Maspin polymorphism associated with apoptosis susceptibility and in vivo tumorigenesis

Abstract

Abstract. Maspin is a tumor suppressor protein that stimulates apoptosis and inhibits motility, invasion and cancer metastasis. We report on a previously uncharacterized Pro/Ser (C to T) polymorphism at amino acid 176 of the human maspin protein. We analyzed the maspin mutation in 17 cancer cell lines and 36 cancer tissues. Association of polymorphic variants on apoptosis, colony formation and in vivo tumor formation was evaluated. Mutant maspin was found to be frequently expressed in gastric cancer (32/36, 89%). According to predicted maspin tertiary structure, the polymorphic residue is located on the surface of the protein proximal to the reactive site loop domain, and thus may significantly affect the protein interactions of maspin. Stable expression of the Pro and Ser forms of maspin in lung cancer cells revealed that cells expressing Ser176 maspin showed significantly decreased apoptosis and increased colony formation compared with those expressing Pro176 maspin. In a mouse model, cells expressing Ser176 maspin showed a higher rate of tumor formation in vivo than those harboring Pro176 maspin. Therefore, P176S (C526T) substitution of maspin may result in a partial loss of the tumor suppressor function of this protein, contributing to decreased susceptibility to apoptosis and malignant progression.

Maspin Suppresses Survival of Lung Cancer Cells through Modulation of Akt Pathway

“…The expression of maspin is frequently lost in human lung cancer (5), and the genetic polymorphism of Maspin has been recently reported (6). In terms of function, substantial evidence supports a role for maspin in apoptosis (7) and metastasis (8)(9)(10), whereas the published data on the role of maspin for the survival of lung cancer cells is relatively limited.…”

“…NCI-H157 cells (5×10 6 ) were inoculated subcutaneously into the nude mice. After the tumor size reached between 60 to 70 mm 3 in volume, the animals were divided into two groups with nine mice per group, and these animals received intratumoral injections of control vector or pCMV-maspin (50 μ g in 50 μ L PBS).…”

Maspin increases Ku70 acetylation and Bax-mediated cell death in cancer cells

“…We have shown that cytoplasmic expression of maspin in lung cancer cells is suppressive of the tumor (13,18). It has also been shown that cancer patients who express higher levels of maspin respond better to chemotherapy (19).…”

“…3B). Previously, we have reported that a maspin mutation (P176S), frequently found in cancer, decreased apoptosis and increased colony formation (13). As shown in Fig.…”

Maspin expression in breast carcinoma

“…However, in a mouse model, a newly identified mutation in Maspin (Ser176 Maspin) showed a higher rate of tumour formation in vivo compared with those harbouring Pro176 Maspin. Therefore, P176S (C526T) substitution of Maspin may result in a partial loss of the tumour suppressor function of this protein, contributing to tumour progression and increased resistance to apoptosis (Jang et al, 2008).…”