Periostin promotes cell cycle in lung fibroblasts
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PROVIDER: PRJNA549462 | ENA |
REPOSITORIES: ENA
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Project description:Idiopathic pulmonary fibrosis (IPF) is a devastating disease with only three to five years of the median survival. Fibroblast proliferation is a hallmark of IPF as well as secretion of extracellular matrix proteins from fibroblasts. However, it is still uncertain how IPF fibroblasts acquire the ability to progressively proliferate. Periostin is a matricellular protein that is highly expressed in the lung tissues of IPF patients and plays a critical role in the pathogenesis of pulmonary fibrosis. However, it remains undetermined whether periostin affects proliferation of lung fibroblasts. In this study, we first comprehensively tried to identify periostin-dependently expressed genes in lung fibroblasts finding that many cell-cycle–related genes are involved in the gene profile. We confirmed that periostin silencing downregulates expression of several cell-cycle–related molecules including the cyclin family, the CDK family, the E2F family, and the transcriptional factors such as B-MYB and FOXM1 in lung fibroblasts. Accordingly, periostin silencing slowed proliferation of lung fibroblasts and affects the distribution of cell cycle particularly at the G1/S checkpoint and drives the cells into G1 arrest. Lung fibroblasts derived from IPF patients also required periostin for maximum proliferation. Moreover, CP4715, a potent inhibitor against integrin V3, a periostin receptor, downregulated proliferation along with expression of cell-cycle–related genes in IPF lung fibroblasts as well as normal lung fibroblasts. These results demonstrate that periostin plays a critical role in proliferation of lung fibroblasts and provide us a beneficial basis to apply the inhibitors against the periostin/integrin V3 interaction to IPF patients.
2020-04-14 | GSE132917 | GEO
Project description:Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are involved in the progression of esophageal squamous cell carcinoma (ESCC). We generated CAF-like cells by direct co-culture of human bone marrow-derived mesenchymal stem cells (MSCs), one of the origins of CAFs, with ESCC cell lines and found that periostin is highly expressed in CAF-like cells. Periostin activated Akt and Erk signaling pathways in ESCC cells, enhancing survival and migration via integrin β4, one of the receptors for periostin. Periostin also enhanced migration of MSCs and macrophages and caused macrophages to acquire tumor-associated macrophage (TAM)-like properties. High periostin expression in cancer stroma was associated with several clinicopathological factors and expressions of CAF markers and numbers of infiltrating TAMs. Moreover, ESCC patients with high periostin expression exhibited significantly poor postoperative outcomes. Thus, periostin secreted from CAFs enhanced the migration of ESCC cells, MSCs, and macrophages and contributed to developing the tumor microenvironment. These results indicate that periostin may be a novel therapeutic target for ESCC.
2024-01-08 | GSE244020 | GEO
Project description:Cancer cell dissemination to sentinel lymph nodes associates with poor patient outcomes, particularly in breast cancer. The process by which cancer cells egress from the primary tumor upon interfacing with the lymphatic vasculature is complex and driven by dynamic interactions between cancer cells and stromal cells, including cancer associated fibroblasts (CAFs). The matricellular protein periostin can distinguish CAF subtypes in breast cancer and is associated with increased desmoplasia and disease recurrence in patients. However, since periostin is secreted, periostin-expressing CAFs are difficult to characterize in situ, limiting our understanding of their specific contribution to cancer progression. Here, we used in vivo genetic labeling and ablation to lineage trace periostin+ cells and characterize their functions during tumor growth and metastasis. Periostin-expressing CAFs were spatially found at periductal and perivascular margins, were enriched at lymphatic vessel peripheries, and were differentially activated by highly-metastatic cancer cells versus poorly-metastatic counterparts. Surprisingly, genetically depleting periostin+ CAFs slightly accelerated primary tumor growth but impaired intratumoral collagen organization and inhibited lymphatic, but not lung, metastases. Periostin ablation in CAFs impaired their ability to deposit aligned collagen matrices and inhibited cancer cell invasion through collagen and across lymphatic endothelial cell monolayers. Thus, highly-metastatic cancer cells mobilize periostin-expressing CAFs in the primary tumor site that promote collagen remodeling and collective cell invasion within lymphatic vessels and ultimately to sentinel lymph nodes.
