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Cytoskeletal alteration modulates cancer cell invasion through RhoA-YAP signaling in stromal fibroblasts.

ABSTRACT: Cancer-associated fibroblasts(CAFs) participate in carcinogenesis through interaction with cancer cells. This study aimed to investigate the mechanism of cytoskeletal alteration of CAFs and its role in invasion of oral squamous cell carcinoma(OSCC).Immortalized normal fibroblasts(hTERT-hNOFs) co-cultured with OSCC cells showed myofibroblastic and senescent phenotypes like CAFs. Thus, this study substituted hTERT-hNOFs for CAFs. Next, the cytoskeletal alteration and its molecular mechanism were investigated in hTERT-hNOFs co-cultured with OSCC. As results, we found that RhoA regulated cytoskeletal organization in fibroblasts surrounding OSCC cells. Furthermore, as a downstream transcriptional factor of RhoA, YAP was mainly localized in the nucleus of hTERT-hNOFs co-cultured with OSCC. Consequently, we examined whether nuclear YAP localization of fibroblasts could influence cancer progression. YAPS127A fibroblasts manifesting nuclear localization of YAP induced cytoskeletal alteration and increased gel contractility and matrix stiffness, and thereby enhances the invasiveness of OSCC cells. In conclusion, the modification of tumor microenvironment, such as cytoskeletal change and matrix remodeling via RhoA-YAP in CAFs, modulates OSCC invasion. These understandings will provide the development of novel approaches for CAFs-based cancer therapy.

SUBMITTER: Kim DK

PROVIDER: S-EPMC6438594 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Cytoskeletal alteration modulates cancer cell invasion through RhoA-YAP signaling in stromal fibroblasts.

Kim Do Kyeong DK Kim Eun Kyoung EK Jung Da-Woon DW Kim Jin J

PloS one 20190328 3

Cancer-associated fibroblasts(CAFs) participate in carcinogenesis through interaction with cancer cells. This study aimed to investigate the mechanism of cytoskeletal alteration of CAFs and its role in invasion of oral squamous cell carcinoma(OSCC).Immortalized normal fibroblasts(hTERT-hNOFs) co-cultured with OSCC cells showed myofibroblastic and senescent phenotypes like CAFs. Thus, this study substituted hTERT-hNOFs for CAFs. Next, the cytoskeletal alteration and its molecular mechanism were i ...[more]

PMID: 30921404

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Project description:BACKGROUND:Idiopathic Pulmonary Fibrosis (IPF) is a debilitating disease characterized by exaggerated extracellular matrix deposition and aggressive lung structural remodeling. Disease pathogenesis is driven by fibroblastic foci formation, consequent on growth factor overexpression and myofibroblast proliferation. We have previously shown that both CTGF overexpression and myofibroblast formation in IPF cell lines are dependent on RhoA signaling. As RhoA-mediated regulation is also involved in cell cycle progression, we hypothesise that this pathway is key to lung fibroblast turnover through modulation of cyclin D1 kinetic expression. METHODS:Cyclin D1 expression was compared in primary IPF patient-derived fibroblasts and equivalent normal control cells. Quantitative real time PCR was employed to examine relative expression levels of cyclin D1 mRNA; protein expression was confirmed by western blotting. Effects of Rho signaling were investigated using transient transfection of constitutively active and dominant negative RhoA constructs as well as pharmacological inhibitors. Cellular proliferation of lung fibroblasts was determined by BrdU incorporation ELISA. To further explore RhoA regulation of cyclin D1 in lung fibroblasts and associated cell cycle progression, an established Rho inhibitor, Simvastatin, was incorporated in our studies. RESULTS:Cyclin D1 expression was upregulated in IPF compared to normal lung fibroblasts under exponential growth conditions (p < 0.05). Serum deprivation inhibited cyclin D1 expression, which was restored following treatment with fibrogenic growth factors (TGF-beta1 and CTGF). RhoA inhibition, using a dominant negative mutant and a pharmacological inhibitor (C3 exotoxin), suppressed levels of cyclin D1 mRNA and protein in IPF fibroblasts, with significant abrogation of cell turnover (p < 0.05). Furthermore, Simvastatin dose-dependently inhibited fibroblast cyclin D1 gene and protein expression, inducing G1 cell cycle arrest. Similar trends were observed in control experiments using normal lung fibroblasts, though exhibited responses were lower in magnitude. CONCLUSION:These findings report for the first time that cyclin D1 expression is deregulated in IPF through a RhoA dependent mechanism that influences lung fibroblast proliferation. This potentially unravels new molecular targets for future anti-IPF strategies; accordingly, Simvastatin inhibition of Rho-mediated cyclin D1 expression in IPF fibroblasts merits further exploitation.

Dataset Information

Cytoskeletal alteration modulates cancer cell invasion through RhoA-YAP signaling in stromal fibroblasts.

Publications

Cytoskeletal alteration modulates cancer cell invasion through RhoA-YAP signaling in stromal fibroblasts.

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