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Characterization of fibroblasts with Son of Sevenless-1 mutation.

ABSTRACT: Although non-syndromic hereditary gingival fibromatosis (HGF) is genetically heterogeneous, etiologic mutations have been identified only in the Son of Sevenless-1 gene (SOS1). To test evidence of increased cell proliferation, we studied histological, morphological, and proliferation characteristics in monolayer and three-dimensional cultures of fibroblasts with the SOS1 g.126,142-126,143insC mutation. Histological assessment of HGF gingiva indicated increased numbers of fibroblasts (30%) and increased collagen (10%). Cell proliferation studies demonstrated increased growth rates and 5-bromo-2-deoxyuridine incorporation for HGF fibroblasts. Flow cytometry showed greater proportions of HGF fibroblasts in the G2/M phase. Attachment of HGF fibroblasts to different extracellular matrix surfaces demonstrated increased formation of protrusions with lamellipodia. HGF fibroblasts in three-dimensional culture showed greater cell proliferation, higher cell density, and alteration of surrounding collagen matrix. These findings revealed that increased fibroblast numbers and collagen matrix changes are associated with mutation of the SOS1 gene in vitro and in vivo.

SUBMITTER: Lee EJ

PROVIDER: S-EPMC2248237 | biostudies-literature | 2006 Nov

REPOSITORIES: biostudies-literature

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Characterization of fibroblasts with Son of Sevenless-1 mutation.

Lee E J EJ Jang S I SI Pallos D D Kather J J Hart T C TC

Journal of dental research 20061101 11

Although non-syndromic hereditary gingival fibromatosis (HGF) is genetically heterogeneous, etiologic mutations have been identified only in the Son of Sevenless-1 gene (SOS1). To test evidence of increased cell proliferation, we studied histological, morphological, and proliferation characteristics in monolayer and three-dimensional cultures of fibroblasts with the SOS1 g.126,142-126,143insC mutation. Histological assessment of HGF gingiva indicated increased numbers of fibroblasts (30%) and in ...[more]

PMID: 17062749

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Project description:Background:Aberrant expression of ubiquitin-specific peptide 22 (USP22) has been detected in various cancers. This study aimed to investigate the role of USP22 and the underlying mechanism in human gastric cancer. Methods:The expression pattern of USP22 in human gastric cancer was detected in a tissue microarray containing 88 pairs of gastric cancer tissue and adjacent normal tissue samples from patients with primary gastric cancer using immunohistochemical staining. The correlation of USP22 expression with clinical characteristics of patients, as well as their prognostic values in the overall survival of patients, were evaluated. USP22-overexpressing SGC7901 and USP22-silencing AGS cells were used to explore the role of USP22 in gastric cancer cell behavior in vitro and in vivo. Chromatin immunoprecipitation was performed to identify differentially expressed genes induced by USP22 overexpression. Western blot analysis was conducted to detect the activation of RAS/ERK and PI3K/AKT signaling in USP22-overexpressing SGC7901 cells and xenograft tumor tissues. Knockdown of RAS activator son of sevenless 1 (SOS1) was performed to investigate the role of SOS1 in USP22-regulated gastric cancer cell behavior and RAS signaling both in vitro and in vivo. Results:USP22 protein expression was significantly increased in human gastric cancer tissues, compared with adjacent normal tissues, and was positively correlated with local tumor stage. Gain- and loss-of-function assays showed that USP22 promoted gastric cancer cell growth and cell cycle transition while suppressing apoptosis in vitro. Consistent results were observed in a xenograft mouse model. Chromatin immunoprecipitation revealed that the overexpression of USP22 induced the upregulation of RAS activator son of sevenless 1 (SOS1) in SGC7901 cells. Western blot analysis showed that USP22 overexpression also induced activation of the RAS/ERK and PI3K/AKT pathways in SGC7901 cells and xenograft tumor tissues. Furthermore, SOS1 silencing could reverse the effects of USP22 on gastric cancer cell behavior and RAS signaling both in vitro and in vivo. Conclusions:Our results suggest that USP22 acts as an oncogene in gastric cancer in a SOS1-dependent manner, identifying the USP22/SOS1/RAS axis as a potential therapeutic target in gastric cancer.

Dataset Information

Characterization of fibroblasts with Son of Sevenless-1 mutation.

Publications

Characterization of fibroblasts with Son of Sevenless-1 mutation.

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