2023-05-03 | GSE231594 | GEO
Project description:Cancer cell dissemination to sentinel lymph nodes associates with poor patient outcomes, particularly in breast cancer. The process by which cancer cells egress from the primary tumor upon interfacing with the lymphatic vasculature is complex and driven by dynamic interactions between cancer cells and stromal cells, including cancer associated fibroblasts (CAFs). The matricellular protein periostin can distinguish CAF subtypes in breast cancer and is associated with increased desmoplasia and disease recurrence in patients. However, since periostin is secreted, periostin-expressing CAFs are difficult to characterize in situ, limiting our understanding of their specific contribution to cancer progression. Here, we used in vivo genetic labeling and ablation to lineage trace periostin+ cells and characterize their functions during tumor growth and metastasis. Periostin-expressing CAFs were spatially found at periductal and perivascular margins, were enriched at lymphatic vessel peripheries, and were differentially activated by highly-metastatic cancer cells versus poorly-metastatic counterparts. Surprisingly, genetically depleting periostin+ CAFs slightly accelerated primary tumor growth but impaired intratumoral collagen organization and inhibited lymphatic, but not lung, metastases. Periostin ablation in CAFs impaired their ability to deposit aligned collagen matrices and inhibited cancer cell invasion through collagen and across lymphatic endothelial cell monolayers. Thus, highly-metastatic cancer cells mobilize periostin-expressing CAFs in the primary tumor site that promote collagen remodeling and collective cell invasion within lymphatic vessels and ultimately to sentinel lymph nodes.
2023-05-05 | GSE231806 | GEO
Project description:BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is a devastating disease with a median survival of only three to 5?years. Fibroblast proliferation is a hallmark of IPF as is secretion of extracellular matrix proteins from fibroblasts. However, it is still uncertain how IPF fibroblasts acquire the ability to progressively proliferate. Periostin is a matricellular protein highly expressed in the lung tissues of IPF patients, playing a critical role in the pathogenesis of pulmonary fibrosis. However, it remains undetermined whether periostin affects lung fibroblast proliferation. METHODS:In this study, we first aimed at identifying periostin-dependently expressed genes in lung fibroblasts using DNA microarrays. We then examined whether expression of cyclins and CDKs controlling cell cycle progression occur in a periostin-dependent manner. We next examined whether downregulation of cell proliferation-promoting genes by knockdown of periostin or integrin, a periostin receptor, using siRNA, is reflected in the cell proliferation of lung fibroblasts. We then looked at whether lung fibroblasts derived from IPF patients also require periostin for maximum proliferation. We finally investigated whether CP4715, a potent inhibitor against integrin ?V?3 (a periostin receptor), which we have recently found blocks TGF-? signaling, followed by reduced BLM-induced pulmonary fibrosis in mice, can block proliferation of lung fibroblasts derived from IPF patients. RESULTS:Many cell-cycle-related genes are involved in the upregulated or downregulated genes by periostin knockdown. We confirmed that in lung fibroblasts, periostin silencing downregulates expression of several cell-cycle-related molecules, including the cyclin, CDK, and, E2F families, as well as transcription factors such as B-MYB and FOXM1. Periostin or integrin silencing slowed proliferation of lung fibroblasts and periostin silencing increased the distribution of the G0/G1 phase, whereas the distribution of the G2/M phase was decreased. Lung fibroblasts derived from IPF patients also required periostin for maximum proliferation. Moreover, CP4715 downregulated proliferation along with expression of cell-cycle-related genes in IPF lung fibroblasts as well as in normal lung fibroblasts. CONCLUSIONS:Periostin plays a critical role in the proliferation of lung fibroblasts and the present results provide us a solid basis for considering inhibitors of the periostin/integrin ?V?3 interaction for the treatment of IPF patients.
| S-EPMC6993476 | biostudies-literature
Project description:We compared transcriptional differences between Periostin siRNA treated and GFP-siRNA treated in OP9 cells using Affymetrix mouse 430_2 array.
2012-01-26 | E-MTAB-519 | biostudies-arrayexpress
Project description:Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized as progressive and irreversible fibrosis in the interstitium of lung tissues. There is still an unmet need to develop a novel therapeutic drug for IPF. We have previously demonstrated that periostin, a matricellular protein, plays an important role in the pathogenesis of pulmonary fibrosis. However, the underlying mechanism of how periostin causes pulmonary fibrosis remains unclear. In this study, we sought to see whether the cross-talk between transforming growth factor-b (TGF-b), a central mediator in the pathogenesis of pulmonary fibrosis, and periostin in lung fibroblasts leads to generation of pulmonary fibrosis and whether taking advantage of the cross-talk between TGF-b and periostin, inhibitors for integrin aVb3, a periostin receptor, can block pulmonary fibrosis in the model mice. We found that there exists a cross-talk between TGF-b and periostin signals via aVb3/b5 converging into Smad3. This cross-talk is important for expression of several downstream molecules of TGF-b including serpin family E member 1, CCN family member 2/connective tissue growth factor, insulin-like growth factor binding protein-3, and IL-11, all of which have been already shown to be important for pulmonary fibrosis. We, moreover, found several potent integrin inhibitors to block the cross-talking with TGF-b signals and CP4715, one of the compounds, improved bleomycin-induced pulmonary fibrosis in mice. These results suggest that the cross-talk between TGF-b and periostin can be targeted for pulmonary fibrosis and that CP4715 can be a potential therapeutic agent to block the cross-talk between TGF-b and periostin.
