Microarray-Based Identification of Tenascin C and Tenascin XB, Genes Possibly Involved in Tumorigenesis Associated with Neurofibromatosis Type 1

Abstract

Purpose: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with a complex variety of clinical manifestations. The hallmark of NF1 is the onset of heterogeneous (dermal or plexiform) benign neurofibromas. Plexiform neurofibromas can give rise to malignant peripheral nerve sheath tumors, which are resistant to conventional therapies. Experimental Design: To identify new signaling pathways involved in the malignant transformation of plexiform neurofibromas, we applied a 22,000-oligonucleotide microarray approach to a series of plexiform neurofibromas and malignant peripheral nerve sheath tumors. Changes in the expression of selected genes were then confirmed by real-time quantitative reverse transcription-PCR. Results: We identified two tenascin gene family members that were significantly deregulated in both human NF1-associated tumors and NF1-deficient primary cells: Tenascin C (TNC) was up-regulated whereas tenascin XB (TNXB) was down-regulated during tumor progression. TNC activation is mainly due to the up-regulation of large TNC splice variants. Immunohistochemical studies showed that TNC transcripts are translated into TNC protein in TNC-overexpressing tumors. Aberrant transcriptional activation of TNC seems to be principally mediated by activator protein transcription factor complexes. Conclusion:TNXB andTNC may be involved in the malignant transformation of plexiform neurofibromas. Anti-TNC antibodies, already used successfully in clinical trials to treat malignant human gliomas, may be an appropriate new therapeutic strategy for NF1.

Molecular evolution of a neurofibroma to malignant peripheral nerve sheath tumor (MPNST) in an NF1 patient: correlation between histopathological, clinical and molecular findings

“…Amplified genomic regions involved both the 5p15.3region, containing the NKD2, IRX4, IRX1, IRX2, TRIO, and HGF genes, and the 17q21-25 region that includes the TOP2A, ETV4, HOXB7, BIRC, and SOX9 genes. Several of these amplified regions, and their associated genes, have been implicated in MPNST development (Storlazzi et al 2006;Lévy et al 2007;Kresse et al 2008;Mantripragada et al 2008Mantripragada et al , 2009Miller et al 2009). Similarly, several of the deleted genomic regions and the related genes, including AP3B1 (5q14.1), PDGFR B (5q31), CDKN2A, and MTAP (9p21), MMP12 (11q22.3), RB1 (13q14.2), and TP53 (17p13.1), have also been reported (Lothe et al 1996, Mantripragada et al 2009).…”

“…Comparison of the \2-Mb genomic changes identified in the tumor DNA against entries in the Database of Genomic Variants did identify two genomic regions that demonstrates LOH at all three loci, while that from region 1 (plexiform neurofibroma) shows no LOH at any of these loci and SOX9 genes (Fig. 6) (Lothe et al 1995(Lothe et al , 1996(Lothe et al , 2001Storlazzi et al 2006;Lévy et al 2004Lévy et al , 2007Kresse et al 2008;Mantripragada et al 2008Mantripragada et al , 2009Miller et al 2009). Deletions at the 15q25.2-q26.3 and 6p25.1 regions were also identified.…”

Prognostic Significance of p14ARF, p15INK4b, and p16INK4a Inactivation in Malignant Peripheral Nerve Sheath Tumors

“…NF1 is an autosomal dominant neurocutaneous disorder with NF1 gene dysfunction, and characterized by multiple neurofibromas and greatly increased risk of developing MPNST. However, loss of both NF1 alleles is not sufficient for malignant change of neurofibromas, and thus additional genetic alterations are thought to be necessary for the malignant transformation (3)(4)(5)(6). To date, however, the detailed molecular events contributing to development of MPNST have been unclear in both NF1-related and sporadic cases.…”

Proteomic research progress in lymphatic metastases of cancers

“…Tenascin-XB is an extracellular matrix glycoprotein composed of heptad repeats, epidermal growth factor-like repeats and fibronectin type III-like repeats, and a globular domain shared with fibrinogen. Although tenascin-XB was reported to be potentially associated with tumour invasion and metastasis, its detailed function is still unclear [56,57]. Herein, the clinical serum proteomics results clearly indicate that tenascin-XB is a promising metastasis biomarker for breast cancer.…”