Loss of DAL-1, a protein 4.1-related tumor suppressor, is an important early event in the pathogenesis of meningiomas

Abstract

Meningiomas are common nervous system tumors, whose molecular pathogenesis is poorly understood. To date, the most frequent genetic alteration detected in these tumors is loss of heterozygosity (LOH) on chromosome 22q. This finding led to the identification of the neurofibromatosis 2 (NF2) tumor suppressor gene on 22q12, which is inactivated in 40% of sporadic meningiomas. The NF2 gene product, merlin (or schwannomin), is a member of the protein 4.1 family of membrane-associated proteins, which also includes ezrin, radixin and moesin. Recently, we identified another protein 4.1 gene, DAL-1 (differentially expressed in adenocarcinoma of the lung) located on chromosome 18p11.3, which is lost in approximately 60% of non-small cell lung carcinomas, and exhibits growth-suppressing properties in lung cancer cell lines. Given the homology between DAL-1 and NF2 and the identification of significant LOH in the region of DAL-1 in lung, breast and brain tumors, we investigated the possibility that loss of expression of DAL-1 was important for meningioma development. In this report, we demonstrate DAL-1 loss in 60% of sporadic meningiomas using LOH, RT-PCR, western blot and immunohistochemistry analyses. Analogous to merlin, we show that DAL-1 loss is an early event in meningioma tumorigenesis, suggesting that these two protein 4.1 family members are critical growth regulators in the pathogenesis of meningiomas. Furthermore, our work supports the emerging notion that membrane-associated alterations are important in the early stages of neoplastic transformation and the study of such alterations may elucidate the mechanism of tumorigenesis shared by other tumor types.

Promoter hypermethylation of the potential tumor suppressor DAL‐1/4.1B gene in renal clear cell carcinoma

“…4.1B is an actin-binding protein involved in actin cytoskeleton organization and actinmediated processes, including cell motility and adhesion. 19,20 It is possible, therefore, to hypothesize that loss of 4.1B function might be involved in metastasis of RCCC cells to distant organs. Our findings that 4.1B promoter methylation is an independent prognostic factor of metastatic recurrence for RCCC patients would support this hypothesis.…”

“…1-21 Interestingly, 4.1B/DAL-1 interacts with spectrin, an actin-binding protein, and over expression results in altered cytoskeleton-associated properties, including cell adhesion and motility. 20 To analyze the role of TSLC1 and 4.1B in RCCC, we analyzed 55 surgically resected RCCC and 19 cell lines in the present study. While we could not detect loss of TSLC1 expression, we did find significant alterations in 4.1B gene expression in these tumors.…”

Clear cell ependymoma: A clinicopathologic and radiographic analysis of 10 patients

“…DAL-1 originally was implicated in the tumorigenesis of nonsmall cell lung carcinoma and subsequently has been associated with additional malignancies, including glial tumors, meningiomas, and breast carcinoma. 21,[32][33][34] Recently, Singh et al 20 used both FISH and immunohistochemistry to evaluate 27 ependymomas for NF2/merlin and DAL-1/DAL-1 at the DNA and protein levels, respectively. They found NF2/merlin losses limited to spinal ependymomas, whereas the majority of DAL-1/DAL-1 losses were detected in intracranial lesions.…”

Alterations of protein 4.1 family members in ependymomas: a study of 84 cases

“…[9][10][11][19][20][21] Secondly, both of these family members are highly expressed in the brain. 22,23 Lastly, we have demonstrated a growth regulatory role for several Protein 4.1 family members in meningiomas, [24][25][26] and preliminary studies have shown that the reintroduction of Protein 4.1R into 4.1R-negative meningioma cell lines results in growth suppression. 27 Based on these observations, we decided to study the Protein 4.1 family members in a larger set of ependymomas.…”