2019-09-17 | GSE124781 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized as progressive and irreversible fibrosis in the interstitium of lung tissues. There is still an unmet need to develop a novel therapeutic drug for IPF. We have previously demonstrated that periostin, a matricellular protein, plays an important role in the pathogenesis of pulmonary fibrosis. However, the underlying mechanism of how periostin causes pulmonary fibrosis remains unclear. In this study, we sought to see whether the cross-talk between transforming growth factor-b (TGF-b), a central mediator in the pathogenesis of pulmonary fibrosis, and periostin in lung fibroblasts leads to generation of pulmonary fibrosis and whether taking advantage of the cross-talk between TGF-b and periostin, inhibitors for integrin aVb3, a periostin receptor, can block pulmonary fibrosis in the model mice. We found that there exists a cross-talk between TGF-b and periostin signals via aVb3/b5 converging into Smad3. This cross-talk is important for expression of several downstream molecules of TGF-b including serpin family E member 1, CCN family member 2/connective tissue growth factor, insulin-like growth factor binding protein-3, and IL-11, all of which have been already shown to be important for pulmonary fibrosis. We, moreover, found several potent integrin inhibitors to block the cross-talking with TGF-b signals and CP4715, one of the compounds, improved bleomycin-induced pulmonary fibrosis in mice. These results suggest that the cross-talk between TGF-b and periostin can be targeted for pulmonary fibrosis and that CP4715 can be a potential therapeutic agent to block the cross-talk between TGF-b and periostin.
2019-09-17 | GSE124780 | GEO
Project description:In this study, we demonstrated that baseline SOX11 expression was significantly higher in dermal fibroblasts (DFs) isolated from patients with SSc than that in controls, and increased in response to TGF-b. We then showed that SOX11 is involved in the expression of periostin and some periostin-dependent fibrotic factors identified in lung fibroblasts previously. Moreover, we identified some fibrotic factors induced by SOX11 in DNA microarrays combining TGF-b induction and SOX11 knockdown. Finally, we showed that genetic deletion of SOX11 in Postn positive fibroblast cells protects from bleomycin (BLM)-induced skin fibrosis. Altogether, our data indicate that SOX11 and periostin forms a vicious circle and that TGF-b activates this circle specifically in SSc dermal fibroblasts.
2023-01-29 | GSE206473 | GEO
Project description:Periostin, a matricellular protein, has been reported to be important in supporting tumor cell dissemination. However, the molecular mechanisms underlying periostin function within the tumor microenvironment are poorly understood. In this study, we observe that loss of periostin decreases esophageal squamous cell carcinoma (ESCC) tumor growth in vivo and demonstrate that periostin cooperates with a conformational missense p53 mutation to enhance invasion. Pathway analyses reveal that invasive esophageal cells expressing periostin and p53R175H mutation display activation of signal transducer and activator of transcription 1 (STAT1) target genes, suggesting that the induction of STAT1 and STAT1-related genes could foster a permissive microenvironment that facilitates invasion of esophageal epithelial cells into the extracellular matrix (ECM). Genetic knockdown of STAT1 in transformed esophageal epithelial cells underscores the importance of STAT1 in promoting invasion and potentiate tumor resistance to genotoxic stress. Furthermore, we find that STAT1 is activated in ESCC xenograft tumors but this activation is attenuated with inducible knockdown of periostin in ESCC tumors. Overall, these results highlight the molecular mechanisms supporting the capacity of periostin in mediating tumor invasion during ESCC development. Pre-clinical study hTERT: EPC cells immortalized by expression of hTERT hTERT_p53: EPC cells expressing hTERT and mutant P53 hTERT_p53_POSTN: EPC cells expressing hTERT, mutant P53, and POSTN.
2016-06-01 | E-GEOD-48999 | biostudies-arrayexpress