Dataset Information

A Soft Microenvironment Protects from Failure of Midbody Abscission and Multinucleation Downstream of the EMT-Promoting Transcription Factor Snail.

ABSTRACT: Multinucleation is found in more than one third of tumors and is linked to increased tolerance for mutation, resistance to chemotherapy, and invasive potential. The integrity of the genome depends on proper execution of the cell cycle, which can be altered through mechanotransduction pathways as the tumor microenvironment stiffens during tumorigenesis. Here, we show that signaling downstream of matrix metalloproteinase-3 (MMP3) or TGF?, known inducers of epithelial-mesenchymal transition (EMT), also promotes multinucleation in stiff microenvironments through Snail-dependent expression of the filament-forming protein septin-6, resulting in midbody persistence, abscission failure, and multinucleation. Consistently, we observed elevated expression of Snail and septin-6 as well as multinucleation in a human patient sample of metaplastic carcinoma of the breast, a rare classification characterized by deposition of collagen fibers and active EMT. In contrast, a soft microenvironment protected mammary epithelial cells from becoming multinucleated by preventing Snail-induced upregulation of septin-6. Our data suggest that tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression.Significance: These findings reveal tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression. Cancer Res; 78(9); 2277-89. ©2018 AACR.

SUBMITTER: Simi AK

PROVIDER: S-EPMC5932229 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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A Soft Microenvironment Protects from Failure of Midbody Abscission and Multinucleation Downstream of the EMT-Promoting Transcription Factor Snail.

Simi Allison K AK Anlaş Alişya A AA Stallings-Mann Melody M Zhang Sherry S Hsia Tiffaney T Cichon Magdalena M Radisky Derek C DC Nelson Celeste M CM

Cancer research 20180226 9

Multinucleation is found in more than one third of tumors and is linked to increased tolerance for mutation, resistance to chemotherapy, and invasive potential. The integrity of the genome depends on proper execution of the cell cycle, which can be altered through mechanotransduction pathways as the tumor microenvironment stiffens during tumorigenesis. Here, we show that signaling downstream of matrix metalloproteinase-3 (MMP3) or TGFβ, known inducers of epithelial-mesenchymal transition (EMT), ...[more]

PMID: 29483094

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Project description:Objectives: CD44, a transmembrane glycoprotein, is involved in the generation of a stem cell niche and maintaining stem cell quiescence. The aim of this study was to evaluate its contribution to ovarian cancer prognosis and progression, as well as explore the possible mechanisms. Materials and Methods: The expression of CD44 in tissue microarray of 90 ovarian cancer patients was detected by immunohistochemistry. Kaplan-Meier method and Cox proportional hazard model were used to evaluate the factors associated with 5-year overall survival and disease-free survival. CD44 was knocked down by small interfering RNA, the expression of Snail, ZEB1, and Caveolin-1 in a stable Snail-expressing ovarian cancer cell line HO8910PM-Snail (HOPM-Snail) and its control cell line HO8910PM-vector (HOPM) was detected by western blotting analysis. Cell clone formation, migration, and invasion of HOPM-Snail and HOPM cells with CD44 silencing were examined by 3-D culture assay, wound healing assay, and transwell assay, respectively. Results: Over-expression of CD44 was associated with advanced histological grade (p = 0.014) and FIGO stage (p = 0.001). Multivariate analysis showed that CD44 expression was an independent prognostic factor to predict both overall survival (p = 0.004) and disease-free survival (p = 0.025) of ovarian cancer patients. Down-regulation of CD44 expression by small silencing RNA abrogated both basal Snail expression and TGF-β1-induced Snail expression in HOPM and HOPM-Snail cells. In addition, CD44 knockdown caused a decrease in ZEB1 expression. RPPA data indicated that Caveolin-1 may be another regulative target of CD44, and western blotting analysis confirmed that CD44 knockdown caused an increase in Caveolin-1 expression. However, there was no noticeable reciprocal regulation among ZEB1, Caveolin-1, and Snail. Moreover, CD44 knockdown caused a decrease in cell clone formation, migration, and invasion of HOPM and HOPM-Snail cells. Conclusions: As both Snail and ZEB1 are crucial inducers of epithelial-to-mesenchymal transition (EMT), our data suggested that CD44 may be crucial for the EMT process of ovarian cancer. Therefore, CD44 may be a potential prognostic marker as well as treatment target for ovarian cancer.

Dataset Information

A Soft Microenvironment Protects from Failure of Midbody Abscission and Multinucleation Downstream of the EMT-Promoting Transcription Factor Snail.

Publications

A Soft Microenvironment Protects from Failure of Midbody Abscission and Multinucleation Downstream of the EMT-Promoting Transcription Factor Snail.

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