerase II accumulate. Finally, we show that MTX-induced relocalization of Sam68 correlates with changes in alternative splicing of its mRNA target CD44, and that MTX-induced CD44 splicing depends on Sam68 expression. These results strongly suggest that Sam68 is part of a RNA-mediated stress response of the cell that modulates alternative splicing in response to DNA damage.
    Nucleic Acids Research 05/2010; 38(9):3005-18. DOI:10.1093/nar/gkq004 · 9.11 Impact Factor
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    • "It seems that XE7 affects splicing of Tra2β1 pre-mRNA independently of ZNF265 and it is possible that the two proteins only bind to each other when they are not functioning as splice factors. Increased levels of CD44v5 have been found in certain tumors (37–39) and siRNA-mediated depletion of CD44v5 decreases tumour cell invasion (40). Since addition of XE7 increases exon 5 inclusion it would be interesting to test if depletion of this protein results in a decrease of CD44v5 inclusion and possibly that of tumour cell invasion, as has been shown for the SR-related protein SRm160 (40). "
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    ABSTRACT: Pre-mRNA splicing is performed by the spliceosome. SR proteins in this macromolecular complex are essential for both constitutive and alternative splicing. By using the SR-related protein ZNF265 as bait in a yeast two-hybrid screen, we pulled out the uncharacterized human protein XE7, which is encoded by a pseudoautosomal gene. XE7 had been identified in a large-scale proteomic analysis of the human spliceosome. It consists of two different isoforms produced by alternative splicing. The arginine/serine (RS)-rich region in the larger of these suggests a role in mRNA processing. Herein we show for the first time that XE7 is an alternative splicing regulator. XE7 interacts with ZNF265, as well as with the essential SR protein ASF/SF2. The RS-rich region of XE7 dictates both interactions. We show that XE7 localizes in the nucleus of human cells, where it colocalizes with both ZNF265 and ASF/SF2, as well as with other SR proteins, in speckles. We also demonstrate that XE7 influences alternative splice site selection of pre-mRNAs from CD44, Tra2-beta1 and SRp20 minigenes. We have thus shown that the spliceosomal component XE7 resembles an SR-related splicing protein, and can influence alternative splicing.
    Nucleic Acids Research 02/2006; 34(17):4976-86. DOI:10.1093/nar/gkl660 · 9.11 Impact Factor
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    ABSTRACT: Inherited and acquired changes in pre-mRNA splicing have been documented to play a significant role in human disease development and many cancer-associated genes are regulated by alternative splicing. Loss of fidelity, variation of the splicing process, even controlled switching to specific splicing alternatives may occur during tumor progression and could play a major role in carcinogenesis. Splice variants that are found predominantly in tumors have clear diagnostic value and may provide potential drug targets. Moreover, understanding the process of aberrant splicing and the detailed characterization of the splice variants may prove crucial to our understanding of malignant transformation. This review discusses the basic mechanism of alternative splicing, alternative splicing in cancer-associated genes, tools to identify splice variants, and the development of clinical tests based on alternatively spliced biomarkers.
    Clinical Biochemistry 08/2004; 37(7):584-94. DOI:10.1016/j.clinbiochem.2004.05.015 · 2.28 Impact Factor
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